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Chemotherapy is widely used in a variety of solid tumors, such as lung cancer, gastric cancer and breast cancer. The genotoxic drugs, such as cisplatin, suppress cancer progression either by inhibition cell proliferation or facilitating apoptosis. However, the chemotherapy resistance remains an urgent challenge in cancer therapy, especially in advanced stages. Several studies showed that the activation of pro-survival pathways, such as PI3K-AKT, participated in mediating chemotherapy resistance. The insights into the molecular mechanisms for underlying chemotherapy resistance are of great importance to improve cancer patient survival in advanced stages. The HOIP protein belongs to the RING family E3 ubiquitin ligases and modulates several atypical ubiquitination processes in cellular signaling. Previous studies showed that HOIP might be an important effector in modulating cancer cell death under genotoxic drugs. Here, we report that HOIP associates with PTEN and facilitates PTEN degradation in cancer cells. Depletion of HOIP causes cell cycle arrest and apoptosis, which effects could be rescued by PTEN silencing. Besides, the survival data from public available database show that HOIP expression correlates with poor survival in several types of chemotherapy-treated cancer patients. In conclusion, our study establishes a novel mechanism by which HOIP modulates PTEN stability and facilitates chemotherapy resistance in malignancies.

Description, Neutrophil-derived exosomes induce tumor cell apoptosis by delivering cytotoxic proteins and activating caspase signaling pathway., Neutrophils are the most abundant innate immune cells in human circulation; however, their derived exosomes have been rarely studied for tumor treatment. Here, we reported that exosomes from neutrophils (N-Ex) induce tumor cell apoptosis by delivering cytotoxic proteins and activating caspase signaling pathway. In addition, we decorated N-Ex with superparamagnetic iron oxide nanoparticles (SPIONs) to achieve higher tumor-targeting therapeutic effect. We further fabricated exosome-like nanovesicles from neutrophils (NNVs) at high yield. Compared with liposome-loaded doxorubicin (DOX) and natural NNVs, DOX-loaded NNVs show an improved inhibition of tumor cell proliferation. Moreover, DOX-loaded, SPION-decorated NNVs selectively accumulate at the tumor sites under an external magnetic field, effectively restraining tumor growth and extensively prolonging the survival rate in mice. Overall, a simple and effective method to engineer N-Ex and NNVs at clinical applicable scale was developed, which enables the efficient and safe drug delivery for targeted and combined tumor therapy.

Breast cancer is one of the most common malignancies worldwide, while the luminal types (ERα positive) accounts for two third of all breast cancer cases. Although ERα positive breast cancer could be effective controlled by endocrine therapy, most of the patients will develop endocrine resistance, which becomes a headache clinical issue for breast cancer field. Endocrine resistance could be caused by multiple pathway disorders, the dys-regulation of ERα signaling might be a critical factor, which makes it urgent and important to reveal the potential molecular mechanism of ERα signaling. In our current study, we identified a new deubiquitination enzyme USP1 through screening the whole DUB (Deubiquitinases) siRNA library. The expression of USP1 is elevated in human breast cancer compared with normal mammary tissues. Importantly, USP1 expression levels are specially correlated with poor survival in ERα positive patients. USP1 depletion inhibited breast cancer cell progression and ERα signaling activity. Immuno-precipitation assays indicate that USP1 associates with ERα and promotes its stability possibly via inhibiting ERα K48-linked poly-ubiquitination. In conclusion, our data implicate a non-genomic mechanism by USP1 via stabilizing ERα protein controls ERα target gene expression linked to breast cancer progression.

In recent years, a large number of circRNAs have been identified in mammalian cells with high-throughput sequencing technologies and bioinformatics. The aberrant expression of circRNAs has been reported in many human diseases including gastric cancer (GC). The number of GC-related circRNAs with validated biological functions and mechanisms of action is growing. CircRNAs are critically involved in GC cell proliferation, apoptosis, migration, and invasion. CircRNAs have been shown to function as regulators of parental gene transcription and alternative splicing and miRNA sponges. Moreover, circRNAs have been suggested to interact with proteins to regulate their expression level and activities. Several circRNAs have been identified to encode functional proteins. Due to their great abundance, high stability, tissue- and developmental-stage-specific expression patterns, and wide distribution in various body fluids and exosomes, circRNAs exhibit a great potential to be utilized as biomarkers for GC. Herein, we briefly summarize their biogenesis, properties and biological functions and discuss about the current research progress of circRNAs in GC with a focus on the potential application for GC diagnosis and therapy.

Chemoresistance is one of the causes associated with poor prognosis in gastric cancer. MicroRNAs (miRNAs) are important regulators of chemoresistance. Exosome-mediated delivery of anti-cancer molecules and drugs have emerged as a new approach for cancer therapy. We first examined the expression of miR-374a-5p in gastric cancer serum by qRT-PCR and explored the clinicopathological parameters. We then performed in vitro cell and molecular studies, including CCK-8 assay, flow cytometry, qRT-PCR, and western blot, to determine the roles of miR-374a-5p in gastric cancer chemoresistance and identified its downstream target by luciferase reporter assay. We also used in vivo animal studies to evaluate the therapeutic efficacy of miR-374a-5p inhibitor and exosome-mediated delivery of miR-374a-5p inhibitor in gastric cancer. miR-374a-5p expression level was elevated in gastric cancer serum, and its upregulation predicted poor prognosis. miR-374a-5p overexpression promoted while miR-374a-5p knockdown inhibited gastric cancer chemoresistance in vitro and in vivo. miR-374a-5p bound to Neurod1 to antagonize its effect on chemoresistance. Exosome-mediated delivery of miR-374a-5p inhibitor could increase Neurod1 expression, promote cell apoptosis, and suppress chemoresistance. miR-374a-5p had a promoting role in gastric cancer chemoresistance, which would provide a novel biomarker for gastric cancer diagnosis and prognosis and offer a potential target for gastric cancer drug resistance therapy. Keywords: miR-374a-5p, chemoresistance, gastric cancer, exosome

Background Exosomes are extracellular vesicles that mediate cellular communication in health and diseases. Neutrophils could be polarized to a pro-tumor phenotype by tumor. The function of tumor-derived exosomes in neutrophil regulation remains unclear. Methods We investigated the effects of gastric cancer cell-derived exosomes (GC-Ex) on the pro-tumor activation of neutrophils and elucidated the underlying mechanisms. Results GC-Ex prolonged neutrophil survival and induced expression of inflammatory factors in neutrophils. GC-Ex-activated neutrophils, in turn, promoted gastric cancer cell migration. GC-Ex transported high mobility group box-1 (HMGB1) that activated NF-κB pathway through interaction with TLR4, resulting in an increased autophagic response in neutrophils. Blocking HMGB1/TLR4 interaction, NF-κB pathway, and autophagy reversed GC-Ex-induced neutrophil activation. Silencing HMGB1 in gastric cancer cells confirmed HMGB1 as a key factor for GC-Ex-mediated neutrophil activation. Furthermore, HMGB1 expression was upregulated in gastric cancer tissues. Increased HMGB1 expression was associated with poor prognosis in patients with gastric cancer. Finally, gastric cancer tissue-derived exosomes acted similarly as exosomes derived from gastric cancer cell lines in neutrophil activation. Conclusion We demonstrate that gastric cancer cell-derived exosomes induce autophagy and pro-tumor activation of neutrophils via HMGB1/TLR4/NF-κB signaling, which provides new insights into mechanisms for neutrophil regulation in cancer and sheds lights on the multifaceted role of exosomes in reshaping tumor microenvironment. Electronic supplementary material The online version of this article (10.1186/s12943-018-0898-6) contains supplementary material, which is available to authorized users.

Circular RNA CDR1as has been demonstrated to participate in various cancer progressions as miRNA sponges. The exact underlying mechanisms of CDR1as on gastric cancer (GC) metastasis remain unknown. Here, we found that CDR1as knockdown facilitated GC cell migration and invasion while its overexpression inhibited the migration and invasion abilities of GC cells in vitro and in vivo. Moreover, epithelial-mesenchymal transition- (EMT-) associated proteins and MMP2 and MMP9 were downregulated by CDR1as. Bioinformatics analysis combined with dual-luciferase reporter gene assays, western blot, RT-qPCR analysis, and functional rescue experiments demonstrated that CDR1as served as a miR-876-5p sponge and upregulated the target gene GNG7 expression to suppress GC metastasis. In summary, our findings indicate that CDR1as suppresses GC metastasis through the CDR1as/miR-876-5p/GNG7 axis.

Gastric cancer is a malignant tumor characterized by high morbidity and invasion. Surgery combined with chemo-radiotherapy is the most common treatment for gastric cancer, while multiple drug resistance always results in treatment failure. Once the anti-tumor drugs enter the tumor foci, tumor cells as well as those found in the microenvironment are affected. However, the effects of drugs on tumor microenvironment (TME) are easily overlooked. In this study, we investigated the effects of the anti-cancer drug 3,3’-diindolylmethane (DIM) on gastric cancer-derived mesenchymal stem cells (GC-MSCs) and their subsequent impact on cancer progression. Surprisingly, we found that the therapeutic concentration of DIM upregulated the expression level of tumor-related factors such as CCL-2, IL-6, and IL-8 in GC-MSCs. The conditioned medium of DIM-treated GC-MSCs promoted the proliferation, invasion, and migration of gastric cancer cells in vitro and tumor growth in vivo. Mechanistically, DIM enhanced the expression of β-TrCP, an E3 ubiquitin ligase leading to IκBα degradation and NF-κB activation in GC-MSCs. The β-TrCP knockdown partially eliminated positive results caused by DIM. Our results showed that the therapeutic dosage of DIM induced cell death in cancer cells, while enhancing MSC paracrine functions in the stroma to offset the original DIM effect on cancer cells. These findings provide a new mechanism of anti-cancer drug resistance and remind us to adjust the chemotherapeutic scheme by combining the anti-cancer drug with an appropriate signaling pathway inhibitor to block the side effects of drug on targeted TME cells.

In response to tumor signals, mesenchymal stem cells (MSCs) are recruited to tumor sites and activated to promote tumor progression. Emerging evidences suggest that in addition to tumor cells, non-tumor cells in tumor microenvironment could also interact with MSCs to regulate their phenotype and function. However, the mechanism for MSCs regulation in gastric cancer has not been fully understood. In this study, we reported that tumor-educated neutrophils (TENs) induced the transformation of MSCs into cancer-associated fibroblasts (CAFs) which in turn remarkably facilitated gastric cancer growth and metastasis. Mechanistic study showed that TENs exerted their effects by secreting inflammatory factors including IL-17, IL-23 and TNF-α, which triggered the activation of AKT and p38 pathways in MSCs. Pre-treatment with neutralizing antibodies to these inflammatory factors or pathway inhibitors reversed TENs-induced transformation of MSCs to CAFs. Taken together, these data suggest that TENs promote gastric cancer progression through the regulation of MSCs/CAFs transformation.

Background Increasing evidence indicates that circular RNAs (circRNAs) are dysregulated in human cancers. The biological roles of circRNAs in gastric cancer (GC) have not been well‐characterized. Methods The GEO database was used to analyze circRNA expression profile in GC. The expression level of target circRNA in tumor tissues and adjacent non‐tumor tissues was detected by reverse transcription‐quantitative PCR. Gene transfection was used to manipulate the expression of circRNAs. The biological roles of circRNAs in cell proliferation, migration, and invasion were determined by cell counting, colony formation, transwell migration, Matrigel invasion, and mouse xenograft tumor assays. The interactions between circRNAs and miRNAs were verified by RNA immunoprecipitation and luciferase reporter assays. Results We found that circHN1 was upregulated in GC tissues and cell lines compared to adjacent non‐tumor tissues and normal gastric epithelial cells. Additionally, circHN1 silencing significantly promoted GC cell growth, colony formation, migration, and invasion, whereas circHN1 overexpression had the opposite effects. CircHN1 overexpression also suppressed gastric cancer growth in the mouse xenograft tumor model. CircHN1 was mainly localized in the cytoplasm of GC cells and could bind to AGO2. MiR‐1248 and miR‐375 were predicted to interact with circHN1 by bioinformatic analyses. MiR‐1248 and miR‐375 overexpression inhibited the activity of the circHN1 luciferase reporter. Conclusion CircHN1 is aberrantly expressed in GC and affects the proliferation and migration of gastric cancer cells by acting as miRNA sponge.

Background The stem cell factor SALL4 is reactivated in human cancers. SALL4 plays diverse roles in tumor growth, metastasis, and drug resistance, but its role in tumor metabolism has not been well characterized. Methods The glycolytic levels of gastric cancer cells were detected by glucose uptake, lactate production, lactate dehydrogenase activity, ATP level, and hexokinase activity. QRT-PCR and western blot were used to detect the changes in the expression of glycolytic genes and proteins. The downstream target genes of SALL4 were identified by microarray. The regulation of hexokinase II (HK-2) by SALL4 was analyzed by luciferase reporter assay and chromatin immunoprecipitation assay. Transwell migration assay, matrigel invasion assay, cell counting assay and colony formation assay were used to study the roles of HK-2 regulation by SALL4 in gastric cancer cells in vitro. The effects of SALL4 on glycolysis and gastric cancer progression in vivo were determined by subcutaneous xenograft and peritoneal metastasis tumor models in nude mice. Results SALL4 knockdown inhibited glucose uptake, lactate production, lactate dehydrogenase activity, ATP level and hexokinase activity in gastric cancer cells, and decreased the expression of glycolytic genes and proteins. Microarray analysis showed that SALL4 knockdown affected glycolysis-related pathway. The regulation of HK-2 gene expression by SALL4 was confirmed by luciferase reporter assay and chromatin immunoprecipitation assay. HK-2 knockdown abrogated the promotion of glycolysis by SALL4 in gastric cancer cells, indicating that HK-2 acts as a downstream effector of SALL4. Moreover, HK-2 knockdown reversed the promoting role of SALL4 in gastric cancer cell proliferation, migration and invasion, suggesting that SALL4 drives gastric cancer progression by upregulating HK-2. Conclusions SALL4 promotes gastric cancer progression through HK-2-mediated glycolysis, which reveals a new mechanism for the oncogenic roles of SALL4 in cancer.

Deregulated expression of chemokines in tumor microenvironment contributes to tumor metastasis by targeting distinct cells. Epithelial-derived neutrophil-activating peptide-78 (ENA78/CXCL5) is upregulated in many cancers and involved in tumor progression. The role and underlying mechanism of CXCL5 in gastric cancer (GC) metastasis remain unclear. In this study, we reported that the expression of CXCL5 was elevated in tumor tissues and positively associated with lymphatic metastasis and tumor differentiation. Stimulation by recombinant human CXCL5 (rhCXCL5) induced epithelial-mesenchymal transition (EMT) in GC cells through the activation of ERK pathway, which enhanced their migration and invasion abilities. The culture supernatant from tumor tissues also enhanced the migration and invasion abilities of GC cells, however, this effect was reversed by pre-treatment with CXCL5 neutralizing antibody. Further studies showed that rhCXCL5 could induce the expression of IL-6 and IL-23 in neutrophils through the activation of ERK and p38 signaling pathways, which in turn facilitated GC cell migration and invasion. The culture supernatant from tumor tissues showed similar effects on neutrophils in a CXCL5-dependent manner. Blockade of IL-6 and IL-23 with neutralizing antibodies reversed the induction of EMT and the increased migration and invasion abilities in GC cells by CXCL5-activated neutrophils. Moreover, CXCL5 activated neutrophils could promote gastric cancer metastasis in vivo. Taken together, our results indicate that CXCL5 acts on gastric cancer cells to induce EMT and mediates pro-tumor activation of neutrophils, which synergistically promotes the metastatic ability of GC cells.

Background Long non-coding RNAs (lncRNAs) have emerged as important regulators of human cancers. However, the functional roles of lncRNAs and the mechanisms responsible for their aberrant expression in gastric cancer (GC) have not been well characterized. Methods In this study, we examined the expression of lncRNA UFC1 in GC by qRT-PCR and explored its correlation with clinicopathological parameters. In vitro cell functional assays and in vivo animal studies were performed to determine the roles of UFC1 in GC progression. Results UFC1 was elevated and predicted poorer prognosis in GC. UFC1 knockdown inhibited while UFC1 overexpression promoted GC cell proliferation, migration, and invasion. UFC1 bound to miR-498 to antagonize its tumor suppressive effect on Lin28b. Suppression of Lin28b by miR-498 could be rescued by UFC1 overexpression, whereas Lin28b overexpression partially rescued UFC1 knockdown-mediated inhibition of GC cell function. Lin28b expression was increased in GC and suggested a co-expression pattern with UFC1. Conclusions UFC1 has a promoting role in GC progression, at least in part, by acting as a miR-498 sponge and derepressing Lin28b expression, which would provide a novel biomarker for GC diagnosis and prognosis and offer a potential target for GC therapy. Electronic supplementary material The online version of this article (10.1186/s13046-018-0803-6) contains supplementary material, which is available to authorized users.

Approximately 18.1×106 new cases of cancer were recorded globally in 2018, out of which 9.6 million died. It is known that people who have Inflammatory Bowel Disease (IBD) turn to be prone to increased risks of developing colorectal cancer (CRC), which has global incident and mortality rates of 10.2% and 9.2%, respectively. Over the years, conventional treatments of IBD and its associated CRC have been noted to provide scarce desired results and often with severe complications. The introduction of biological agents as a better therapeutic approach has witnessed a great deal of success in both experimental and clinical models. With regard to mesenchymal stem cell (MSC) therapy, the ability of these cells to actively proliferate, undergo plastic differentiation, trigger strong immune regulation, exhibit low immunogenicity, and express abundant trophic factors has ensured their success in regenerative medicine and immune intervention therapies. Notwithstanding, MSC-based therapy is still confronted with some challenges including the likelihood of promoting tumor growth and metastasis, and possible overestimated therapeutic potentials. We review the success story of MSC-based therapy in IBD and its associated CRC as documented in experimental models and clinical trials, examining some of the challenges encountered and possible ways forward to producing an optimum MSC therapeutic imparts.

The antitumor effect of prostaglandin D2 (PGD2) on gastric cancer (GC) has been known for decades. However, the mechanism of PGD2's control of GC growth is unclear. Cancer stem cells (CSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. Herein, we discovered that signaling between PGD2 and its receptor (PTGDR2) has the ability to restrict the self-renewal of GC cells in vitro and suppress tumor growth and metastasis in vivo. To obtain these findings, we first determined that PGD2 synthase (L-PTGDS) and PTGDR2 expression were lower in GC tissues than adjacent tissues and was associated with the patients’ prognosis. Moreover, the expression of L-PTGDS and PTGDR2 was negatively correlated with the GC-CSC markers Sall4 and Lgr5 in GC tissues. Second, L-PTGDS and PTGDR2 expression were knocked down in CSC-like cells, resulting in enhanced expression of CSC markers and self-renewal ability. Direct PGD2 stimulation and L-PTGDS overexpression produced the opposite effect. Thirdly, PGD2 inhibited tumor growth and incidence rate in a subcutaneous tumor model and suppressed liver and mesenteric metastasis in a peritoneal metastasis model. Interfering with the expression of PTGDR2 reversed these effects in vivo. Last, a mechanistic study found that PGD2 inhibited STAT3 phosphorylation and nuclear expression. Further experiments revealed that the inhibitory effect of PGD2 on the expression of CSC markers disappeared after mutations were introduced into STAT3 phosphorylation (Thr705) site. In short, this study reveals a novel function of PGD2/PTGDR2 signaling on CSC regulation and provides a new way to control the development of GC.

// Bin Zhang 1 , Aihua Gong 1 , Hui Shi 1 , Qingli Bie 1 , Zhaofeng Liang 1 , Peipei Wu 1 , Fei Mao 1 , Hui Qian 1 and Wenrong Xu 1, 2 1 Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P.R. China 2 The Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu, P.R. China Correspondence to: Wenrong Xu email: icls@ujs.edu.cn Hui Qian email: lstmmmlst@163.com Keywords: YAP, 14-3-3ζ, MDM2, hippo, gastric cancer Received: April 04, 2017 Accepted: May 09, 2017 Published: May 19, 2017 ABSTRACT Growing evidence indicates that 14-3-3ζ and yes-associated protein (YAP) substantially promote tumorigenesis and tumor development. However, the regulatory mechanism underlying these two proteins remains unknown. Herein, we report a new regulatory role of 14-3-3ζ in the phosphorylation of YAP and the feedback inhibition of 14-3-3ζ by YAP. YAP and 14-3-3ζ expression exhibited a negative correlation in gastric cancer (GC) tissues. Moreover, patients with higher YAP and lower 14-3-3ζ expression had poor prognoses. Studies have revealed that 14-3-3ζ promotes cytoplasmic retention and suppresses the transcriptional activity of YAP by inducing its phosphorylation. Furthermore, we observed that the overexpression of YAP significantly reduced the expression of 14-3-3ζ by inducing its ubiquitination. YAP, 14-3-3ζ, and mouse double minute 2 homolog (MDM2) were colocalized, and the knockdown of MDM2 by siRNA attenuated the YAP-induced decrease of 14-3-3ζ. The binding of 14-3-3ζ and MDM2 was also restrained when the expression of YAP was interfered. Our results indicated the presence of a 14-3-3ζ–YAP negative regulatory feedback loop, which has a crucial role in cell proliferation and survival and is a potential target for the clinical treatment of GC.

MicroRNAs (miRNAs) play critical roles in the growth, metastasis and therapeutic resistance of liver cancer. Accumulating evidence suggests that miR‑498 is aberrantly expressed in several human malignancies. However, the role and underlying mechanism of miR‑498 in liver cancer remain unclear. In the present study, we investigated the potential roles and clinical value of miR‑498 in liver cancer. We found that the miR‑498 expression level was significantly lower in liver cancer patient tissues than that in healthy control tissues. The expression of miR‑498 was also decreased in liver cancer cell lines compared to that noted in a normal human normal liver cell line. miR‑498 overexpression markedly inhibited liver cancer cell proliferation, migration and invasion. miR‑498 overexpression induced cell cycle arrest and apoptosis while it suppressed epithelial‑mesenchymal transition (EMT) in liver cancer cells. Bioinformatic analysis and luciferase reporter assay further identified zinc finger E‑box binding homeobox 2 (ZEB2) as a novel target of miR‑498. Furthermore, ZEB2 knockdown recapitulated the inhibitory effects of miR‑498 overexpression in liver cancer cells. ZEB2 overexpression rescued the inhibition of liver cancer cell proliferation, migration, and invasion by miR‑498, indicating that ZEB2 acts as a downstream effector of miR‑498 in liver cancer cells. Thus, we demonstrated that miR‑498 suppresses the growth and metastasis of liver cancer cells, partly at least, by directly targeting ZEB2, suggesting that miR‑498 may serve as a potential biomarker for the diagnosis and therapy of liver cancer.

Xu Zhang,1,2,* Peng Zhang,1,* Meng Shao,1 Xueyan Zang,1 Jiayin Zhang,1 Fei Mao,1 Hui Qian,1,2 Wenrong Xu1,2 1Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China; 2Zhenjiang Key Laboratory of Gastrointestinal Cancer, Jiangsu University, Zhenjiang, Jiangsu 212013, China *These authors contributed equally to this work Background: Increasing evidence suggests that SALL4 plays oncogenic roles in cancer development and progression. We have previously shown that SALL4 is highly expressed in gastric cancer, and its upregulation is associated with lymph node metastasis and poor prognosis. The role of SALL4 in gastric cancer metastasis and the underlying mechanism remain unclear.Materials and methods: The biological roles of SALL4 in gastric cancer cell mobility, migration, and invasion were investigated by wound healing, transwell migration assay, and Matrigel invasion assay. The effects of SALL4 on epithelial–mesenchymal transition (EMT) in gastric cancer cells were examined by quantitative real-time PCR and Western blot. The downstream target genes of SALL4 were identified by microarray. The regulation of TGF-β1 by SALL4 in gastric cancer cells was analyzed by luciferase reporter assay and chromatin immunoprecipitation assay.Results: SALL4 knockdown inhibited, while SALL4 overexpression promoted the motility, migration, and invasion abilities of gastric cancer cells in vitro. SALL4 knockdown also suppressed the peritoneal metastasis of gastric cancer cells in nude mice. SALL4 knockdown suppressed, while SALL4 overexpression induced the activation of TGF-β/SMAD signaling pathway and triggered EMT in gastric cancer cells. TGF-β1 was identified as a direct target gene of SALL4. The results of chromatin immunoprecipitation study and luciferase reporter assay further confirmed that SALL4 bound to the promoter of TGF-β1 gene and activated its expression. TGF-β1 knockdown reversed SALL4-mediated promotion of gastric cancer cell motility, migration, and invasion, indicating that TGF-β1 acts as a downstream effector of SALL4. Furthermore, the expression of TGF-β1 was found to be closely associated with that of SALL4 in gastric cancer tissues.Conclusion: SALL4 promotes the metastasis of gastric cancer, at least partly, by directly activating TGF-β1, suggesting that SALL4 may serve as a new target for gastric cancer therapy. Keywords: gastric cancer, SALL4, TGF-β1, EMT, metastasis

Gastric cancer tissue-derived MSC-like cells (GC-MSC) share similar characteristics to bone marrow MSC (BM-MSC); however, the phenotypical and functional differences and the molecular mechanism of transition between the two cell types remain unclear. Compared to BM-MSC, GC-MSC exhibited the classic phenotype of reactive stroma cells, a stronger gastric cancer promoting capacity and lower expression of miR-155-5p. Inhibition of miR-155-5p by transfecting miRNA inhibitor induced a phenotypical and functional transition of BM-MSC into GC-MSC-like cells, and the reverse experiment deprived GC-MSC of tumor-promoting phenotype and function. NF-kappa B p65 (NF-κB p65) and inhibitor of NF-kappa B kinase subunit epsilon (IKBKE/IKKε) were identified as targets of miR-155-5p and important for miRNA inhibitor activating NF-κB p65 in the transition. Inactivation of NF-κB by pyrrolidine dithiocarbamic acid (PDTC) significantly blocked the effect of miR-155-5p inhibitor on BM-MSC. IKBKE, NF-κB p65 and phospho-NF-κB p65 proteins were highly enriched in MSC-like cells of gastric cancer tissues, and the latter two were correlated with the pathological progression of gastric cancer. In GC-MSC, the expression of miR-155-5p was downregulated and NF-κB p65 protein was increased and activated. NF-κB inactivation by PDTC or knockdown of its downstream cytokines reversed the phenotype and function of GC-MSC. Taken together, our findings revealed that miR-155-5p downregulation induces BM-MSC to acquire a GC-MSC-like phenotype and function depending on NF-κB p65 activation, which suggests a novel mechanism underlying the cancer associated MSC remodeling in the tumor microenvironment and offers an effective target and approach for gastric cancer therapy.

As a natural health supplement, 3,3′-diindolylmethane (DIM) is proposed as a preventive and chemotherapeutic agent for cancer by inhibiting cell proliferation and inducing cell apoptosis. However, we found that in contrary to high level of DIM (30 μM), low level of DIM (1 μM and 10 μM) obviously promoted gastric cancer cell growth and migration. In addition, we found that low level of DIM increased the expression of stemness factors and enhanced the pluripotency of gastric cancer cells. Low level of DIM promoted gastric cancer progression by inducing the PORCN-dependent secretion of Wnt4 and the activation of β-catenin signaling. Wnt4 knockdown reversed the effects of low level of DIM on gastric cancer cells. The results of in vivo studies showed that gastric cancer cells treated with low level of DIM (1 μM) grew faster and expressed higher level of Wnt4 than control cells. Taken together, our findings indicate that low level of DIM activates autocrine Wnt4 signaling to enhance the progression of gastric cancer, which may suggest an adverse aspect of DIM in cancer therapy. Our findings will provide a new aspect for the safety of DIM in its clinical application.

Background Exosomes are critically involved in cancer development and progression. The exosomal contents have been suggested as ideal cancer biomarkers. In this study, we investigated the expression of exosomal proteins in the serum of gastric cancer patients and their roles in gastric cancer. Methods The proteomic profile of exosomes from the serum of gastric cancer patients was detected by using LC-MS/MS. The expression of TRIM3 in exosomes from the serum of gastric cancer patients and healthy controls was assessed by ELISA and western blot. Immunohistochemistry was used to detect TRIM3 expression in gastric cancer tissues and their matching adjacent tissues. The growth and migration abilities of gastric cancer cells with TRIM3 overexpression or knockdown in vitro were evaluated by colony formation assay and transwell migration assay. The effects of TRIM3 overexpression or knockdown on gastric cancer growth and metastasis in vivo were investigated by using subcutaneous xenograft tumor and peritoneal metastasis mouse model. The effects of TRIM3-overexpressing exosomes on gastric cancer growth and metastasis in vitro and in vivo were also evaluated. Results We found that the expression levels of TRIM3 mRNA and protein were decreased in gastric cancer tissues compared to the matched control tissues. In addition, the levels of TRIM3 protein in the serum exosomes of gastric cancer patients were lower than that in healthy controls. We demonstrated that TRIM3 overexpression reduced while TRIM3 knockdown promoted the growth and metastasis of gastric cancer in vitro and in vivo through the regulation of stem cell factors and EMT regulators. Moreover, exosomes-mediated delivery of TRIM3 protein could suppress gastric cancer growth and metastasis in vitro and in vivo. Conclusions Taken together, our findings suggest that exosomal TRIM3 may serve as a biomarker for gastric cancer diagnosis and the delivery of TRIM3 by exosomes may provide a new avenue for gastric cancer therapy. Electronic supplementary material The online version of this article (10.1186/s13046-018-0825-0) contains supplementary material, which is available to authorized users.

Macroautophagy/autophagy plays a dual role in cancer depending on the stage of tumorigenesis. Autophagy prevents tumor initiation by suppressing chronic tissue damage, inflammation, accumulation of damaged organelles and genome instability. Autophagy can also sustain tumor metabolism and provide nutrients for tumor growth and survival via nutrient recycling. Moreover, autophagy is required for benign tumors to progress to malignant tumors. Emerging evidence indicates that autophagy or mitophagy can inactivate tumor suppressors such as TP53/TRP53/p53 to promote tumor progression once carcinogenesis has been initiated.

Objectives Long noncoding RNAs (lncRNAs) play important roles in cancer development and progression. The deregulated expression of LINC00978 has been reported in human cancers. However, the expression pattern and biological roles of LINC00978 in gastric cancer (GC) remain unclear. In this study, we investigated the potential roles and clinical value of LINC00978 in gastric cancer. Materials and methods QRT-PCR was performed to investigate the expression of LINC00978 in gastric cancer cell lines, tissues and serum samples. Cell counting, colony formation, transwell migration and matrigel invasion assays were performed to determine the effects of shRNA-mediated knockdown of LINC00978 on gastric cancer cell functions. In vivo tumour growth assay was also conducted. Flow cytometry, immunohistochemistry, western blot and qRT-PCR were used for potential mechanism study. Results LINC00978 expression level was elevated in GC tumour tissues, serum samples and cell lines. The expression level of LINC00978 was significantly correlated with tumour size (P = 0.02), lymphatic metastasis (P = 0.009) and TNM stage (P = 0.009). LINC00978 knockdown inhibited the proliferation of GC cells by suppressing cell cycle progression and inducing apoptosis. LINC00978 knockdown also inhibited the migration and invasion of GC cells. In addition, LINC00978 knockdown inhibited the activation of TGF-β/SMAD signalling pathway and the process of epithelial-mesenchymal transition (EMT) in GC cells. Moreover, the in vivo tumorigenicity of LINC00978 knockdown GC cells in mice was significantly decreased. Conclusions LINC00978 promotes gastric cancer progression and may serve as a potential biomarker for GC.

MicroRNA-373 (miR-373) has been reported to be an oncogene in a number of solid human tumors. However, the role of miR‑373 in gastric cancer has not been completely elucidated and the mechanisms remain unclear. In the present study, we compared miR‑373 expression between clinical gastric cancer tissues and paired non‑tumorous tissues by reverse transcription‑quantitative polymerase chain reaction. The impact of miR‑373 on proliferation, migration and invasion in gastric cancer cells was additionally investigated. Hsa‑miR‑373 mimics were applied to mimic the function of endogenous miR‑373. A colony formation assay and flow cytometry were performed to analyze the proliferation of gastric cancer cells. Wound healing and Transwell invasion assays were employed to detect the migratory and invasive abilities of gastric cancer cells. Western blotting was used to test the expression of epithelial‑mesenchymal transition‑associated proteins. The results demonstrated that the level of miR‑373 in gastric cancer was upregulated compared with paired non‑tumorous tissues. It was confirmed that miR‑373 inhibited the migration and invasion of the gastric cancer cell lines SGC‑7901 and HGC‑27 by downregulating vimentin expression. The results of the present study demonstrated an oncogenic role of miR‑373 in the metastasis of human gastric cancer, and may provide a novel therapeutic strategy for gastric cancer.

CircRNAs are a class of RNA molecules that structurally form closed loops. CircRNAs are abundant in eukaryotic transcripts and show certain levels of tissue and cell specificity. CircRNAs have been suggested to regulate gene expression at transcriptional, post-transcriptional, and translational levels. An increasing number of studies have shown that circRNAs play important roles in the development and progression of diseases including cancer. In particular, circRNAs have shown great potential in cancer diagnosis, prognosis, and therapy. In this review, we provide an overview of the biogenesis and characteristics of circRNAs, succinctly describe their functions, and comprehensively discuss about the recent advances in the roles of circRNAs in cancer with an emphasis on their clinical values. Electronic supplementary material The online version of this article (10.1186/s13046-017-0624-z) contains supplementary material, which is available to authorized users.

Long noncoding RNAs (LncRNAs) play important roles in tumor development and progression. The expression of lncRNAs is frequently dysregulated in human cancer. DANCR (anti-differentiation noncoding RNA) is a newly identified lncRNA in human cancer, however, its functional roles and clinical value in gastric cancer (GC) remains unknown. In this study, we investigated the expression of DANCR in the tumor tissues and serum of GC patients and analyzed the correlation between DANCR expression levels and the clinicopathological characteristics. Our results showed that the expression of DANCR was higher in the tumor tissues than that in the adjacent non-cancerous tissues. The expression level of DANCR was also elevated in the serum of GC patients compared to that of healthy controls. The expression levels of DANCR were significantly associated with tumor size, TNM stage, lymphatic metastasis and invasion depth. DANCR knockdown inhibited the proliferation of GC cells by inducing cell cycle arrest and cell apoptosis. In addition, DANCR knockdown suppressed gastric cancer growth in vivo. Moreover, DANCR knockdown inhibited the migration and invasion of GC cells via the suppression of epithelial-mesenchymal transition (EMT). However, DANCR overexpression had the opposite effect. DANCR is activated by SALL4 in gastric cancer cells and exerted its oncogenic activities through the activation of β-catenin pathway. Taken together, our findings suggest that DANCR promotes the progression of gastric cancer and have the potential to serve as a novel diagnostic biomarker.

Tobacco smoke (TS) is the most important single risk factor for bladder cancer. Epithelial–mesenchymal transition (EMT) is a transdifferentiation process, involved in the initiation of TS-related cancer. Cancer stem cells (CSCs) have an essential role in the progression of many tumors including TS-related cancer. However, the molecular mechanisms of TS exposure induced urocystic EMT and acquisition of CSCs properties remains undefined. Wnt/β-catenin pathway is critical for EMT and the maintenance of CSCs. The aim of our present study was to investigate the role of Wnt/β-catenin pathway in chronic TS exposure induced urocystic EMT, stemness acquisition and the preventive effect of curcumin. Long time TS exposure induced EMT changes and the levels of CSCs’ markers were significant upregulated. Furthermore, we demonstrated that Wnt/β-catenin pathway modulated TS-triggered EMT and stemness, as evidenced by the findings that TS elevated Wnt/β-catenin activation, and that TS-mediated EMT and stemness were attenuated by Wnt/β-catenin inhibition. Treatment of curcumin reversed TS-elicited activation of Wnt/β-catenin, EMT and CSCs properties. Collectively, these data indicated the regulatory role of Wnt/β-catenin in TS-triggered urocystic EMT, acquisition of CSCs properties and the chemopreventive effect of curcumin.

Cancer-associated mesenchymal stem cells (MSCs) are critically involved in tumor development and progression. However, the mechanisms of action for MSCs in cancer remain largely unknown. Herein, we reported that the expression of Yes-associated protein 1 (YAP) was higher in gastric cancer derived mesenchymal stem cells (GC‑MSCs) than that in bone marrow derived MSCs (BM‑MSCs). YAP knockdown not only inhibited the growth, migration and invasion, and stemness of GC‑MSCs, but also suppressed their promoting effect on gastric cancer growth in vitro and in vivo. In addition, the interference of YAP expression in GC‑MSCs also attenuated the promoting role of gastric cancer cells in endothelial cell tube formation and migration. Mechanistically, YAP knockdown reduced the activation of β-catenin and its target genes in gastric cancer cells by GC‑MSCs. Taken together, these findings suggest that YAP activation in GC‑MSCs plays an important role in promoting gastric cancer progression, which may represent a potential target for gastric cancer therapy.

Emerging evidence has revealed that neutrophils have phenotypic and functional plasticity. Neutrophils could be polarized towards a pro-tumor phenotype by tumor-derived factors. In the present study, we investigated the role of the interaction with neutrophils on the functions of gastric cancer cells in vitro. Human promyelocytic leukemia HL-60 cells were induced to differentiate into neutrophil-like cells (HL-60N) using dimethyl sulfoxide (DMSO). Human gastric cancer cells were co-cultured with HL-60N cells or treated with the conditioned medium (CM) of cancer-activated HL-60N cells. The migration and invasion of gastric cancer cells were significantly enhanced while their proliferation was minimally altered. The expression of pro-inflammatory factors including IL-6, IL-8, IL-1β, and TNFα was significantly increased in cancer-activated HL-60N cells, which induced the activation of the ERK pathway and epithelial-mesenchymal transition (EMT) in gastric cancer cells. Blocking the ERK pathway activation reversed the promoting effects of cancer-activated HL-60N cells on gastric cancer cell migration and invasion. In addition, mouse gastric cancer cell derived CM could also increase the expression of pro-inflammatory factors in mouse bone marrow neutrophils, which in turn enhanced the migration and invasion of mouse gastric cancer cells. Collectively, our findings revealed that the interaction with neutrophils promoted gastric cancer cell migration and invasion through the activation of the ERK pathway and the induction of EMT, indicating that neutrophils may play an important role in gastric cancer metastasis. Therefore, targeting neutrophil-cancer cell interaction may provide a new strategy for the treatment of gastric cancer.

Acute kidney injury (AKI) is a common and serious medical condition associated with poor health outcomes. Autophagy is a conserved multistep pathway that serves a major role in many biological processes and diseases. Recent studies have demonstrated that autophagy is induced in proximal tubular cells during AKI. Autophagy serves a pro‑survival or pro‑death role under certain conditions. Furthermore, mesenchymal stem cells (MSCs) have therapeutic potential in the repair of renal injury. This review summarizes the recent progress on the role of autophagy in AKI and MSCs‑based therapy for AKI. Further research is expected to prevent and treat acute kidney injury.

Metastatic melanoma is the most aggressive form of skin cancer and is refractory to therapy. MicroRNAs have been recently discovered as novel molecules that provide therapeutic benefits against melanoma. This work aims to examine the effects of miR-26a and let-7a on the growth and invasiveness of malignant melanoma in vitro and in vivo. In addition, we elucidate the mechanism of action by identifying the target gene of miR-26a. Both miR-26a and let-7a inhibited proliferation and invasiveness and halted the cell cycle at the G1/G0 phase in SKMEL-28 and WM1552C malignant melanoma cell lines. Moreover, miR-26a potently induced apoptosis and downregulated the expressions of microphthalmia-associated transcription factor (MITF) and MAP4K3 in both cell lines. The luciferase reporter assay demonstrated that miR-26a suppresses MITF expression by binding the 3′-UTR, suggesting that MITF is a bona fide target of miR-26a. SiRNA knockdown of the MITF gene confirmed that miR-26a reduced cell viability and induced apoptosis by regulating MITF. Using a murine model, we also found miR-26a significantly retarded the growth of melanoma tumors in vivo. In conclusion, miR-26a and let-7a suppressed the growth and invasiveness of melanoma cells, suggesting that miR-26a and let-7a may represent novel therapies for malignant melanoma.

Long noncoding RNAs (lncRNAs) are emerging as new players in various diseases including cancer. LncRNAs have been shown to play multifaceted roles in the development, progression, and metastasis of cancer. In this review, we highlight the lncRNAs that are critically involved in the pathogenesis of digestive system cancers (DSCs). We summarize the roles of the lncRNAs in DSCs and the underlying mechanisms responsible for their functions. The DSC-associated lncRNAs interact with a wide spectrum of molecules to regulate gene expression at transcriptional, post-transcriptional, and translational levels. We also provide new insights into the clinical significance of these lncRNAs, which are found to be closely associated with the aggressiveness of DSCs and could predict the prognosis of DSC patients. Moreover, lncRNAs have been suggested as promising therapeutic targets in DSCs. Therefore, better understanding of the functional roles of lncRNAs will provide new biomarkers for DSC diagnosis, prognosis, and therapy.

Exosomes are nano-sized membrane vesicles secreted by both normal and cancer cells. Emerging evidence indicates that cancer cells derived exosomes contribute to cancer progression through the modulation of tumor microenvironment. However, the effects of exosomes derived from gastric cancer cells on macrophages are not well understood. In this study, we investigated the biological role of gastric cancer cells derived exosomes in the activation of macrophages. We demonstrated that gastric cancer cells derived exosomes activated macrophages to express increased levels of proinflammatory factors, which in turn promoted tumor cell proliferation and migration. In addition, gastric cancer cells derived exosomes remarkably upregulated the phosphorylation of NF-κB in macrophages. Inhibiting the activation of NF-κB reversed the upregulation of proinflammatory factors in macrophages and blocked their promoting effects on gastric cancer cells. Moreover, we found that gastric cancer cells derived exosomes could also activate macrophages from human peripheral blood monocytes through the activation of NF-κB. In conclusion, our results suggest that gastric cancer cells derived exosomes stimulate the activation of NF-κB pathway in macrophages to promote cancer progression, which provides a potential therapeutic approach for gastric cancer by interfering with the interaction between exosomes and macrophages in tumor microenvironment.

Exosomes have emerged as a novel mode of intercellular communication. Exosomes can shuttle bioactive molecules including proteins, DNA, mRNA, as well as non-coding RNAs from one cell to another, leading to the exchange of genetic information and reprogramming of the recipient cells. Increasing evidence suggests that tumor cells release excessive amount of exosomes, which may influence tumor initiation, growth, progression, metastasis, and drug resistance. In addition, exosomes transfer message from tumor cells to immune cells and stromal cells, contributing to the escape from immune surveillance and the formation of tumor niche. In this review, we highlight the recent advances in the biology of exosomes as cancer communicasomes. We review the multifaceted roles of exosomes, the small secreted particles, in communicating with other cells within tumor microenvironment. Given that exosomes are cell type specific, stable, and accessible from body fluids, exosomes may provide promising biomarkers for cancer diagnosis and represent new targets for cancer therapy.

Mesenchymal stem cells (MSCs) play an important role in chemoresistance. Exosomes have been reported to modify cellular phenotype and function by mediating cell-cell communication. In this study, we aimed to investigate whether exosomes derived from MSCs (MSC-exosomes) are involved in mediating the resistance to chemotherapy in gastric cancer and to explore the underlying molecular mechanism. We found that MSC-exosomes significantly induced the resistance of gastric cancer cells to 5-fluorouracil both in vivo and ex vivo. MSC-exosomes antagonized 5-fluorouracil-induced apoptosis and enhanced the expression of multi-drug resistance associated proteins, including MDR, MRP and LRP. Mechanistically, MSC-exosomes triggered the activation of calcium/calmodulin-dependent protein kinases (CaM-Ks) and Raf/MEK/ERK kinase cascade in gastric cancer cells. Blocking the CaM-Ks/Raf/MEK/ERK pathway inhibited the promoting role of MSC-exosomes in chemoresistance. Collectively, MSC-exosomes could induce drug resistance in gastric cancer cells by activating CaM-Ks/Raf/MEK/ERK pathway. Our findings suggest that MSC-exosomes have profound effects on modifying gastric cancer cells in the development of drug resistance. Targeting the interaction between MSC-exosomes and cancer cells may help improve the efficacy of chemotherapy in gastric cancer.

Neutrophils are predominant immune cells that protect the host from microbial infection. The roles of neutrophils in tumor have long been ignored due to their short life span and terminal differentiation phenotype. In recent years, emerging evidence indicates that neutrophils have phenotypic and functional plasticity. Neutrophils eliminate malignant cells by releasing the antimicrobial and cytotoxic contents in their granules or secreting immune mediators to recruit and activate other antitumor effector cells. On the contrary, tumor derived factors can convert neutrophils into a pro-tumor phenotype. Neutrophils have been shown to facilitate tumorigenesis, promote tumor growth and metastasis, stimulate tumor angiogenesis, and mediate immunosuppression. The number of neutrophils in blood and tumor tissues of cancer patients is associated with disease progression and patient outcome. In this review, we summarize the recent progress of neutrophils in the pathogenesis of cancer with an emphasis on neutrophil polarization. Better understanding of the mechanisms that regulate the dichotomy of neutrophils will not only shed light on their roles in cancer but also provide new approaches for cancer diagnosis and treatment.

The stem cell factor SALL4 (Sal-like protein 4) plays important roles in the development and progression of cancer. SALL4 is critically involved in tumour growth, metastasis and therapy resistance. However, the underlying mechanisms responsible for the oncogenic roles of SALL4 have not been well characterized. In this study, we demonstrated that SALL4 knockdown by short hairpin RNA greatly inhibited the proliferation, migration and invasion of gastric cancer cells. We further confirmed the inhibitory effects of SALL4 knockdown on gastric cancer cells by using a tetracycline-inducible system. Mechanistically, SALL4 knockdown downregulated the expression of CD44. The results of luciferase assay and chromatin immunoprecipitation study showed that SALL4 bound to CD44 promoter region and transcriptionally activated CD44. The results of rescue study revealed that CD44 overexpression antagonized SALL4 knockdown-mediated inhibition of gastric cancer cell proliferation, migration, and invasion in vitro and gastric cancer growth in vivo. Collectively, our findings indicate that SALL4 promotes gastric cancer progression through directly activating CD44 expression, which suggests a novel mechanism for the oncogenic roles of SALL4 in gastric cancer and represents a new target for gastric cancer therapy.

Background: MicroRNAs (miRNAs) are involved in gastric cancer development and progression. However, the expression and role of miRNAs in gastric cancer stromal cells are still unclear. Methods: The miRNAs differentially expressed in gastric cancer tissue-derived mesenchymal stem cells (GC-MSCs) relative to adjacent non-cancerous tissue-derived MSCs (GCN-MSCs) and in cancer tissues relative to adjacent non-cancerous tissues were screened using miRNA microarray and validated by quantitative RT–PCR. The impact of GC-MSCs on HGC-27 cells was observed in vitro using colony formation and transwell assays, and these cells were subcutaneously co-injected into mice to assess tumour growth in vivo. Exogenous downregulation of miR-221 expression in cells was achieved using an miRNA inhibitor. Results: miR-214, miR-221 and miR-222 were found to be commonly upregulated in GC-MSCs and cancer tissues. Their levels were tightly associated with lymph node metastasis, venous invasion and the TNM stage. Gastric cancer tissue-derived mesenchymal stem cells significantly promoted HGC-27 growth and migration and increased the expression of miR-221 via paracrine secretion, and the targeted inhibition of miR-221 in GC-MSCs could block its tumour-supporting role. GC-MSC-derived exosomes were found to deliver miR-221 to HGC-27 cells and promoted their proliferation and migration. Conclusions: Gastric cancer tissue-derived mesenchymal stem cells favour gastric cancer progression by transferring exosomal miRNAs to gastric cancer cells, thus providing a novel mechanism for the role of GC-MSCs and new biomarkers for gastric cancer.

SALL4, a zinc-finger transcriptional factor for embryonic stem cell self-renewal and pluripotency, has been suggested to be involved in tumorigenesis. The role of SALL4 in human gastric cancer, however, remains largely unknown. In this study, we demonstrated that SALL4 was aberrantly expressed at both mRNA and protein levels in human gastric cancer tissues, and SALL4 level was highly correlated with lymph node metastasis. Enforced expression of SALL4 enhanced the proliferation and migration of human gastric cancer cells, whereas knockdown of SALL4 by siRNA led to the opposite effects. In addition, SALL4 overexpression promoted the growth and metastasis of gastric xenograft tumor in vivo. SALL4 overexpression induced epithelial-mesenchymal transition (EMT) in gastric cancer cells, with increased expression of Twist1, N-cadherin and decreased expression of E-cadherin. Moreover, SALL4 promoted the acquirement of stemness in gastric cancer cells through the induction of Bmi-1 and Lin28B. Taken together, our findings indicate that SALL4 has oncogenic roles in gastric cancer through the modulation of EMT and cell stemness, suggesting SALL4 as a novel target for human gastric cancer diagnosis and therapy.

Circulating miR-17-5p and miR-20a (miR-17-5p/20a) have been demonstrated to be elevated in the plasma of gastric cancer patients. However, the clinical significance of the circulating levels of these microRNAs (miRNAs), the predictive power for prognosis and application for monitoring of chemotherapeutic effects remain unclear. To this end, we measured plasma miR-17-5p/20a levels in unpaired pre-operative (n=65), post-operative (n=16) and relapse (n=6) gastric cancer patient groups. The 3-year overall survival rate for the unpaired pre-operative patients was recorded. The circulating levels of miR-17-5p/20a were also tested in paired pre-operative and post-operative plasma from 14 gastric cancer patients. We found that the concentrations of miR-17-5p/20a were significantly associated with the differentiation status and TNM stages of gastric cancer. The miRNA levels in the different groups reflected pathological tumor progression. Kaplan-Meier curve analysis revealed that high expression levels of miR-17-5p/20a were significantly correlated with poor overall survival. Cox regression analysis demonstrated that the level of plasma miR-20a was an independent risk predictor for prognosis. An in vivo mouse tumor model was established and antagomirs against miR-17-5p/20a were applied as chemotherapeutics to perform tumor treatment. An assay of serum miR-17-5p/20a levels showed that the levels of serum miRNAs were notably reduced in post-treated mice with tumor volume regression. Taken together, the levels of circulating miR-17-5p/20a may be a promising non-invasive molecular marker for pathological progression, prediction of prognosis and monitoring of chemotherapeutic effects for gastric cancer.

Cell-free nucleic acids in plasma have been reported to be a novel tumor marker. However, their exact significance in gastric cancer is unclear. In the present study, we focused on circulating CXCR4 and Bmi-1 mRNA in plasma and evaluated their diagnostic values for patients with gastric cancer. CXCR4 and Bmi-1 mRNA levels, as well as levels of CEA and CA19-9 proteins, were determined in the plasma of 89 gastric cancer patients. The levels of these markers were significantly higher in cancer patients than in healthy subjects; however, there was a decrease in their expression after surgery. The sensitivity of detection for the combination of circulating CXCR4 and Bmi-1 mRNA was higher than the sensitivities of detection for CEA and CA19-9. In patients expressing both genes, CXCR4 and Bmi-1 mRNA levels were strongly correlated. Expression of the two circulating genes was also strongly correlated with the CEA level, and was significantly associated with the age of the patient, histological type, clinical stage, extent of cell differentiation and gastric cancer metastasis. Our results indicate that the combined expression of circulating CXCR4 and Bmi-1 mRNA represents a novel tumor marker, superior to traditional markers such as CEA and CA19-9, for the diagnosis and monitoring of gastric cancer.

Accumulating evidence indicate that macrophages activate mesenchymal stem cells (MSCs) to acquire pro-inflammatory phenotype. However, the role of MSCs activated by macrophages in gastric cancer remains largely unknown. In this study, we found that MSCs were activated by macrophages to produce increased levels of inflammatory cytokines. Cell colony formation and transwell migration assays revealed that supernatants from the activated MSCs could promote both gastric epithelial cell and gastric cancer cell proliferation and migration. In addition, the expression of epithelial-mesenchymal transition (EMT), angiogenesis, and stemness-related genes was increased in activated MSCs. The phosphorylated forms of NF-κB, ERK and STAT3 in gastric cells were increased by active MSCs. Inhibition of NF-κB activation by PDTC blocked the effect of activated MSCs on gastric cancer cells. Co-injection of activated MSCs with gastric cancer cells could accelerate gastric cancer growth. Moreover, human peripheral blood monocytes derived macrophages also activated MSCs to prompt gastric cancer cell proliferation and migration. Taken together, our findings suggest that MSCs activated by macrophage acquire pro-inflammatory phenotype and prompt gastric cancer growth in an NF-κB-dependent manner, which provides new evidence for the modulation of MSCs by tumor microenvironment and further insight to the role of stromal cells in gastric carcinogenesis and cancer progression.

Background Mesenchymal stem cells (MSCs) promote tumor growth by differentiating into carcinoma-associated fibroblasts (CAFs) and composing the tumor microenvironment. However, the mechanisms responsible for the transition of MSCs to CAFs are not well understood. Exosomes regulate cellular activities by mediating cell-cell communication. In this study, we aimed to investigate whether cancer cell-derived exosomes were involved in regulating the differentiation of human umbilical cord-derived MSCs (hucMSCs) to CAFs. Methodology/Principal Findings We first showed that gastric cancer cell-derived exosomes induced the expression of CAF markers in hucMSCs. We then demonstrated that gastric cancer cell-derived exosomes stimulated the phosphorylation of Smad-2 in hucMSCs. We further confirmed that TGF-β receptor 1 kinase inhibitor attenuated Smad-2 phosphorylation and CAF marker expression in hucMSCs after exposure to gastric cancer cell-derived exosomes. Conclusion/Significance Our results suggest that gastric cancer cells triggered the differentiation of hucMSCs to CAFs by exosomes-mediated TGF-β transfer and TGF-β/Smad pathway activation, which may represent a novel mechanism for MSCs to CAFs transition in cancer.