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Huang Z, Liang H, Chen L. Onco Targets Ther. 2020;13:2193–2202. We, the Editor and Publisher of the journal OncoTargets and Therapy have retracted the published article. Following publication, concerns were raised regarding the use of non-verifiable cell lines described in the article. The concerns related specifically to the use of cell lines which were found to be either contaminated, wrongly identified, improperly indexed, unavailable through external cell line repositories, and/or lacking publications describing their establishment. Overall, these concerns raised doubts about the validity of the findings described in the article. The corresponding author did not respond to our queries and was unable to provide information relating to the use of these cell lines or provide original data relating to the study. As verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the corresponding author was notified of this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Lan Q, Tan X, He P, Li W, Tian S, Dong W. Onco Targets Ther. 2021;14:1429–1440. We, the Editor and Publisher of the journal OncoTargets and Therapy have retracted the published article. Following publication, concerns were raised regarding the use of non-verifiable cell lines described in the article. The concerns related specifically to the use of cell lines which were found to be either contaminated, wrongly identified, improperly indexed, unavailable through external cell line repositories, and/or lacking publications describing their establishment. Overall, these concerns raised doubts about the validity of the findings described in the article. The corresponding author did respond to our queries but was unable to provide satisfactory information relating to the use of these cell lines or provide satisfactory original data relating to the study. As verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the corresponding author was notified of this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

He L, Lei Y, Hou J, Wu J, Lv G. Onco Targets Ther. 2020;13:5901–5911. We, the Editor and Publisher of the journal OncoTargets and Therapy have retracted the published article. Following publication, concerns were raised regarding the use of non-verifiable cell lines described in the article. The concerns related specifically to the use of cell lines which were found to be either contaminated, wrongly identified, improperly indexed, unavailable through external cell line repositories, and/or lacking publications describing their establishment. Overall, these concerns raised doubts about the validity of the findings described in the article. The corresponding author did not respond to our queries and was unable to provide information relating to the use of these cell lines or provide original data relating to the study. As verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the corresponding author was notified of this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Tao W, Li Y, Zhu M, Li C, Li P. Onco Targets Ther. 2019;12:8841–8851. We, the Editor and Publisher of the journal OncoTargets and Therapy have retracted the published article. Following publication of the article, concerns were raised about the duplication of images from Figures 4 and 5 with images from an unrelated article. Specifically, The images for Figure 4D, BGC803 and BGC823, Ctrl, have been duplicated with images for Figure 4A, miR-519a mimics NC, 0Gy and Figure 4G, miR-519a mimics+OE-EphA2, 2Gy, respectively, from Gong S, Li Y, Lv L, et al. Restored microRNA-519a enhances the radiosensitivity of non-small cell lung cancer via suppressing EphA2. Gene Ther. 2022;29:588–600. https://doi.org/10.1038/s41434-020-00213-x. The image for Figure 5D, BGC803, pcNORAD+miR-214, has been duplicated with the image for Figure 4G, si-EphA2, 0Gy from Gong S, et al (2022). The corresponding author did not respond to our queries and was unable to provide a satisfactory explanation for how the images came to be duplicated or provide satisfactory original data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the corresponding author was notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Beatrice Riccò,* Giulio Martinelli,* Camilla Bardasi, Massimo Dominici, Andrea Spallanzani, Massimiliano Salati Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy*These authors contributed equally to this workCorrespondence: Andrea Spallanzani, Department of Oncology and Hematology, University Hospital of Modena, Via del Pozzo, 71, Modena, MO, 41125, Italy, Tel +390594223310, Fax +390594223289, Email andrea.spallanzani@gmail.comAbstract: Gastric cancer (GC) still ranks as the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide. Despite the recent progress in the therapeutic algorithm of the advanced disease with the advent of immune checkpoint inhibitors (ICIs) and next-generation HER2-directed therapies, survival rates remain poor, with a median survival hardly exceeding 12 months. Furthermore, only 40% of patients remain eligible for second- and later-line treatments due to the aggressiveness of the disease and the rapid deterioration of performance status (PS). Thus, current research is focusing either on the identification of novel treatment options or the development of personalized strategies to optimize the continuum of care and ultimately improve patients’ outcome. In this article, we provide an overview of the current treatment landscape for advanced GC with a particular emphasis on later-line treatments and outline novel perspectives on the horizon.Keywords: gastric cancer, gastroesophageal cancer, continuum of care, target therapies

Yao S, Yan W. Onco Targets Ther. 2018;11:8465–8479. We, the Editors and Publisher of OncoTargets and Therapy, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figures 1, 2, 3, 4, 5, and 6 with images from other unrelated articles. Specifically, Images for Figure 1H have been duplicated with images for Figure 1b from Ji K, Lin K, Wang Y, et al. TAZ inhibition promotes IL-2-induced apoptosis of hepatocellular carcinoma cells by activating the JNK/F-actin/mitochondrial fission pathway. Cancer Cell Int. 2018;18:117. https://doi.org/10.1186/s12935-018-0615-y; Figure 2H from Feng J, Li H, Zhang Y, et al. Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway. Cellular Physiology and Biochemistry. 2018;51(5):2359–2376. https://doi.org/10.1159/000495896 and Figure 4G from Wei B, Wang M, Hao W, He X. RETRACTED ARTICLE: Mst1 facilitates hyperglycemia-induced retinal pigmented epithelial cell apoptosis by evoking mitochondrial stress and activating the Smad2 signaling pathway. Cell Stress and Chaperones. 2019;24:259–272. https://doi.org/10.1007/s12192-018-00963-z. Images for Figure 1K have been duplicated with images for Figure 1H, Figure 4H and Figure 5f from Geng C, Wei J, Wu C. Yap-Hippo pathway regulates cerebral hypoxia-reoxygenation injury in neuroblastoma N2a cells via inhibiting ROCK1/F-actin/mitochondrial fission pathways. Acta Neurol Belg. 2020;120:879–892. https://doi.org/10.1007/s13760-018-0944-6 and Wei B, et al (2019), respectively. Images for Figure 2G have been duplicated with images for Figure 2C from Li P, Zhao S, Hu Y. SFRP2 modulates non‑small cell lung cancer A549 cell apoptosis and metastasis by regulating mitochondrial fission via Wnt pathways. Molecular Medicine Reports. 2019;20:1925–1932. https://doi.org/10.3892/mmr.2019.10393 and Figure 7a from Ji K, et al (2018). Images for Figure 3A have been duplicated with images for Figure 1D and 3J from Zhang, W, Liu K, Pei Y, Ma J, Tan J, Zhao J. Mst1 regulates non-small cell lung cancer A549 cell apoptosis by inducing mitochondrial damage via ROCK1/F‑actin pathways. International Journal of Oncology. 2018;53:2409–2422. https://doi.org/10.3892/ijo.2018.4586; Figure 1H from Xu P, Zhang G, Sha L, Hou S. RETRACTED: DUSP1 alleviates cerebral ischaemia reperfusion injury via inactivating JNKMff pathways and repressing mitochondrial fission. Life Sciences. 2018;210:251–262. https://doi.org/10.1016/j.lfs.2018.08.049; Figure 4C from Zhao S, Li P, Wang P, et al. “Nurr1 promotes lung cancer apoptosis via enhancing mitochondrial stress and p53-Drp1 pathway”. Open Life Sciences. 2019;14(1):262–274. https://doi.org/10.1515/biol-2019-0030 and Figure 4C from Jieensinue S, Zhu H, Li G, et al. Tanshinone IIA reduces SW837 colorectal cancer cell viability via the promotion of mitochondrial fission by activating JNK-Mff signaling pathways. BMC Cell Biol. 2018;19:21. https://doi.org/10.1186/s12860-018-0174-z. Images for Figure 3H have been duplicated with images for Figure 6F and Figure 7A from Zhang W, et al (2018) and Zhang J, Sun L, Li W, et al. Overexpression of macrophage stimulating 1 enhances the anti-tumor effects of IL-24 in esophageal cancer via inhibiting ERK-Mfn2 signaling-dependent mitophagy. Biomedicine & Pharmacotherapy. 2019;114:108844. https://doi.org/10.1016/j.biopha.2019.108844, respectively. Images for Figure 4A have been duplicated with images for Figure 3A from Chen Z, Wang C, Yu N, et al. INF2 regulates oxidative stress-induced apoptosis in epidermal HaCaT cells by modulating the HIF1 signaling pathway. Biomedicine & Pharmacotherapy. 2019;111:151–161. https://doi.org/10.1016/j.biopha.2018.12.046. Images for Figure 4C have been duplicated with images for Figure 3H from Zhou T, Chang L, Luo Y, Zhou Y, Zhang J. Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy. Redox Biology. 2019;21:101120. https://doi.org/10.1016/j.redox.2019.101120. Images for Figure 5A have been duplicated with images for Figure 1O from Xu P, et al (2018). Images for Figure 6A have been duplicated with images for Figure 1a from Zhang X, Li F, Cui Y, et al. RETRACTED ARTICLE: Mst1 overexpression combined with Yap knockdown augments thyroid carcinoma apoptosis via promoting MIEF1-related mitochondrial fission and activating the JNK pathway. Cancer Cell Int. 2019;19:143. https://doi.org/10.1186/s12935-019-0860-8 and Figure 5A from Ouyang H, Zhou E, Wang H. RETRACTED ARTICLE: Mst1-Hippo pathway triggers breast cancer apoptosis via inducing mitochondrial fragmentation in a manner dependent on JNK–Drp1 axis. Onco Targets Ther. 2019;12:1147–1159. https://doi.org/10.2147/OTT.S193787. Images for Figure 6D have been duplicated with images for Figure 5H from Cao J, Wei R, Yao S. Matrine has pro-apoptotic effects on liver cancer by triggering mitochondrial fission and activating Mst1-JNK signalling pathways. J Physiol Sci. 2019;69:185–198. https://doi.org/10.1007/s12576-018-0634-4. The authors did not respond to our queries and were unable to provide an explanation for the duplicated images or provide data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors were notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Annesha Chatterjee, Jordana Maria Azevedo-Martins, Matthew D Stachler University of California San Francisco, Department of Pathology, San Francisco, CA, USACorrespondence: Matthew D Stachler, University of California San Francisco, 513 Parnassus Ave HSW450B, San Francisco, CA, 94143, Tel +1 514 419-1902, Email Matthew.Stachler@UCSF.eduAbstract: Gastric cancer is a significant global health problem as it is the fifth most prevalent cancer worldwide and the fourth leading cause of cancer-related mortality. While cytotoxic chemotherapy remains the primary treatment for advanced GC, response rates are limited. Recent progresses, focused on molecular signalling within gastric cancer, have ignited new hope for potential therapeutic targets that may improve survival and/or reduce the toxic effects of traditional therapies. Carcinomas are generally initiated when critical regulatory genes get mutated, but the progression to malignancy is usually supported by the non-neoplastic cells that create a conducive environment for transformation and progression to occur. Interleukin 33 (IL-33) functions as a dual activity cytokine as it is also a nuclear factor. IL-33 is usually present in the nuclei of the cells. Upon tissue damage, it is released into the extracellular space and binds to its receptor, suppression of tumorigenicity 2 (ST2) L, which is expressed on the membranes of the target cells. IL-33 signalling activates the T Helper 2 (Th2) immune response among other responses. Although the studies on the role of IL-33 in gastric cancer are still in the early stages, they have revealed potentially important (though sometimes conflicting) functions or roles in cancer development and progression. The pro-tumorigenic roles include induction and the recruitment of tumor-associated immune cells, promoting metaplasia progression, and inducing stem cell like and EMT properties in gastric cancer cells. Therapeutic interventions to disrupt these functions may provide a unique strategy for gastric cancer prevention and treatment. This review aims to provide a summary of the role of IL-33 in GC, state its multiple functions in relation to GC, and show potential avenues for promising therapeutic investigation.Keywords: gastric cancer, interleukin-33, therapeutic target

Li H, Yao G, Zhai J, Hu D, Fan Y. Onco Targets Ther. 2019;12:11701–11713. We, the Editors and Publisher of OncoTargets and Therapy, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figures 4 and 5 with images from other unrelated articles. Specifically, The image for Figure 4B, BGC803, pcFTX, has been duplicated with the image for Figure 5C, DU145, si-HDGF from Situ J, Zhang H, Jin Z, Li K, Mao Y, Huang W. MicroRNA-939 Directly Targets HDGF to Inhibit the Aggressiveness of Prostate Cancer via Deactivation of the WNT/β-Catenin Pathway. Onco Targets Ther. 2020;13:4257-4270. https://doi.org/10.2147/OTT.S250101 (RETRACTED). The image for Figure 4D, BGC823, pcFTX, has been duplicated with the image for Figure 4G, Inhibitor from Wang M, Yu R, Ling X, et al. COPB2 promotes metastasis and inhibits apoptosis of lung adenocarcinoma cells through functioning as a target of miR-216a-3p. Transl Cancer Res. 2020;9(4):2648-2659. http://dx.doi.org/10.21037/tcr.2020.02.65. The images for Figure 5B, ctrl and pcFTX+miR-144, have been duplicated with the images for Figure 7A, BCAP-37, Mimics, and Figure 2C, Y79, Agomir-NC, from Zhang L, Ding F. Hsa_circ_0008945 promoted breast cancer progression by targeting miR-338-3p. Onco Targets Ther. 2019;12:6577-6589. https://doi.org/10.2147/OTT.S213994 and Xu L, Li W, Shi Q, et al. MicroRNA‑936 inhibits the malignant phenotype of retinoblastoma by directly targeting HDAC9 and deactivating the PI3K/AKT pathway. Oncology Reports. 2020;43:635-645. https://doi.org/10.3892/or.2020.7456 (RETRACTED), respectively. In addition, the images for Figure 4D, BGC823, Ctrl and Figure 5D, pcFTX+miR-144, have been duplicated. The authors did not respond to our queries and were unable to provide an explanation for the duplicated images or provide data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors were notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Anderley Gordon, Edwina Johnston, David K Lau, Naureen Starling Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UKCorrespondence: Naureen Starling, Gastrointestinal and Lymphoma Unit, The Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, United Kingdom, Tel +44 2086426011, Email Naureen.Starling@rmh.nhs.ukAbstract: Despite recent advances in the systemic treatment of gastroesophageal cancers, prognosis remains poor. Comprehensive molecular analyses have characterized the genomic landscape of gastroesophageal cancer that has established therapeutic targets such as human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR) and programmed death ligand 1 (PD-L1). The aberrant fibroblast growth factor receptor 2 (FGFR2) pathway is attractive for targetable therapy with FGFR inhibition based on preclinical data showing a pivotal role in the progression of gastric cancer (GC). FGFR2 amplification is the most common FGFR2 gene aberration in gastroesophageal cancer, and most associated with diffuse GC, which is often linked to poorer prognostic outcomes. There has been considerable progress with drug development focused on FGFR inhibition. At present, there is no approved FGFR inhibitor for FGFR2 positive gastroesophageal cancer. A selective FGFR2b monoclonal antibody bemarituzumab is currently being investigated in the first phase III randomized trial for patients with first line advanced GC, which may change the treatment paradigm for FGFR2b positive GC. The role of FGFR signalling, specifically FGFR2, is less established in oesophageal squamous cell cancer (ESCC) with a paucity of evidence for clinical benefit in these patients. Precision medicine is part of the wider approach in gastrointestinal cancers; however, it can be challenging due to heterogeneity and here circulating tumour DNA (ctDNA) for patient selection may have future clinical utility. In our review, we outline the FGFR pathway and focus on the developments and challenges of targeting FGFR2 driven gastroesophageal cancers.Keywords: gastric cancer, gastroesophageal cancer, FGFR2, molecular targets, novel therapies

Donghui Cao,1,&ast; Tongrong Su,2,&ast; Yanhua Wu,1 Zhifang Jia,1 Yingli Fu,1 Yuanlin Sun,2 Meishan Jin,3 Yueqi Wang,1 Jiaxin Yi,1 Yingnan Cui,2 Yuzheng Zhang,1 Haiyong Lv,1 Limei Qu,3 Jing Jiang,1 Xueyuan Cao2 1Division of Clinical Epidemiology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, People’s Republic of China; 3Division of Pathology, First Hospital of Jilin University, Changchun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xueyuan Cao, Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China, Email jd3d2ub@jlu.edu.cnPurpose: Gastric cancer (GC) remains a prevalent aggressive tumor with high morbidity and mortality globally. The identification of GC subtypes based on molecular features improved the prediction of prognosis and the selection of targeted therapies. PTEN is a characteristic tumor suppressor, while its association with different GC subtypes was unknown.Patients and Methods: The cohort consisted of 248 patients diagnosed with gastric cancer who were hospitalized and received radical gastrectomy. In addition, PTEN gene expression matrix of STAD was retrieved from TCGA. The mRNA and protein levels of PTEN and PD-L1 were detected using qRT-PCR and IHC staining. Multivariate logistic regression and Kaplan–Meier analysis were used to examine the relationship between PTEN expression and clinical characteristics.Results: In our study, PTEN was downregulated in gastric tumors both in mRNA and protein levels. Its inactivation was closely linked to higher histological grade (P = 0.005), neural invasion (P = 0.012), depth of invasion (P = 0.021), lymph metastasis (P = 0.026), and TNM stage (P = 0.001) of GC in the present study. Moreover, according to the molecular subtypes, high PTEN expression was related to high TPS score of PD-L1 positively (P = 0.010) but was not associated with MSI and EBV infection. Further, TCGA data validated that PTEN was indeed correlated with histological grade and invasion depth and positively related to PD-L1 expression (R = 0.29, adjusted P < 0.001).Conclusion: The above results suggested that PTEN expression was a useful marker in gastric carcinogenesis and progression and in the selection of immunotherapy-based treatments for GC patients.Keywords: gastric cancer, PTEN, molecular subtype, PD-L1, biomarker

Zhou Y, Li R, Yu H, Wang R, Shen Z. Onco Targets Ther. 2017;10:3893-3905. We, the Editors and Publisher of OncoTargets and Therapy, have retracted the following article. Since publication, concerns have been raised about the integrity of the data in the article. This includes the duplication of images from Figures 2, 4 and 5 with images from unrelated articles. Specifically, The western blot images for Figure 2D, CRMP4 and GAPDH, have been duplicated with the images for Figure 4B, CTHRC1 and GAPDH, respectively, from Lai Yh, Chen J, Wang Xp, et al. Collagen triple helix repeat containing-1 negatively regulated by microRNA-30c promotes cell proliferation and metastasis and indicates poor prognosis in breast cancer. J Exp Clin Cancer Res. 2017;36:92. https://doi.org/10.1186/s13046-017-0564-7. The image for Figure 4B, Cell invasion, NC, has been duplicated with the image for Figure 6D, Cell invasion, BGC823-shNC from Guo H, Xia B. Collapsin response mediator protein 4 isoforms (CRMP4a and CRMP4b) have opposite effects on cell proliferation, migration, and invasion in gastric cancer. BMC Cancer. 2016;16:565. https://doi.org/10.1186/s12885-016-2593-6. The image for Figure 5D, BGC823, has been duplicated with the image for Figure 1c, CTHRC1, Carcinoma tissue, from Chen G, Wang D, Zhao X, et al. miR-155-5p modulates malignant behaviors of hepatocellular carcinoma by directly targeting CTHRC1 and indirectly regulating GSK-3β-involved Wnt/β-catenin signaling. Cancer Cell Int. 2017;17:118. https://doi.org/10.1186/s12935-017-0469-8. The images for Figure 6B, miR-130a + CRMP4-shRNA, have been duplicated. When approached for an explanation, the authors did not respond to our queries, nor did they provide original data for their study. As the findings could not be verified the Editor and Publisher made the decision to retract the article and the authors were notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Wang C, Li X, Zhang J, Ge Z, Chen H, Hu J. Onco Targets Ther. 2018;11:7853–7864. We, the Editors and Publisher of OncoTargets and Therapy, have retracted the published article. Since publication, concerns have been raised about the integrity of the data in the article. This includes the duplication of images in Figures 2, 3, 4 and 5. Specifically, The western blot images for Figure 2C, AGS/5-FU and Figure 2D, SGC-7901/5-FU, have been duplicated. The flow cytometry images for Figure 2H, SGC-7901/5-FU and Figure 4H, SGC-7901/5-FU, have been duplicated. The western blot bands for Figure 3B, AGS/5-FU and SGC-7901/5-FU, have been duplicated. The western blot bands for Figure 5A, AGS/5-FU and Figure 5B, SGC-7901/5-FU, have been duplicated. When approached for an explanation, the authors did not respond to our queries, nor did they provide original data for their study. As verifying the validity of the published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors were notified of this. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Li Dai,&ast; Xiangren Jin,&ast; Liuxing Wang, Haibin Wang, Zhiqiang Yan, Guanghai Wang, Baichuang Liang, Fu Huang, Yuling Luo, Taichun Chen, Qian Wang Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qian Wang, Tel +8615885004333, Email Wangqian118@outlook.comAbstract: Currently, effective therapies for advanced gastric cancer with systemic metastasis are lacking. Pharmacological research has been slowly progressing over the past decades. Here, we report the case of a 56-year-old female with human epidermal growth factor receptor 2 (HER2) expression (IHC 2+/FISH-) in gastric cancer with systemic metastasis. The first-line therapeutic regime consisted of systemic administration of camrelizumab, local arterial infusion of oxaliplatin and arterial embolization, oral apatinib, and PS scheme (oral tegafur-gimeracil-oteracil (S-1) and paclitaxel (PTX), which was administered both intraperitoneally and systemically). After the treatment, a 3-month progression-free survival (PFS) was observed. Due to the occurrence of CTCAE grade 4 adverse reactions, the patient could not tolerate chemotherapy. In the second line of treatment, we replaced the PS scheme with disitamab vedotin and continued the use of carrilizumab and apatinib. After four cycles, efficacy evaluation showed that it was stable disease (SD), only CTCAE 1/2 grade adverse reactions occurred, and endoscopy examination showed local tumor control with a reduction in the ulcer lesion. At the time of submission of the current manuscript, a 6-month PFS was achieved and the treatment was continued. Due to the safety and efficacy of disitamab vedotin observed in our case, we propose that disitamab vedotin could be a promising drug for the treatment of advanced gastric cancer patients with HER2 expression.Keywords: gastric cancer, human epidermal growth factor receptor 2, disitamab vedotin

Li M, Cai O, Tan S. Onco Targets Ther. 2019;12:11345–11357. At the authors request, the Editor and Publisher of Onco Targets and Therapy are retracting the published article. Concerns were raised regarding the duplication of cell invasion and migration images. Specifically, The image for Figure 2D, Invasion, BGC823, sh-LOXL1-AS1, has been duplicated with the image for Figure 4D, Invasion, AGS, miR-142-5p. The image for Figure 2D, Invasion, BGC823, sh-NC, has been duplicated with the image for Figure 4D, Invasion, AGS, Control. Figure 2D, Invasion, AGS, Vector, has been duplicated with the image for Figure 4D, Migration, AGS, LOXL1-AS1+miR-142-5p. In addition, the western blot bands in Figure 5C, AGS, PIK3CA and BGC823, PIK3CA appear to have been duplicated. The authors could not provide a satisfactory explanation for the duplicated images and could only provide partial data for their study. As the findings could not be adequately verified the authors requested to retract the article and the Editor and Publisher agreed with this decision. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Lionel Aurelien Kankeu Fonkoua,1,2 Harry H Yoon1 1Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA; 2Department of Hematology, Mayo Clinic, Rochester, MN, 55905, USACorrespondence: Harry H YoonMayo Clinic, 200 First Street SW, Rochester, MN, 55905, USAEmail Yoon.Harry@mayo.eduAbstract: Esophagogastric cancer (EGC) is a heterogeneous group of malignancies that collectively represent the 2nd leading cause of cancer deaths worldwide. While surgery in combination with chemotherapy and/or radiation therapy represents the primary curative treatment for early stage disease, survival outcomes for the majority of patients with later-stage disease remain poor. Cytotoxic chemotherapy with platinum doublets such as 5-FU/leucovorin/oxaliplatin is the mainstay of treatment with incremental benefits provided by targeted therapy (trastuzumab, trastuzumab deruxtecan, ramucirumab) and immunotherapy (pembrolizumab, nivolumab). In this article, we provide an updated review and perspectives on the management of advanced EGC. We examine the distinct epidemiological, etiological and molecular features of each disease entity comprising EGC. After reviewing the critical studies that established conventional systemic cytotoxic and targeted therapeutics, we elaborate on recent promising and complex data with immune checkpoint inhibition focusing on implications of tumor histology and PD-L1 expression in the tumor microenvironment. We also highlight novel diagnostic and therapeutic strategies to build on these recent advances.Keywords: esophagogastric cancer, gastric cancer, esophageal cancer, targeted therapy, immunotherapy, precision medicine

Yue Zhang, Xue Bai, Yi Zhang, Yan Li Department of Gerontology and Geriatrics, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Yue ZhangDepartment of Gerontology and Geriatrics, Shengjing Hospital of China Medical University, 36 Sanhao Road, Shenyang, 110004, People’s Republic of ChinaEmail zhangyue_cmu@163.comObjective: The dishevelled-associated activator of morphogenesis 1 (DAAM1) has been reported to be closely associated with human cancers. However, its involvement in human gastric cancer (GC) remains largely unexplored. This study aimed to investigate the clinical significance and biological roles of Daam1 in human GC.Methods: Daam1 protein expression was examined in 124 cases of gastric adenocarcinomas using immunohistochemistry. Daam1 plasmid and siRNA transfection were carried out in SGC7901 and AGS cell lines. CCK-8, colony formation, Annexin V/PI, JC-1 staining, and Western blotting were used to explore the biological functions and potential underlying mechanisms of Daam1 in GC cells.Results: Our results showed that Daam1 was overexpressed in GC specimens. A high Daam1 level was associated with tumor-node-metastasis (TNM) stage, T status, nodal metastasis, and poor patient survival. Analysis of the Oncomine dataset revealed upregulation of Daam1 mRNA in GC tissues. Western blot showed that Daam1 protein expression was higher in GC cell lines compared to the normal GES-1 cell line. CCK-8 and colony formation assays showed that ectopic Daam1 expression upregulated the cell growth rate and colony number in SGC-7901 cells, while Daam1 siRNA knockdown downregulated the growth rate and colony number in AGS cells. CCK-8 and Annexin V/PI apoptosis assays demonstrated that Daam1 overexpression decreased cisplatin sensitivity and downregulated cisplatin-induced apoptosis. JC1 staining showed that Daam1 overexpression upregulated, while Daam1 depletion downregulated mitochondrial membrane potential. Mechanistically, Daam1 overexpression downregulated p21 and upregulated p-ERK and p-AKT. The increased proliferation rate and decreased cisplatin sensitivity/apoptosis induced by ectopic Daam1 were reversed after treatment with AKT and ERK inhibitors.Conclusion: Taken together, our results showed that Daam1 overexpression was associated with poor prognosis and promoted malignant activity via regulation of ERK and AKT pathways in GC cells, indicating Daam1 is a malignant biomarker and potential therapeutic target in GC.Keywords: Daam1, ERK, AKT, apoptosis, gastric cancer

Xin Li,1,&ast; Xiaoqiang Gu,1,&ast; Jiahua Xu,1,&ast; Ling Chen,2,&ast; Hongwei Li,1 Dan Meng,1 Haoran Bai,1 Jinzu Yang,1 Jianxin Qian1 1Department of Oncology, Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, 200032, People’s Republic of China; 2Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, 200437, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinzu Yang; Jianxin QianDepartment of Oncology, Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, 200032, People’s Republic of ChinaEmail kingzuy@126.com; jianxinqiang3@163.comBackground: HER2-positive patients with advanced gastric cancer have a poor prognosis, and trastuzumab-resistant patients lack effective treatment.Case Presentation: We report a 72-year-old male with HER2-positive gastric cancer. The patient had metastatic tumor during adjuvant chemotherapy after surgery, followed by second-line chemotherapy, and achieved a progression-free survival (PFS) of 4.5 months. Subsequent third-line chemotherapy treatment also failed. Fortunately, the patient had a significant tumor response and 8.5 months of PFS on trastuzumab combined with chemotherapy. After trastuzumab resistance, the patient was treated with programmed cell death protein-1 inhibitor combined with apatinib, which selectively inhibited VEGFR2, but the effect was not satisfactory. Finally, the patient was treated with capecitabine combined with pyrotinib, an irreversible TKI, acting on HER2. The tumor shrank significantly after this treatment.Conclusion: The mechanism and countermeasures of trastuzumab resistance were discussed in this case. For patients with HER2-positive advanced gastric cancer, pyrotinib can achieve good results after trastuzumab resistance.Keywords: HER2, gastric cancer, trastuzumab, pyrotinib

Yuan-Jie Liu,1,2 Jie-Pin Li,1– 3 Ying Zhang,1,2 Meng-Jun Nie,1,2 Yong-Hua Zhang,3 Shen-Lin Liu,1,2 Xi Zou1 1Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China; 2No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China; 3Department of Oncology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People’s Republic of ChinaCorrespondence: Shen-Lin Liu; Xi Zou Email zxvery@126.com; lsljsszyy@126.comPurpose: Follistatin-related gene 3 (FSTL3), an established oncogene, can modulate target gene expression via members of the transforming growth factor β (TGF-β) superfamily. The present study was conducted to evaluate the expression of FSTL3 in gastric cancer (GC) and to determine its prognostic significance. We also evaluated the possible mechanisms involved in the oncogenic role of FSTL3 in gastric carcinogenesis and development.Methods: We obtained data from the Human Protein Atlas, MethSurv, cBioPortal, UALCAN, TIMER, GEPIA, STRING, GeneMANIA, ONCOMINE, and MEXPRESS databases and examined it using R software. RNAi was used to establish stable FSTL3-knockdown (shFSTL3) and overexpression (OE) cell strains. Western blot; enzyme-linked immunosorbent (ELISA); and immunohistochemical (ICH), immunofluorescence, and phalloidin staining were used for examining protein expression. Cell invasion and migration were determined using transwell and scratch-wound assays. After tumor-associated macrophage (TAM) generation, co-culturing of cancer cells with TAMs was performed to confirm the relationship between FSTL3 and TAMs.Results: In GC patients, FSTL3 mRNA and protein levels were upregulated. FSTL3 expression was significantly linked to cancer stage as well as to pathological tumor grade in GC. Moreover, a high expression of FSTL3 was associated with a dismal survival duration in patients with GC. Furthermore, functional enrichment analysis demonstrated that FSTL3 overexpression could activate epithelial–mesenchymal transition (EMT) by promoting F-actin expression and BMP/SMAD signaling. Finally, immunofluorescence staining confirmed that the overexpression of FSTL3 promoted the proliferation of M2 TAMs.Conclusion: Taken together, our findings suggest that FSTL3 may be involved in GC progression via the promotion of BMP/SMAD signaling-mediated EMT and M2 macrophage activation.Keywords: FSTL3, biomarker, gastric cancer, EMT, M2 macrophages

Seda Kahraman,1 Suayib Yalcin2 1Y&inodot;ld&inodot;r&inodot;m Beyaz&inodot;t University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey; 2Hacettepe University Institute of Cancer, Department of Medical Oncology, Ankara, TurkeyCorrespondence: Suayib YalcinHacettepe University Institute of Cancer, Department of Medical Oncology, S&inodot;hhiye, Ankara, TurkeyTel +90-5053780639Email syalcin@hacettepe.edu.trAbstract: Gastric cancer (GC) is the fifth most common cancer worldwide. Despite recent improvements in treatment quality and options, advanced gastric cancer remains one of the hardest to cure cancers, with a median overall survival (OS) of 10– 12 months and a 5-year OS of approximately 5– 20%. There is an unmet need for further efforts to palliate disease-related symptoms, improve quality of life, increase tumor response rate, and prolong progression free and overall survival while balancing the toxicities of therapy. The most common type of GC is adenocarcinoma, which demonstrates morphological, biological, and clinical heterogeneity. A plethora of genomic alterations and the activation of numerous molecular pathways including human epidermal growth receptor 2 (HER2), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor-2 (FGFR2), mesenchymal epidermal transforming factor receptor (MET), and the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) are responsible for the complex heterogeneity of GC. Efforts to validate the therapeutic effects of inhibiting some of these aberrantly expressed pathways have failed to lead to a clinically meaningful outcome apart from the overexpression/amplification of the HER2 gene, inhibition of which has had a significant impact on clinical practice. The only available biomarkers to guide the effective treatment of patients with advanced GC are HER2 overexpression, MSI/PD-L1 status, and FGFR alterations. Various anti-HER2 agents have been evaluated after the success of the ToGA trial, but none led to a significant enough clinical improvement to be considered a viable alternative for HER2-targeted therapy in advanced GC until the global Keynote-811 trial, which added pembrolizumab to trastuzumab in combination with chemotherapy. This combination demonstrated a survival advantage for the first time in the 11 years since ToGA. Trastuzumab deruxtecan (T-DXd) was also found to be effective in patients who had already received > 2 previous lines of treatment. Despite these promising avenues, the optimal management of HER-2 positive GC still requires further development.Keywords: gastric cancer, HER-2, trastuzumab, targeted therapy

Xiaomeng Zhao,1,* Nan Ye,1,* Xueke Feng,1 Haiyan Ju,1 Ruixia Liu,1 Wenyu Lu1– 3 1School of Chemical Engineering and Technology, Tianjin University, Tianjin, the People’s Republic of China; 2Key Laboratory of System Bioengineering, Tianjin University, Tianjin, the People’s Republic of China; 3Collaborative Innovation Center of Chemical Science and Engineering, Tianjin University, Tianjin, the People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenyu Lu No. 135, Yaguan Road, Haihe Education Park, Jinnan District, Tianjin, the People’s Republic of ChinaTel +86-22-85356523Fax +86-22-27400973Email wenyulu@tju.edu.cnPurpose: The purpose of this study was to investigate the relationship between microRNA-29b-3p (miR-29b-3p) and myc-associated zinc finger protein (MAZ) expression and the effects of this interaction on the proliferation, migration, and invasion of gastric cancer cells.Methods: qPCR and Western blots were used to detect the expression of miR-29b-3p and MAZ. The dual luciferase reporter gene system was used to explore whether MAZ is the target of miR-29b-3p. Cell function experiments and a mouse tumorigenesis model were used to determine the effects of miR-29b-3p overexpression and MAZ depletion on proliferation, migration, and invasion in gastric cancer cell lines and on tumor growth.Results: The expression level of miR-29b-3p was low and the expression level of MAZ was high in gastric cancer cells compared with normal human gastric mucosal epithelial cells. MAZ was the target gene of miR-29b-3p. The upregulation of miR-29b-3p reduces the expression of MAZ. Overexpression of miR-29b-3p and downregulation of MAZ inhibited the proliferation and migration of cancer cells and induced apoptosis by controlling the expression of autophagy-related proteins. MiR-29b-3p mimics inhibit tumor growth in mice.Conclusion: MiR-29b-3p inhibits the migration and invasion of gastric cancer cells by regulating the autophagy-related protein MAZ.Keywords: gastric cancer, microRNA, autophagy, migration, invasion

Xuan Feng,1,2 Feng Xue,3 Guihua He,4 Suiping Huang,4 Qing Ni1,3 1Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, People’s Republic of China; 2Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou, 225001, Jiangsu, People’s Republic of China; 3Department of Surgery, Affiliated Hospital of Yangzhou University, Yangzhou, 225000, Jiangsu, People’s Republic of China; 4Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510120, People’s Republic of ChinaCorrespondence: Suiping Huang; Qing Ni Email gzdoctorhsp@126.com; nqingnn@163.comPurpose: Banxia xiexin decoction (BXXX) is a classical Chinese herbal compound for the treatment of gastrointestinal diseases. Its ingredients are also considered helpful for cancer rehabilitation. Here, we will explore the regulatory mechanism of BXXX acting on PD-L1 in gastric cancer (GC).Methods: GC samples and the general baseline data of the patients were collated. Immunohistochemical (IHC) detected the expression of programmed cell death-ligand 1(PD-L1), hypoxia-inducible factor-1 (HIF-1), epidermal growth factor receptor (EGFR), interferon-γ receptor (IFNGR) and Toll-like receptor 4 (TLR4). ELISA detected the expressions of EGF, IFNG and IL-6 in serum samples. Network tools were used to analyze the potential molecules of BXXX. In the cell experiment, CCK-8 detected the cell proliferation. Tunel detected the apoptosis. Western blot detected the expression of related proteins. In animal experiments, the tumor volume of GC-bearing mice was observed. Expression of EGF, IFNG and IL-6 in the serum of tumor-bearing GC mice were detected by ELISA. Western blot detected the expression of related proteins.Results: The expressions of PD-L1, HIF-1, EGFR, IFNGR and TLR4 in the tissues of GC patients were significantly increased, and the expressions of EGF, IFNG and IL-6 in serum were increased. The molecular results of the network tools showed that BXXX and its main components have a targeting effect on the key molecules of each pathway in the PD-L1 regulatory network. Cell experiments showed that BXXX can inhibit the expression of PD-L1, HIF-1, EGFR and TLR4, but has no significant effect on the expression of IFNGR, thus inhibiting the proliferation and promoting the apoptosis of GC cells. The results were consistent with the animal experiments on tumor-bearing gastric cancer mice.Conclusion: BXXX inhibited the expression of PD-L1 through multi-target and multi-pathway regulation of major oncogenes in GC, thus effect cell proliferation and apoptosis.Keywords: banxia xiexin decoction, gastric cancer, PD-L1, multi-target and multi-pathway

Ning Xie,1,2,* Yifei Pan,3,* Jian Wu,4 Yunfan Bai,3 Cailan Xiao,1,2 Xiaoliang Gao,4 Jinhai Wang,1,2 Na Liu1,2 1Department of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Shaanxi Key Laboratory of Gastrointestinal Motility Disorders, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Japan; 4Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Na Liu; Jinhai Wang Email liuna1@xjtu.edu.cn; jinhaiwang@hotmail.comBackground: Our previous studies demonstrate that ARL4C is the most critical clinical biomarker for gastric cancer (GC) patients among ARL family members (ARLs) and functions as an oncogene in GC. However, its underlying mechanisms in GC need to be further illustrated. In this study, we aim to explore the upstream and downstream molecular mechanisms of ARL4C in GC cells.Methods: The genetic alteration of ARL4C in GC is analyzed by cBioPortal database. Potential ARL4C-targeted microRNAs (miRs) are predicted by three databases. The high-throughput RNA sequencing is performed to explore the underlying mechanisms of ARL4C in GC cells. The effects of predicted microRNAs on ARL4C, the RNA-sequencing results validation and the biological functions of ARL4C in GC cells are illustrated by in vitro experiments.Results: Genetic analyses indicate that ARL4C is significantly upregulated in GC, which is not caused by gene amplification. MicroRNAs prediction shows the high relevance between ARL4C and miR-302 members. Moreover, miR-302c or miR-302d transfection reduces ARL4C protein expression in GC cells. Based on the high-throughput RNA sequencing of ARL4C-knockdown cells, enrichment analyses demonstrate that ARL4C is closely related to cell growth and involved in p53 signaling. Moreover, there are strong gene–gene interactions between ARL4C and genes in p53 signaling, and ARL4C downregulation could inhibit the protein expression of MDM2, a critical gene in p53 pathway. Further functional experiments demonstrate that ARL4C silencing leads to cell cycle arrest and increased cell apoptosis in AGS and MKN45 cells.Conclusion: Our data suggest that miR-302c and miR-302d may function as the upstream regulators of ARL4C. And, ARL4C might promote GC cell cycle progression via regulating p53 signaling. Our findings provide novel insights into the key role of ARL4C and the underlying mechanisms in GC progression, thus facilitating the development of ARL4C-targeted therapy.Keywords: ARL4C, gastric cancer, miRNA-302s, p53, cell cycle, apoptosis

Jianliang Chen,1,2,* Shengqiang Cai,1,2,* Tianchun Gu,1,2 Fei Song,1,2 Yingchun Xue,1,2 Di Sun1,2 1Department of General Surgery, People’s Hospital of Jingjiang, Taizhou, 214500, Jiangsu, People’s Republic of China; 2Seventh Clinical Medical College of Yangzhou University, Taizhou, 214500, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Di SunDepartment of General Surgery, People’s Hospital of Jingjiang, 28 Zhongzhou Road, Jingjiang, Taizhou, 214500, Jiangsu, People’s Republic of ChinaTel +86-18052633030Email 1093730063@qq.comIntroduction: MiRNAs have been proven to modulate the progression of gastric cancer (GC). In this field, we evaluated the role and mechanism of miR-140-3p in GC.Methods: Western blotting and qRT-PCR were used to detect the levels of miR-140-3p and BCL2. The interaction of miR-140-3p and BCL2 was confirmed by dual-luciferase reporter and miRNA pull-down assays. CCK-8, EdU, wound healing, and Transwell invasion assays were performed to evaluate cell proliferation, migration and invasion. Autophagy was analyzed using Western blot analysis of the LC3-II/I ratio and immunofluorescence staining. A xenograft model was established to reveal the role of miR-140-3p in tumorigenesis.Results: In GC cell lines and tissues, miR-140-3p was highly expressed, and BCL2 was expressed at low levels. MiR-140-3p directly inhibited BCL2 expression and indirectly promoted BECN1 expression, and BCL2 inhibited BECN1 expression. MiR-140-3p overexpression or silencing restrained or facilitated migration, invasion and EMT in GC cells. Moreover, we noticed that overexpression or downregulation of miR-140-3p promoted or suppressed BECN1-dependent autophagy in GC cells. BCL2 introduction or BECN1 silencing in GC cells partially blocked the effects of miR-140-3p. In conclusion, miR-140-3p directly downregulated the expression of BCL2, BCL2 downregulation further activated BECN1-dependent autophagy, and autophagy activation further inhibited EMT.Conclusion: miR-140-3p may act as a tumor suppressor by targeting BCL2 and regulating downstream BECN1-induced autophagy and metastasis in GC progression.Keywords: miR-140-3p, gastric cancer, BCL2, BECN1, autophagy, EMT

Lin S, Wang H, Yang W, Wang A, Geng C. Onco Targets Ther. 2020;13:337–349. The Editor and Publisher of OncoTargets and Therapy wish to retract the published article. Concerns were raised regarding the alleged duplication of cell colony images in Figure 4 with the same images from Figure 9. Specifically, Figure 4A, HGC-27, Control, appears to have been duplicated with the same image for Figure 9C, siRNA-NC+Leu, which has been flipped. Figure 4A, HGC-27, siRNA-NC, appears to have been duplicated with the same image for Figure 9C, Control, which has been flipped. Figure 4A, HGC-27, siRNA-CCAT2, appears to have been duplicated with the same image for Figure 9C, siRNA-CCAT2+Leu, which has been flipped. Figure 4B, HGC-27, Control, appears to have been duplicated with the same image for Figure 9D, siRNA-CCAT2+Leu, which has been flipped. Figure 4B, HGC-27, siRNA-NC appears to have been duplicated with the same image for Figure 9D, siRNA-NC+Leu, which has been flipped. Figure 4B, HGC-27, siRNA-CCAT2, appears to have been duplicated with the same image for Figure 9D, Control, which has been flipped. The authors did not respond to our queries and no explanation for the alleged image duplication was provided. The Editor determined the reported study to be unreliable and requested for the article to be retracted. The authors were notified of this. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Hongzhu Zhang,1,* Tingting Fu,1,* Cuiping Zhang2 1Department of Gastroenterology, Jinan Jigang Hospital, Jinan, Shandong, 250101, People’s Republic of China; 2Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cuiping ZhangDepartment of Gastroenterology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Shinan District, Qingdao, Shandong, 266000, People’s Republic of ChinaEmail zhangcuiping66@sohu.comAim: The purpose of our study was to investigate the effects of miR-1249 in gastric cancer.Methods: By analyzing the data obtained from TCGA database, the expression and prognosis of miR-1249 in gastric cancer patients were analyzed. Then, CCK8, colony forming and transwell assays were used to test cell proliferation and motility. The cell apoptosis was detected by flow cytometry. The Pearson correlation coefficient analyzed was applied to analyze the correlation between GNA11 and miR-1249. qRT-PCR and Western blotting assays were employed to detect the mRNA and protein levels.Results: We discovered that miR-1249 was highly expressed and was associated with a worse prognosis in gastric cancer patients. Besides, miR-1249 was up-regulated in gastric cancer cell lines (AGS, MKN45 and SNU1). More interestingly, miR-1249 exerted facilitating impacts on gastric cancer cell proliferation and motility, whereas miR-1249 acted as a suppressing effect on gastric cancer apoptosis. G protein subunit alpha 11 (GNA11) was a target gene of miR-1249 and was negatively correlated with miR-1249. Furthermore, GNA11 was negatively regulated by miR-1249. Additionally, GNA11 was lowly expressed in gastric cancer tissues and cell lines, as well as low GNA11 expression, was related to poor overall survival results in gastric cancer patients. The promoting influences of miR-1249 over-expression on AGS cell proliferation and motility was rescued by GNA11 over-expression, which might be achieved by regulating PI3K/AKT/mTOR signalling pathway.Conclusion: Above all, we concluded that miR-1249 was concerned with the progression of gastric cancer through regulating GNA11, suggesting that miR-1249 and GNA11 might serve as predictive biomarkers for gastric cancer therapy.Keywords: gastric cancer, miR-1249 mimic/inhibitor, G protein subunit alpha 11, target, proliferation, apoptosis, PI3K/AKT/mTOR pathway

Qingzhi Lan,1,2 Xiaoping Tan,3,* Pengzhan He,1,2,* Wei Li,1,2 Shan Tian,1,2 Weiguo Dong1 1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Central Laboratory of Renmin Hospital, Wuhan, People’s Republic of China; 3Department of Gastroenterology, The First Affiliated Hospital of Yangtze University, Jingzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weiguo DongDepartment of Gastroenterology, Renmin Hospital of Wuhan University, No. 238 Zhang Zhi-Dong Road, Wuhan, 430060, People’s Republic of ChinaTel +86-27-88041911Fax +86-27-88042992Email dongweiguo@whu.edu.cnIntroduction: Gastric cancer (GC) is the sixth most common malignant tumor and the third leading cause of cancer-related death in the world. Studies have shown that TRIM protein can regulate transcription factor activity and is associated with many cancers. However, the role of TRIM11 in gastric cancer remains unclear.Methods: TRIM11 protein levels were examined in 36 cases of GC tissues and 4 gastric cancer cell lines. TRIM11 overexpression and knockdown cells were constructed in MGC-803, HGC-27 and SGC-7901, respectively. The biological roles and mechanisms of TRIM11 were examined using CCK8, colony formation, transwell migration assay, invasion assay, Western blotting, Immunohistochemistry and in vivo nude mice experiments.Results: We found that TRIM11 was upregulated in gastric cancer tissues and gastric cancer cell lines. Functionally, TRIM11 overexpression increased growth rate, colony formation, invasion and migration ability, EMT and β-catenin protein level and its downstream proteins such as CyclinD1 and C-myc, while TRIM11 knockdown shows the opposite effects.Conclusion: In summary, our data show that TRIM11 is overexpressed in GC. TRIM11 promotes proliferation, migration, invasion and EMT of gastric cancer by activating β-catenin signaling.Keywords: TRIM11, gastric cancer, proliferation, migration, invasion, EMT

Yushuang Luo, Pengjie Yu, Junhui Zhao, Qijing Guo, Baohua Fan, Yinzhuo Diao, Yulong Jin, Jing Wu, Chengwu Zhang Department of Oncology, Affiliated Hospital of Qinghai University, Xining 810001, People’s Republic of ChinaCorrespondence: Chengwu ZhangDepartment of Oncology, Affiliated Hospital of Qinghai University, Xining 810001, People’s Republic of ChinaEmail cwzhang19@163.comBackground: Gastric cancer (GC) is one of the most common malignant tumors and the second most frequent cause of cancer death worldwide. Crocin is a kind of bioactive constituent found in the stigmas of saffron, which has shown various pharmacological activities.Methods: In this study, we investigated the inhibitory effect of crocin on gastric cancer AGS cells proliferation and explored the underlying mechanism. A series of methods were used including cell counting kit assay, gene microarray analysis, qRT-PCR, Celigo image cytometry, cell clone formation assay, Western blot, and cell xenograft growth in vivo.Results: The results indicated that crocin inhibited AGS cells proliferation and promoted cell apoptosis. Further studies suggested that crocin decreased a series of genes expression, among which TPM4 gene downregulation inhibited the tumor cells proliferation and tumor growth in mice, and overexpression of TPM4 gene abolishes the inhibitory effect of crocin. Further study using microarray analysis suggested that knocking down of TPM4 altered genes related to the proliferation and apoptosis of cells.Discussion: Crocin could inhibit the gastric cancer cells AGS cells proliferation by regulating TPM4 gene expression, and TPM4 may be a promising therapeutic target for GC treatment.Keywords: gastric cancer, crocin, TPM4, HER2

Kailin Ding,1,* Xian Chen,2,* Yong Li,2 Wenzhu Li,2 Yongsong Ye,3 Tingting He,4 Wenjing Wang,4 Haibo Zhang2 1The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Department of Imaging, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4OrigiMed, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haibo ZhangDepartment of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, People’s Republic of ChinaTel +86-20-81887233Email haibozh@gzucm.edu.cnAbstract: Gastric cancer is common, especially in East Asian countries, and is associated with high recurrence and mortality rates. Currently, there is no standard third-line treatment for metastatic gastric cancer. In this report, we present the case of a 69-year-old man with advanced gastric cancer, whose tumor was negative for human epidermal growth factor receptor 2 (HER2) according to immunohistochemical analysis. Next-generation sequencing performed on paraffin sections of the postoperative tumor samples indicated the presence of the ERBB3 V104L mutation. The patient received irinotecan plus pyrotinib as a third-line therapy and achieved a progression-free survival of 7.6 months with a high quality of life. Therefore, the combined administration of irinotecan and pyrotinib may improve the clinical condition of patients with gastric cancer harboring an ERBB3 mutation. Moreover, ERBB3 could be a potential therapeutic target for gastric cancer.Keywords: ERBB3, gastric cancer, irinotecan, pyrotinib, third-line therapy

Zhipeng Zhu,1 Sihao Lin,1 Xiaofang Wu,2 Jiuhua Xu,2 Lulu Li,1 Weipeng Ye,2 Jiayi Li,3 Zhengjie Huang1,2 1Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People’s Republic of China; 2Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, People’s Republic of China; 3Department of Medical Oncology, Xiamen Cancer center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People’s Republic of ChinaCorrespondence: Zhengjie HuangDepartment of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, 55 Zhen Hai Road, Si Ming District, Xiamen, Fujian 361003, People’s Republic of ChinaTel +86-592-2139280Fax +86-592-2137368Email huangzhengjie@xmu.edu.cnBackground: Cisplatin is a vital chemotherapy regimen for gastric cancer (GC), while partial response is observed (approximately 40%) because of drug resistance. Thus, it is urgent to improve drug sensitivity to improve the therapeutic effect of cisplatin on GC.Purpose: The study was performed to explore the synergistic effect of decitabine and cisplatin in GC.Materials and Methods: Cancer and matched adjacent tissues from patients with GC were obtained and quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry were performed to evaluate Sox2 expression level. Methylation-specific PCR (MSP) was performed to assess the effect of 5-aza-2ʹ-deoxycytidine (5-Aza-CdR) on Sox2 promoter. Cell proliferation assay, scratch-wound migration assay and Transwell invasion ability were performed to assess the effect of 5-Aza-CdR on proliferation, migration and invasion ability. Meantime, the effect of 5-Aza-CdR was also investigated in gastric cell lines BGC-823 and nude mouse xenograft tumor model. Finally, the anti-cancer effect of decitabine, cisplatin and their combination treatment were investigated in a BGC-823 and nude mouse xenograft tumor model, Sox2 methylation level, Sox2 expression of BGC-823 and xenograft tumors were analyzed by MSP, qRT-PCR and Western blot.Results: Sox2 expression was significantly associated with different differentiated degrees, depth of invasion (0.0011), lymph node metastasis (0.0013), and TNM stage (0.0002). Next, methylation inhibitor 5-Aza-CdR restored Sox2 expression to promote proliferation, migration and invasion in vitro and in vivo. Finally, cisplatin and decitabine was found to be synergistic to inhibit proliferation of xenograft tumors. Likewise, cisplatin and decitabine were also synergistic to induce Sox2 DNA demethylation to promote Sox2 mRNA and protein expression in BGC-823 and xenograft tumors.Conclusion: Cisplatin and decitabine could be synergistic to induce Sox2 DNA demethylation to promote expression of the Sox2 gene, which exerted an anti-tumor effect on GC. It may suggest an insight for innovative therapeutics of GC.Keywords: Sox2, DNA demethylation, gastric cancer, decitabine, cisplatin, anti-tumor

Chengwu Tang, Wenming Feng, Ying Bao, Cheng Chen Department of General Surgery, First People’s Hospital Affiliated to Huzhou Normal College, Huzhou, People’s Republic of ChinaCorrespondence: Cheng Chen Department of General SurgeryFirst People’s Hospital Affiliated to Huzhou Normal College, No. 158 Guangchang Hou Road, Huzhou, Zhejiang Province 313000, People’s Republic of ChinaTel +86 05722039346Fax +86 05722023728Email wjc_hzyy@sina.comObjective: To assess the effectiveness and safety of treatment consisting of maintenance chemotherapy (MCT) with S-1 following S-1 plus oxaliplatin (SOX) chemotherapy for stage 3 gastric cancer (GC) after D2 gastrectomy.Methods: In this retrospective study, we enrolled 255 patients with stage 3 GC who underwent D2 gastrectomy between February 2011 and May 2014. The SOX regimen chemotherapy was administrated to all of the patients as adjuvant therapy. The SOX regimen consisted of S-1 (for patients with a body surface area [BSA] of less than 1.25 m2, 80 mg/d; 100 mg/d for BSA=1.25 m2- < 1.5 m2, and 120 mg/d for BSA≥ 1.5 m2, in 2 divided doses for 14 d) and oxaliplatin (130 mg/m2 given on Day 1), repeated every 21 d for 8 cycles. Following SOX chemotherapy, 122 of these patients received maintenance chemotherapy (the MCT group) with S-1, whereas 133 patients (the control group) received no MCT. The MCT consisted of S-1 (80, 100, or 120 mg daily based on BSA, in 2 divided doses for 14 d), repeated every 21 d for 8 cycles at most. The chemotherapy was discontinued if unacceptable toxicity or disease progression occurred or upon the request of the patient. All cases were followed up, and overall survival (OS), recurrence-free survival (RFS), and toxicities were compared.Results: The MCT group exhibited a distinctly higher 5-year OS (P=0.0425) and RFS (P=0.0479) than those of the control group. The incidence of hand-foot syndrome was markedly greater in the MCT group (P=0.0026). No toxicity-related death occurred.Conclusion: Maintenance chemotherapy with S-1 following the SOX regimen chemotherapy provides significant survival benefit for stage 3 GC after D2 gastrectomy.Keywords: gastric cancer, chemotherapy, overall survival, recurrence-free survival

Tongtong Qi,1 Yonghong Dong,2 Zili Gao,1 Jun Xu3 1Department of General Surgery, Shanxi Medical University, Taiyuan, Shanxi 030001, People’s Republic of China; 2Department of Gastroenteropancreatic & Hernia Surgery, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi 030012, People’s Republic of China; 3Department of General Surgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, People’s Republic of ChinaCorrespondence: Yonghong Dong Tel +86 13803408484Email youthdong007@163.comAbstract: Huaier (Trametes robiniophila Murr), a Chinese traditional herb of medicine, has demonstrated promising curative effects in clinical treatment for various tumors. There are documented experiments showing the biological functions of Huaier with its antineoplastic molecular mechanisms: restraining proliferation and metastasis, arresting cell cycle, inducing apoptosis, pyrosis, and autophagy, anti-intratumoral angiogenesis, attenuating characteristics of tumor stem-like cells, interfering with the function of the tumor-related immune system, reversing drug resistance, and enhancing the sensitivity to chemotherapeutic drugs, etc. In addition, studies suggest that non-coding RNA (ncRNA) acts a pivotal part in cancer occurrence and development, and demonstrates that Huaier adjusts the performance of certain lncRNA (long non-coding RNA) and proceeds to affect the microRNA and its target genes, rendering an anti-tumor effect. Huaier also modulates the expression of lncRNA to attenuate the activity of ncRNA-sponged microRNA and then inhibits the expression of downstream target genes. We summarize and illustrate the experimentally confirmed anti-cancer molecular mechanisms of Huaier, to inspire new ideas for researchers in relevant fields.Keywords: Huaier, antineoplastic mechanisms, breast cancer, gastric cancer, liver cancer, pulmonary cancer

Yong Zhou,1,* Zhongqi Li,1,* Xuan Wu,1 Laizhen Tou,1 Jingjing Zheng,2 Donghui Zhou1 1Department of Oncology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, People’s Republic of China; 2Department of General Surgery, Lishui Municipal Central Hospital, Lishui, Zhejiang 323000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Donghui ZhouDepartment of Oncology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, People’s Republic of China, Email 1193076@zju.edu.cnBackground: Gastric cancer is one of the most malignant tumors all over the world. It has been reported that proteins play key roles during the tumorigenesis of gastric cancer. To identify novel potential targets for gastric cancer, differential expressed proteins between gastric cancer and adjacent normal tissues were analyzed with proteomics and bioinformatics tool.Methods: The differentially expressed proteins between gastric cancer and adjacent normal tissues were analyzed by Omicsbean (multi-omics data analysis tool). Cell viability was tested by CCK-8 assay. Flow cytometry was used to measure cell apoptosis and cycle. Transwell assay was used to test cell migration and invasion. Gene and protein expressions were detected by RT-qPCR, immunohistochemistry and Western blot, respectively.Results: MAGOH and MAGOHB were found to be notably upregulated in gastric cancer tissues compared with that in normal tissues. Knockdown of MAGOH significantly inhibited the proliferation of gastric cancer cells via inducing the cell apoptosis. In addition, MAGOH knockdown induced G2 phase arrest in gastric cancer cells. Moreover, MAGOH knockdown notably inhibited migration and invasion of gastric cancer cells. Importantly, double knockdown of MAGOH and MAGOHB exhibited much better anti-tumor effects on gastric cancer compared with alone treatment. Finally, double knockdown of MAGOH and MAGOHB mediated the tumorigenesis of gastric cancer via regulation of RAF/MEK/ERK signaling.Conclusion: MAGOH knockdown inhibited the tumorigenesis of gastric cancer via mediation of b-RAF/MEK/ERK signaling, and double knockdown of MAGOH and MAGOHB exhibited much better anti-tumor effects. This finding might provide us a new strategy for the treatment of gastric cancer.Keywords: gastric cancer, MAGOH/MAGOHB, b-RAF/MEK/ERK signaling

Jianming Wei,1,* Xibo Gao,2,* Yulan Qin,3 Tong Liu,1 Yani Kang3 1Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, People’s Republic of China; 2Department of Dermatology, Tianjin Children’s Hospital, Tianjin 300074, People’s Republic of China; 3School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai 200240, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yani Kang Tel +86-21-3420-7324Email kangyani@sjtu.edu.cnPurpose: Gastric cancer (GC) is a type of malignant cancer with a poor prognosis. The iron’s metabolism plays an important role in the process of GC. The aim of this study was to evaluate the effectiveness of SLC22A17, associated with iron metabolism, in predicting the prognosis of GC patients.Materials and Methods: We analyzed genes related to iron metabolism of gastric cancer mRNA-seq data from TCGA database. We identified an iron metabolism-related SLC22A17 as an independent prognostic factor using univariate and multivariate Cox regression analysis.Results: Further research showed that SLC22A17 was related with many pathways involved in the process of gastric cancer, and the expression was associated with diverse cancer-infiltrating immune cells. The expression of SLC22A17 was associated with T (Topography).Conclusion: We validated that SLC22A17 associated with iron metabolism could serve as a prognostic biomarker for GC patients.Keywords: gastric cancer, iron metabolism, SLC22A17, prognostic marker

Hong Zhu, Jin-Hai Tang, Shi-Meng Zhang, Jia-Ping Qian, Xin Ling, Xiao-Ying Wu, Ling-Xia Yang Department of Gastroenterology, Suzhou Ninth People’s Hospital, Suzhou, Jiangsu Province, People’s Republic of ChinaCorrespondence: Ling-Xia Yang Email ylxnjq@163.comBackground: Gastric cancer (GC) is a common cancer with high incidence and mortality worldwide. In recent years, accumulating evidence has shown that long noncoding RNAs (lncRNAs) exert critical roles in the development and progression of cancer by acting as a tumor initiator or suppressor. LINC00963 is a newly reported lncRNA related to cancer, and its role in GC remains unclear.Materials and Methods: The expression levels of LINC00963, miR-612, and cell division cycle 5-like protein (CDC5L) were measured using quantitative real-time PCR or Western blot. The biological functions of LINC00963, miR-612, and CDC5L in GC cells were analyzed by transwell and proliferation experiments. The expression of CDC5L in patients with GC was evaluated using the Oncomine database. Bone marrow-derived dendritic cells (DCs) were derived from C57BL/6 mice.Results: LINC00963 expression was higher in GC tissues than in adjacent normal tissues. Similar results were found in GC cell lines and normal human gastric epithelial cells. Upregulation of LINC00963 was related to the poor prognosis of patients with GC. Knockdown of LINC00963 inhibited the proliferation, invasion, and metastasis but promoted the apoptosis of GC cells. Furthermore, silencing of LINC00963 in GC cells significantly suppressed the tumor growth of GC. Bioinformatics analysis indicated that LINC00963 could target miR-612 by functioning as a competing endogenous RNA. The expression of miR-612 decreased in GC tissues and cell lines. Meanwhile, LINC00963 expression was negatively associated with miR-612. CDC5L was a direct target of miR-612. miR-612 suppressed the expression of CDC5L in GC tissues and cells. Moreover, LINC00963 inhibited the differentiation and maturation of DCs by regulating miR-612 expression in DCs.Conclusion: LINC00963 promoted the progression of GC by competitively binding to miR-612 to regulate the expression of CDC5L and mediated DC-related anti-tumor immune response. Thus, targeting LINC00963 may be a promising therapeutic strategy for GC.Keywords: lncRNA LINC00963, gastric cancer, miR-612, CDC5L, dendritic cells

Yuan Xu,1 Chao Liang,1 Xianlei Cai,1 Miaozun Zhang,1 Weiming Yu,1 Qinshu Shao2 1Department of Gastrointestinal Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo 315000, People’s Republic of China; 2Department of Gastrointestinal Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou 310014, People’s Republic of ChinaCorrespondence: Yuan XuDepartment of Gastrointestinal Surgery, Ningbo Medical Center Lihuili Hospital, No. 57 Xingning Road, Yinzhou District, Ningbo 315000, Zhejiang Province, People’s Republic of ChinaTel +86-0574-87018617Email xu565831937@163.comPurpose: Recent studies have established the ability of centromere protein-A (CENP-A) to perform as an oncogene, regulating tumor progression. The aim of this research was to explore the relationship between CENP-A expression and clinical significance in gastric cancer (GC) patients.Materials and Methods: Experiments with a microarray were conducted using the Affymetrix U133 plus 2.0 GeneChip Array. Upregulated differentially expressed genes (DEGs) were identified via the GEO2R and intersected using a Venn diagram. Bioinformatic databases Omcomine, GEPIA, and Ualcan were applied to investigate the expression level of CENP-A in GC. The real-time quantitative RT-PCR (qRT-PCR) was used to validate the level of CENP-A mRNA in GC. Immunohistochemistry (IHC) was employed to verify the protein levels of CENP-A, while the relationship between CENP-A expression and patients’ clinical parameters in GC was explored through the use of IHC. Kaplan-Meier analysis was conducted to evaluate the prognostic significance of CENP-A. Additionally, the Kaplan-Meier plotter database (KM plotter) was used to verify the prognostic function of CENP-A in GC patients.Results: The results indicated that CENP-A was significantly overexpressed, both in protein and mRNA levels of GC tissues, compared to adjacent noncancerous tissues (P< 0.05). Furthermore, we observed that CENP-A expression was positively associated with TNM stage, tumor classification, lymph node metastasis, distant metastasis, and Lauren type (P< 0.05). Kaplan-Meier analysis showed that patients with an overexpression of CENP-A had significantly poorer overall survival (OS) times (P< 0.05). Multivariate analysis suggested CENP-A may serve as an independent predicting factor for the poor outcome of GC patients.Conclusion: Our results show that CENP-A upregulation is significantly correlated with advanced tumor progression and poor prognosis. CENP-A may function as a novel potential biomarker for predicting the clinical outcomes of GC patients.Keywords: CENP-A, gastric cancer, survival analysis, poor prognosis

Huijie Gao,1 Jincheng Ma,1 Yanhui Cheng,1 Peiming Zheng2 1Department of Oncology, The First Affiliated Hospital of Henan University, Kaifeng, Henan 475000, People’s Republic of China; 2Department of Clinical Laboratory, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan 450003, People’s Republic of ChinaCorrespondence: Peiming Zheng Email zpm8266@163.comPurpose: Macrophages are a major component of the tumour microenvironment and play an important role in chemoresistance of cancer. However, how exosomal microRNAs (miRNAs) derived from macrophages contribute to the development of doxorubicin resistance in gastric cancer (GC) are not clearly defined. The aim of this study was to investigate whether macrophage-derived exosomes mediate doxorubicin resistance in GC.Methods: Exosomes isolated from macrophage culture medium were characterized and co-cultured with GC cells and the miR-223 level was detected using real-time quantitative PCR (RT-qPCR). The internalization of exosomes and transfer of miR-223 were observed via immunofluorescence. Macrophages were transfected with an miR-223 inhibitor or negative control. Cell Counting Kit-8 and flow cytometry were employed to explore the effect of macrophage-derived exosomes on the doxorubicin resistance of GC cells. Western blot and RT-qPCR assay were also performed to explore the regulation of GC chemotherapy resistance by exosomal miR-223.Results: Here, the macrophages and macrophage-derived exosomes promoted doxorubicin resistance in GC cells. MiR-223 was enriched in macrophage-derived exosomes and they could be transferred to co-cultivated GC cells. The miR-223 knockdown in macrophages could reduce the effects of exosomes on GC cells. Functional studies revealed that exosomal miR-223 derived from macrophages promoted doxorubicin resistance in GC cells by inhibiting F-box and WD repeat domain-containing 7 (FBXW7). Clinically, the expression of miR-223 significantly increased in GC tissues and high expression of plasma exosomal miR-223 was highly linked with doxorubicin resistance in GC patients.Conclusion: The exosomal transfer of macrophage-derived miR-223 conferred doxorubicin resistance in GC and targeting exosome communication may be a promising new therapeutic strategy for GC patients.Keywords: exosome, miR-223, macrophage, doxorubicin resistance, gastric cancer

Yongyuan Li,1,2,* Hongjie Liu,3,* Yu Cui,1 Hekai Chen,1 Xuejun Cui,1 Jianping Shao,1 Feng Su,1 Xianghui He2 1Department of General Surgery, The Fifth Central Hospital, Tianjin 300450, People’s Republic of China; 2Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, People’s Republic of China; 3Department of Radiology, The Fifth Central Hospital, Tianjin 300450, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xianghui HeDepartment of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, People’s Republic of ChinaEmail tjmughyy@163.comBackground: Gastric cancer (GC) is one of the most common and lethal malignancies worldwide. Therefore, a better understanding of the mechanism of its malignant progression and chemoresistance will be helpful for the treatment of patients with GC.Methods: The gene expression profiles downloaded from GEO database and the TargetScan Human were used to identify the key regulation model based on miRNA by bioinformatics analyses. The regulation of miRNA to target was clarified by luciferase assay, qPCR, and Western blotting. Then, the in vitro and in vivo experiments were further conducted by overexpression or knockdown of miRNA and/or target to examine the regulation effects and clarify the mechanism.Results: In the present study, miR-424-3p was identified to be differentially expressed among normal gastric, GC, and chemoresistant GC tissues. Target analysis results indicated that ABCC2, a chemoresistance-related gene, was a regulated target of miR-424-3p. The in vitro and in vivo experiment results further demonstrated that miR-424-3p relied on ABCC2-induced chemoresistance to promote GC proliferation and metastasis.Conclusion: Overall, this study revealed that miR-424-3p contributed to the malignant progression and chemoresistance of GC. Thus, miR-424-3p could be a potential target for the treatment of GC.Keywords: gastric cancer, miR-424-3p, chemoresistance, malignant progression

Tuanhe Sun, Kang Li, Kun Zhu, Rong Yan, Chengxue Dang, Dawei Yuan Department of Surgical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of ChinaCorrespondence: Dawei YuanDepartment of Surgical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, Shaanxi 710061, People’s Republic of ChinaEmail dwyuan@mail.xjtu.edu.cnBackground: Cisplatin resistance results in the failure of platinum-based chemotherapy and relapse of gastric cancer. We aimed to investigate the potential regulating role of SNHG6/miR-325-3p/GITR in reversing cisplatin resistance.Patients and Methods: A total of 137 gastric cancer patients were recruited. qRT-PCR and ELISA were used to test the expression of target genes. CCK-8 and caspase 3/7 kit were used to test the cell viability and apoptosis rate. Dual luciferase reporter gene and RNA-pull down assay were used to investigate the potential interaction between target genes.Results: SNHG6 and GITR were up regulated in gastric cancer; however, miR-325-3p was down-regulated. Besides, SNHG6, miR-325-3p and GITR expression were associated with gastric cancer prognosis. Then, we found that GITR and SNHG6 promoted proliferation and inhibited apoptosis of MKN45 and MKN45 cisplatin resistance cell line; however, miR-325-3p inhibited proliferation and promoted apoptosis of these cell lines. Furthermore, SNHG6 might bind to miR-325-3p to regulate its expression, and miR-325-3p directly interacted with the 3`UTR of GITR.Conclusion: SNHG6 binds to miR-325-3p, which directly interacted with GITR to regulate cisplatin resistance of gastric cancer.Keywords: gastric cancer, cisplatin resistance, GITR, SNHG5, miR-325-3p

Xi Yang,1 Qunxiong Zhang,1 Bugao Guan2 1Digestive Department, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, Jiangsu, People’s Republic of China; 2Department of General Surgery, People’s Hospital of Jinhu, Huaian, Jiangsu, People’s Republic of ChinaCorrespondence: Bugao GuanDepartment of General Surgery, People’s Hospital of Jinhu, 160 Shenhua Avenue, Jinhu, Huaian, Jiangsu, People’s Republic of ChinaEmail guanbugao@163.comBackground: Gastric cancer is a prevalent primary stomach tumor. Cisplatin is frequently used to treat gastric cancer. However, the resistance of cisplatin in gastric cancer often occurs, which brings a heavy burden to gastric cancer treatment.Methods: In this study, we revealed a novel underlying mechanism about cisplatin-resistant effect in gastric cancer. A Cell Counting Kit-8 (CCK-8) cell viability assay and a xenograft model were performed to evaluate the function of circRNA in the cisplatin resistance of gastric cancer.Results: Compared with control groups, we observed that circ_0110805 was highly expressed, the mRNA and protein expression levels of ENDOPDI were dramatically upregulated, and the expression of miR-299-3p was significantly downregulated in gastric cancer cells, cisplatin-resistant gastric cancer tissues or cells. Functionally, circ_0110805 knockdown improved cisplatin sensitivity, induced cell apoptosis, whereas repressed cell viability, migration and invasion in AGS/DDP and HGC-27/DDP cells, which was reversed by miR-299-3p inhibitor. Additionally, ENDOPDI overexpression hindered the effects of miR-299-3p on cisplatin sensitivity and gastric cancer progression. Circ_0110805 knockdown enhanced cisplatin sensitivity in vivo. Mechanistically, circ_0110805 acted as a sponge of miR-299-3p and its targeted ENDOPDI.Conclusion: We showed that circ_0110805 knockdown increased the sensitivity of gastric cancer to cisplatin, which also repressed gastric cancer progression by sponging miR-299-3p to downregulate ENDOPDI expression. It might provide a new insight for future studying cisplatin-resistant gastric cancer.Keywords: cisplatin, sensitivity, circ_0110805, miR-299-3p, ENDOPDI, gastric cancer

Naama Halpern,1,2 Albert Grinshpun,3 Ben Boursi,1,2 Talia Golan,1,2 Ofer Margalit,1,2 Dan Aderka,1,2 Eitan Friedman,2,4 Yael Laitman,2,3 Ayala Hubert,3 Luna Kadouri,3 Tamar Hamburger,3 Inbal Barnes-Kedar,2,5 Zohar Levi,2,6 Irit Ben-Aharon,2,7 Baruch Brenner,2,7 Yael Goldberg,2,5 Tamar Peretz,3 Einat Shacham-Shmueli1,2 1Department of Oncology, Sheba Medical Center, Tel-Hashomer, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 4The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel; 5Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; 6Division of Gastroenterology, Rabin Medical Center, Early Detection and High Risk Unit, Petach Tikva, Israel; 7Institute of Oncology, Davidoff Center, Rabin Medical Center, Petach Tikva, IsraelCorrespondence: Naama HalpernDepartment of Oncology, Sheba Medical Center, Tel-Hashomer, Rmat Gan, IsraelTel +972-3-530-2668Fax +972-3-5304958Email naama.halpern@sheba.gov.ilBackground: The prognosis of gastric cancer (GC) is poor with a median overall survival (OS) of less than 12 months in advanced-stage disease. The search for distinct genetic subgroups of GC patients and predictive biomarkers is ongoing. While BRCA1 or BRCA2 germline mutations (gBRCAm) have potential therapeutic implications in ovarian, breast and pancreatic cancers, their significance in GC patients has not been established.Patients and Methods: A retrospective multi-center data analysis of GC patients with gBRCAm was conducted, detailing the clinical characteristics and disease course in this unique subset of patients.Results: Ten GC patients with gBRCAm were identified, six of them with metastatic disease. The median OS of all ten GC patients was 47.5 (13– 192) months. Median OS for patients diagnosed with operable disease was 55.5 (13– 192) months and of the patients with metastatic disease (calculated from metastatic disease diagnosis) 32 (15– 52) months with an exceptional 1-, 2- and 3-year survival rate of 100%, 83.3% and 50%, respectively.Conclusion: These preliminary data suggest that gBRCAm in GC patients are associated with a favorable prognosis. Furthermore, gBRCAm might be a predictive biomarker to DNA-damaging agents response in GC patients, similarly to its established role in other malignancies. Further research is needed to confirm our findings.Keywords: gastric cancer, BRCA1, BRCA2, DNA-damaging agents, PARP inhibitors

Xiaofei Wang,1,* Xudong Song,1,* Guang Cheng,2,* Jingwen Zhang,3 Liru Dong,1 Jie Bai,1 Dan Luo,1 Yanjie Xiong,1 Shuang Li,1 Fang Liu,1 Yuanyuan Sun,1 Xin Wang,1 Yuyang Li,1 Yunning Huang4 1Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei, People’s Republic of China; 2Central Laboratory of Clinical Medical College, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei, People’s Republic of China; 3School of Basic Medical Science, NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, NingXia Medical University, Yinchuan 750004, NingXia, People’s Republic of China; 4Department of Gastrointestinal Surgery, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750001, Ningxia, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunning HuangDepartment of Gastrointestinal Surgery, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750001, Ningxia, People’s Republic of ChinaEmail nxhyncc@126.comObjective: Increasing evidences suggest that mitochondrial calcium uniporter (MCU), a selective channel responsible for mitochondrial Ca2+ uptake, is involved in the progression of several cancers. In this study, we aimed to observe the clinical implications and biological functions of MCU in gastric cancer.Methods: The expression of MCU in 90 pairs of gastric cancer tissues and adjacent normal tissues was examined using immunohistochemistry and correlation between MCU expression and clinical features was analyzed. After construction of stable MCU knockdown or overexpression gastric cancer cells, mitochondrial membrane potential (MMP), wound healing and transwell assays were performed to examine MMP levels, migration and invasion. Subcutaneous xenograft tumors induced by gastric cancer cells transfected with MCU siRNAs or controls were constructed. Immunofluorescence was used to detect CD34 expression. Western blot was used to detect the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), epithelial-mesenchymal transition (EMT)-related proteins.Results: MCU had a higher expression in gastric cancer tissues than normal tissues. Compared to gastric cancer tissues, its expression was significantly higher after omental metastasis. MCU expression was significantly correlated with depth of invasion (p=0.048), lymph metastasis (p=0.027), TNM stage (p=0.036) and distant metastasis (p=0.029). Patients with high MCU expression indicated a worse prognosis than those with its low expression (p=0.0098). MCU significantly increased the MMP levels of gastric cancer cells. Wound healing and transwell assay results showed that MCU promoted migration and invasion of gastric cancer cells. In vivo, MCU knockdown significantly inhibited tumor growth and angiogenesis. Both in vitro and in vivo, silencing MCU suppressed the expression of HIF-1α and VEGF as well as activity of EMT processes.Conclusion: Our findings suggested that highly expressed MCU could promote migration, invasion, angiogenesis and growth of gastric cancer, which could become a potential therapeutic marker for gastric cancer.Keywords: gastric cancer, mitochondrial calcium uniporter, invasion, angiogenesis, epithelial–mesenchymal transition

Zhe Song,1 Nan Jia,1 Wei Li,1 Xiao-Yu Zhang2 1Second Department of General Surgery, Cangzhou Central Hospital, Cangzhou, Hebei Province, Mainland China; 2Department of Thyroid and Breast III, Cangzhou Central Hospital, Cangzhou, Hebei Province, Mainland ChinaCorrespondence: Xiao-Yu ZhangDepartment of Thyroid and Breast III, Cangzhou Central Hospital, Cangzhou, Hebei Province, People’s Republic of ChinaEmail zhangxiaoyu9321@163.comBackground: Chemotherapy resistance has long been recognized as a major obstacle to cancer treatment. Therefore, elucidating the underlying mechanisms of chemotherapy resistance is conducive to developing new strategies to improve patients’ response to chemotherapy drugs.Materials and Methods: Real-time quantitative PCR (QPCR) was applied to measure the expression levels of lncRNAs. LINC01572 was down-regulated or up-regulated in GC cells transfected with either LINC01572 shRNA or overexpression vectors. In vitro and in vivo experiments were conducted to investigate the role of LINC01572 in autophagy-related chemotherapy resistance.Results: Compared with the parental cells, drug-resistant GC cells had a higher level of LINC01572. Silencing of LINC01572 inhibited chemotherapy-induced autophagy, while its knockout sensitized GC cells against chemotherapy drugs. As a competitive endogenous RNA of miR-497-5p, LINC01572 weakened the inhibitory effect of miR-497-5p on ATG14, leading to chemically induced autophagy and chemotherapy resistance in GC cells.Conclusion: A new mechanism of GC autophagy-related chemotherapy resistance regulated by lncRNA was explored in this study, providing a new perspective for understanding chemotherapy resistance.Keywords: LINC01572, miR-497-5p, gastric cancer, drug resistance

Chao Wu, Meng-hua Zeng, Gang Liao, Kun Qian, Hui Li Department of Gastrointestinal Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, People’s Republic of ChinaCorrespondence: Hui LiDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, People’s Republic of ChinaEmail lh_cool0127@163.comIntroduction: Neuropilin-1 (NRP1) binds to many ligands and co-receptors and affects cell survival and migration, which is essential for tumor progression. However, there are still largely unknowns about how NRP1 affects the epithelial–mesenchymal transition (EMT)-related malignant progression in gastric cancer.Methods: We used TCGA to analyze the expression of NRP1 in gastric cancer and its impact on patient survival. In in vitro experiments, transwell, wound healing and colony formation assays were used to evaluate the effects of NRP1 and ginsenoside Rg3 on the invasion, migration and proliferation of gastric cancer cells. In in vivo experiments, we evaluated the overexpression and knockdown of NRP1 and the effect of ginsenoside Rg3 on tumor growth.Results: We found that NRP1 is highly expressed in advanced gastric cancer and associated with poor prognosis. Knockdown of NRP1 expression can inhibit the proliferation and metastasis of gastric cancer cells. Mechanically. NRP1 interacts with fibronectin-1 (FN1) to promote the malignant progression of gastric cancer cells through ECM remodeling. In addition, we found that ginsenoside Rg3 can block the interaction of NRP1 and FN1 and inhibit the progression of gastric cancer.Conclusion: Our study suggested that the interaction of NRP1 and FN1 is crucial for the malignant progression of gastric cancer. This may provide a new perspective and potential treatment methods for the treatment of gastric cancer.Keywords: gastric cancer, neuropilin-1, fibronectin-1, epithelial–mesenchymal transition, ginsenoside Rg3

Jianzheng Wang,1,* Qingli Li,1,* Xiaojiao Cheng,1 Baiwen Zhang,1 Jiacheng Lin,1 Yao Tang,1 Fuli Li,1 Chung S Yang,2 Timothy C Wang,3 Shuiping Tu1 1Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People’s Republic of China; 2Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; 3Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA*These authors contributed equally to this workCorrespondence: Shuiping Tu; Jianzheng WangDepartment of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, People’s Republic of ChinaTel +862168385623; +16696079698Email tushuiping@yahoo.com; 46962384@qq.comBackground: Murine bone marrow-derived myofibroblasts (BMFs) have previously been shown to promote gastric cancer growth. However, whether BMFs promote gastric cancer cell metastasis remains largely unknown.Methods: Wound healing assay, Transwell invasion and migration assay and 3D organotypic co-culture systems were conducted to study the effects of BMFs on invasion and migration of gastric cancer cells and the invasion and migration ability of gastric cancer stem cell-like cells (CSC-LCs) induced by BMFs. We employed two animal model to study the role of BMFs on the in vivo metastasis of gastric cancer cells and the metastatic ability of gastric BMF-induced CSC-LCs. A human gastric cancer tissue microarray and TCGA gastric cancer database were analysed to study the relationship between the expression of IL-6 and TGF-β 1 and clinicopathological characteristics and survival in gastric cancer.Results: We found that BMFs promoted the in vitro migration and invasion of gastric cancer cells. BMFs promoted liver, lung, subcutaneous, and splenic metastases of MKN28 cells in the spleen injection liver metastasis model and co-injection of caudal vein (IOCV) mouse model. BMFs reprogrammed non-gastric cancer stem cell (CSC) to CSC-LCs and enhanced CSC-LC migration and metastasis. BMF-derived IL-6 and gastric cancer cell-secreted TGF-β 1 mediated the interaction between BMFs and gastric cancer cells, promoting tumour metastasis. BMFs enhanced the expressions of STAT3 and p-STAT3 in co-cultured gastric cancer cells. A combination of Napabucasin and Galunisertib exhibited the strongest inhibition of cell migration compared to when administered alone. Gastric cancer tissue array and TCGA database indicated that the overexpression of IL-6 and TGF-β 1 was associated with gastric cancer metastasis.Conclusion: Our results demonstrated that BMFs promote gastric cancer metastasis through the activation of the TGF-β 1 and IL-6/STAT3 signalling pathways. Targeting the inhibition of these interactions may be a potent therapeutic strategy for addressing gastric cancer metastasis.Keywords: bone marrow-derived myofibroblasts, gastric cancer, metastasis, IL-6, TGF-β 1

Ting Han,1 Zhengwu Cheng,1 Menglin Xu,2 Xiaoming Wang,3 Jian Wu,1 Xiaosan Fang3 1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People’s Republic of China; 2Department of Oncology, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People’s Republic of China; 3Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People’s Republic of ChinaCorrespondence: Xiaosan FangDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, No. 2 Zheshan West Road, Jinghu District, Wuhu 241000, Anhui Province, People’s Republic of ChinaEmail xiaosanfang2020@163.comObjective: In the present study, we aimed to explore the potential oncogenic property and the internal mechanism of yes-associated protein (YAP) in gastric cancer (GC).Materials and Methods: YAP protein levels were evaluated in human GC tissues and paired normal tissues using immunohistochemistry (IHC). The role of YAP in regulating GC cell proliferation and migration was verified by genetic manipulation in vitro. Western blot analysis was used to determine the molecular signaling to explain the mechanism of the observed YAP effects in GC.Results: Nuclear YAP protein expression was upregulated in GC tissues, and high nuclear YAP level was significantly correlated with lymph node metastasis (LNM) and tumor node metastasis (TNM) stage in patients suffered from GC. YAP knockdown inhibited GC cell proliferation, migration and epithelial–mesenchymal transition (EMT) progress in vitro, whereas YAP elevation did the opposite. YAP regulated glioma-associated oncogene-1 (Gli1) expression independent of smoothened homolog (SMO). YAP modulated protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway in GC cells.Conclusion: YAP enhanced GC cell proliferation and migration potentially via its regulation of Gli1 expression through the non-classical Hedgehog pathway, indicating suppression of YAP/Gli1 signaling axis may highlight a new entry point for combination therapy of GC.Keywords: YAP, proliferation, migration, Hedgehog pathway, gastric cancer

Jun Zhang,1 Hai-yan Piao,2 Yue Wang,1 Xiang-yu Meng,1 Dong Yang,1 Yan Zhao,1 Zhi-chao Zheng1 1Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province 110042, People’s Republic of China; 2Medical Oncology Department of Gastrointestinal Cancer, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province 110042, People’s Republic of ChinaCorrespondence: Zhi-chao Zheng Professor of Gastric Cancer DepartmentLiaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province 110042, People’s Republic of ChinaTel +86-24-31916823Fax +86-24-24315679Email zhengzhichao@cancerhosp-ln-cmu.comBackground: Gastric cancer (GC) accounts for high mortality. RNA methylation has recently gained interest as markers in specific tumors. This study aimed to uncover the function of the roles of 25 RNA methylation regulators in GC.Methods: RNA sequence and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. “STRING” and R were performed to analyze the correlation among the methylase. COX and LASSO were performed to screen for prognostic associated RNA methylation regulators. A prognostic model was established based on the expression of methylase. RT-PCR and immunohistochemistry detected the expression of methylase in GC cells and tissue. Kaplan–Meier curve and Cox analysis were applied to evaluate the effectiveness of the model.Results: The prediction model was established based on the expression of m6A RNA methylation regulators FTO (fat mass and obesity-associated) and RBM15 (RNA binding motif protein 15). Based on the model, GC patients were divided into “high risk” and “low risk” groups to compare the differences in survival. The model was re-evaluated with the clinical data of our center.Conclusion: The two-methylase combination model was an independent prognostic factor of GC.Keywords: gastric cancer, prognosis, least absolute shrinkage and selection operator, survival analysis, RNA methylation

Ya-Nan Sheng,1,* Ying-Hua Luo,2,* Shao-Bin Liu,3,* Wan-Ting Xu,3 Yu Zhang,3 Tong Zhang,3 Hui Xue,3 Wen-Bo Zuo,3 Yan-Nan Li,3 Chang-Yuan Wang,1,4 Cheng-Hao Jin1,3,4 1Department of Food Science and Engineering, College of Food Science, Heilongjiang Bayi Agricultural University, Daqing 163319, People’s Republic of China; 2Department of Grass Science, College of Animal Science & Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, People’s Republic of China; 4National Coarse Cereals Engineering Research Center, Daqing 163319, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cheng-Hao Jin; Chang-Yuan WangDepartment of Food Science and Engineering, College of Food Science, Heilongjiang Bayi Agricultural University, Daqing 163319, People’s Republic of ChinaTel +86 13351747387; +86 13836961288Email jinchenghao3727@qq.com; 2633204897@qq.comBackground: Zeaxanthin, a carotenoid commonly found in plants, has a variety of biological functions including anti-cancer activity.Purpose: This study aimed to investigate the potential mechanisms of zeaxanthin in human gastric cancer cells.Methods: CCK-8 assay was used to examine the cytotoxic effect of zeaxanthin on human gastric cancer cells. Flow cytometry was used to analyse AGS cell cycle distribution and apoptosis status. Western blot analysis was used to detect the expression levels of cycle-related proteins (Cyclin A, Cyclin B1, CDK1/2, p21, and p27), apoptosis-related proteins (Bcl-2, Bad, caspase-3, PARP), MAPK, AKT, STAT3, and NF-κB.Results: CCK-8 assay showed that zeaxanthin has obvious cytotoxic effects on 12 types of human gastric cancer cells, but no obvious toxic effect on normal cells. In addition, flow cytometry and Western blotting results showed that zeaxanthin induces apoptosis by reducing mitochondrial membrane potential; increasing Cytochrome C, Bax, cleaved-caspase-3 (cle-cas-3), and cleaved-PARP (cle-PARP) expression levels; and decreasing Bcl-2, pro-caspase-3 (pro-cas-3), and pro-PARP expression levels. Additionally, zeaxanthin caused cell cycle arrest at the G2/M phase by increasing the levels of p21 and p27 and reduced the levels of AKT, Cyclin A, Cyclin B1, and Cyclin-dependent kinase 1/2 (CDK1/2). Furthermore, after zeaxanthin treatment, the expression levels of reactive oxygen species (ROS), p-JNK, p-p38, and I-κB increased, and the expression levels of p-ERK, p-AKT, STAT3, and NF-κB decreased. However, the ROS scavenger N-acetylcysteine (NAC) and MAPK inhibitors inhibited zeaxanthin-induced apoptosis, and under the action of zeaxanthin, MAPK regulated NF-κB and STAT3, and reduced their protein expression levels.Conclusion: Zeaxanthin has a potential effect against gastric cancer cells through the ROS-mediated MAPK, AKT, NF-κB, and STAT3 signaling pathways, and it is expected to become a new drug for the treatment of human gastric cancer.Keywords: zeaxanthin, ROS, gastric cancer, apoptosis, cell cycle arrest

Xiaolin Dong,1,2,* Xirui Fan,3,* Xiaoxue He,3 Sijin Chen,3 Weikang Huang,3 Jianpeng Gao,2,3 Yun Huang,2,3 Hui Wang2,3 1Department of Neurology, The Affiliated Yan’An Hospital of Kunming Medical University, Kunming 650051, Yunnan, People’s Republic of China; 2Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan, People’s Republic of China; 3Department of Gastroenterology, The Affiliated Yan’An Hospital of Kunming Medical University, Kunming 650051, Yunnan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun Huang; Hui WangThe Affiliated Yan’An Hospital of Kunming Medical University, No. 245 Renmin East Road, Kunming 650051, Yunnan, People’s Republic of ChinaEmail 9542287@qq.com; weihool@163.comPurpose: Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide. tRNA-derived fragments (tRFs) have been identified as potential biomarkers and cancer therapeutic targets. However, the influence of tRFs on GC remains unknown. The key tRFs were researched in vitro function and mechanism.Patients and Methods: Here, differentially expressed tRFs between GC and paracancerous tissues were identified by small RNA sequencing, and the role of key tRF was evaluated in vitro.Results: Eight tRFs were significantly differentially expressed between GC tissues and adjacent tissues: five were significantly upregulated and three were downregulated in GC tissues. The results of target gene prediction and functional enrichment analysis showed that tRFs with different expressions were mainly involved in cell adhesion and connection, cell migration, wingless-type (Wnt), mitogen-activated protein kinase (MAPK), and cancer signaling pathways. Quantitative real-time polymerase chain reaction (qRT-PCR) indicated that the expression of tRF-24-V29K9UV3IU and its target genes (CCND2, FZD3, and VANGL1) in GC tissues and cells was decreased compared with those in the control group. Importantly, overexpression of tRF-24-V29K9UV3IU inhibited cell proliferation, migration and invasion, while promoted cell apoptosis of GC cells.Conclusion: This study suggests that tRF-24-V29K9UV3IU may hinder GC tumor progression by inhibiting cell proliferation, migration, invasion, while promoting cell apoptosis by regulating the Wnt signaling pathways.Keywords: gastric cancer, tRF, invasion and migration, cell apoptosis, tRF-24-V29K9UV3IU

Wenxing Li, Jiming Duan, Wenbin Shi, Liqiang Lei, Pin Lv Department of General Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030001, People’s Republic of ChinaCorrespondence: Wenxing Li Department of General SurgeryThe Second Hospital of Shanxi Medical University, No. 382 Wuyi Street, Taiyuan 030001, People’s Republic of ChinaEmail li_wenxing@sina.cnIntroduction: Long non-coding RNA (lncRNA) NCK1-AS1 could regulate multiple cancer progression. However, little is known regarding the roles and acting mechanisms of NCK-AS1 in gastric cancer (GC) progression. This work was aimed to explore the relationship between NCK1-AS1 and GC progression to illustrate the mechanisms of NCK1-AS1.Methods: NCK1-AS1 expression level in GC tissues and cells was measured with a quantitative real-time PCR method. In vitro experiments including cell counting kit-8 assay, colony formation assay, wound-healing assay, and transwell invasion assay were employed to detect biological roles of NCK1-AS1 in GC progression. In vivo experiments were performed to analyze the roles of NCK1-AS1 on GC malignant phenotype. Moreover, mechanisms behind the biological roles of NCK1-AS1 in GC were investigated using bioinformatic analysis, luciferase activity reporter assay, RNA immunoprecipitation assay, and rescue experiments.Results: NCK1-AS1 was found to have elevated expression in GC tissues and cells in comparison with normal counterparts. Loss-of-function experiments showed knockdown of NCK1-AS1 refrained GC cell proliferation, colony formation, migration, and invasion in vitro. Animal experiments showed silence of NCK1-AS1 suppresses tumor growth in vivo. Functionally, NCK1-AS1 serves as a sponge for microRNA-137 (miR-137) to upregulate nucleoporin 43 (NUP43) expression in GC. Rescue experiments proved the carcinogenic role of NCK1-AS1/miR-137/NUP43 axis in GC progression.Discussion: In conclusion, the NCK1-AS1/miR-137/NUP43 axis was identified that could contribute to GC malignancy behaviors.Keywords: gastric cancer, NCK1-AS1, miR-137, nucleoporin 43, tumor treatment

Yanhua Xu,1– 3,* Shan Kong,1– 3,* Xinyue Qin,4 Shaoqing Ju1 1Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, People’s Republic of China; 2Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, People’s Republic of China; 3School of Medicine, Nantong University, Nantong, 226019, People’s Republic of China; 4School of Public Health, Nantong University, Nantong, 226019, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaoqing Ju Department of Laboratory MedicineAffiliated Hospital of Nantong University, Nantong 226001, Jiangsu, People’s Republic of ChinaTel/Fax +86 513 85052335Email jsq814@hotmail.comPurpose: Due to the lack of specific and sensitive detection indicators, most patients with GC are already in the advanced stage at the time of diagnosis. Therefore, it is urgent to search for effective diagnostic biomarkers that can be applied in clinic.Materials and Methods: We screened out circ_0004771 through circRNA sequencing. Exonuclease digestion assay, agarose gel electrophoresis (AGE) and Sanger sequencing verified the potential of circ_0004771 being a biomarker. Additionally, we established quantitative real-time fluorescent polymerase chain reaction (qRT-PCR) to detect the expression level of circ_0004771 and evaluated the methodology. What’s more, we collected plasma samples from 120 GC patients, 40 superficial gastritis patients, 20 postoperative GC patients, 20 postoperative recurrence patients and 120 healthy donors. We constructed the receiver operating characteristic curve (ROC) to appraise its diagnostic efficacy.Results: The expression level of circ_0004771 is up-regulated in GC tissues, which is consistent with circRNA sequencing result (P=0.0001). Circ_0004771 can serve as a promising biomarker because of its stable structure and longer half-life. Plasma circ_0004771 expression is markedly richer in GC patients than that in normal people (P< 0.0001), and the area under the ROC (AUC) is 0.831 (95% CI: 0.779– 0.883). The diagnostic efficacy of circ_0004771 is higher than that of CEA (AUC=0.747, 95% CI: 0.686– 0.808) and CA199 (AUC=0.508, 95% CI: 0.433– 0.583). Higher diagnostic efficacy can be achieved by combination diagnosis for distinguishing GC patients from normal people (AUC=0.864). Besides, the expression level of circ_0004771 can distinguish GC patients from gastritis patients (AUC=0.845, 95% CI: 0.772– 0.917). The plasma circ_0004771 expression in GC patients decreased to normal after surgery (P< 0.0001). In addition, plasma circ_0004771 expression increased again in patients with postoperative recurrence.Conclusion: Plasma circ_0004771 is differentially expressed in GC patients, postoperative GC patients and patients with recurrence, suggesting that plasma circ_0004771 can be used as a novel diagnostic and dynamic monitoring biomarker in GC.Keywords: circular RNA, circ_0004771, biomarker, gastric cancer, diagnosis