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Background: Ovarian cancer is one of the most common malignant tumors in female reproductive system. The expression of CD147 and human epididymis protein 4 (HE4) are both upregulated and associated with malignant progression in ovarian cancer. However, the important role of interaction between CD147 and HE4 in the invasion and metastasis of ovarian cancer remains unclear. Methods: The co-expression and co-localization of CD147 and HE4 in cells and tissues of ovarian cancer were detected by co-immunoprecipitation, immunohistochemistry and immunocytochemistry, double-labeling immunofluorescence method. The interaction between CD147 and annexin A2 (ANXA2) was also investigated. Furthermore, we detect the regulatory relationship between CD147 and HE4 by Western blot. Transwell assay and scratch test were conducted to explore the effect of CD147-HE4 interaction on migration and invasion of ovarian cancer. Results: The protein CD147 and HE4 were co-immunoprecipitated and co-located in the cytoplasm and membrane of ovarian cancer tissues and cells. Both of two proteins were highly expressed and positively associated with advanced FIGO stages, poor differentiation degree and poor prognosis of ovarian cancer, and HE4 was confirmed as an independent risk factor for CD147 in ovarian cancer tissues. What's more, AXNA2 was also identified as a CD147 interacting protein in ovarian cancer. It is further confirmed that interaction between CD147 and HE4 can affect the invasion and metastasis of ovarian cancer. Conclusion: This study demonstrated that HE4 and ANXA2 were both CD147 interacting proteins, the expression of CD147 and HE4 can affect each other, and HE4 could promote the invasion and metastasis of ovarian cancer by regulating the expression of CD147, which may provide novel thought for early diagnosis and therapeutic target of ovarian cancer.

Bone sarcomas are rare cancers accompanied by metastatic disease, mainly including osteosarcoma, Ewing sarcoma and chondrosarcoma. Extracellular vesicles (EVs) are membrane vesicles released by cells in the extracellular matrix, which carry important signal molecules, can stably and widely present in various body fluids, such as plasma, saliva and scalp fluid, spinal cord, breast milk, and urine liquid. EVs can transport almost all types of biologically active molecules (DNA, mRNA, microRNA (miRNA), proteins, metabolites, and even pharmacological compounds). In this review, we summarized the basic biological characteristics of EVs and focused on their application in bone sarcomas. EVs can be use as biomarker vehicles for diagnosis and prognosis in bone sarcomas. The role of EVs in bone sarcoma has been analyzed point-by-point. In the microenvironment of bone sarcoma, bone sarcoma cells, mesenchymal stem cells, immune cells, fibroblasts, osteoclasts, osteoblasts, and endothelial cells coexist and interact with each other. EVs play an important role in the communication between cells. Based on multiple functions in bone sarcoma, this review provides new ideas for the discovery of new therapeutic targets and new diagnostic analysis., Highlights New role of EVs in cell–cell communication in bone sarcoma. New clinical practicality and future application prospects of EVs. EVs can be use as biomarker vehicles for diagnosis and prognosis in bone sarcomas. Bone sarcomas cells derived EVs may influence angiogenesis, osteoclastogenesis, immunomodulation, drug resistance, invasion, and migration processes.

In this study, we investigated the effects of calycosin on breast cancer cell progression and their underlying mechanisms. Calycosin dose- and time-dependently inhibited proliferation, migration, and invasion by T47D and MCF-7 breast cancer cells by downregulating basic leucine zipper ATF-like transcription factor (BATF) expression. Moreover, BATF promoted breast cancer cell migration and invasiveness by increasing TGFβ1 mRNA and protein levels. Bioinformatics analysis, dual luciferase reporter assays, and chromatin immunoprecipitation assays confirmed the presence of BATF-binding sites in the promoter sequence of TGFβ1 gene. Calycosin treatment inhibited epithelial-mesenchymal transition (EMT) of breast cancer cells by significantly increasing E-cadherin levels and decreasing N-cadherin, Vimentin, CD147, MMP-2, and MMP-9 levels through downregulation of BATF and TGFβ1. TGFβ1 knockdown reduced the migration and invasiveness of BATF-overexpressing breast cancer cells, whereas incubation with TGFβ1 enhanced the migration and invasiveness of calycosin-treated breast cancer cells. Our findings demonstrated that calycosin inhibited EMT and progression of breast cancer cells by suppressing BATF/TGFβ1 signaling. This suggests calycosin would be a promising therapeutic option for breast cancer patients.

Recent reports showed that haematological and neurological expressed 1‐like (HN1L) gene participated in tumorigenesis and tumour invasion. However, the expression and role of HN1L in breast cancer remain to be investigated. Here, bioinformatics, western blot and immunohistochemistry were used to detect the expression of HN1L in breast cancer. Wound healing, transwell assay, immunofluorescence assay and mass spectrum were used to explore the role and mechanism of HN1L on the migration and invasion of breast cancer, which was confirmed in vivo using a nude mice model. Results showed that HN1L was significantly over‐expressed in breast cancer tissues, which was positively correlated with M metastasis of breast cancer patients. Silencing HN1L significantly inhibited the invasion and metastasis of breast cancer cells in vitro and lung metastasis in nude mice metastasis model of breast cancer. Mechanistically, HN1L interacted with HSPA9 and affected the expression of HMGB1, playing a key role in promoting the invasion and metastasis of breast cancer cell. These results suggested that HN1L was an appealing drug target for breast cancer.

Summary MicroRNAs (miRNAs) are a family of small non-coding (18–22 nucleotide) RNA molecules. These molecules regulate gene expression by either inhibiting mRNA translation or by degrading mRNA. A single miRNA can control the expression of target genes, and the expression of a target gene can be regulated by multiple miRNAs. They are key regulators of various biological and pathological processes. These include cell proliferation, development and tumorigenesis. Novel studies have discovered definite signature miRNAs in the initiation and progression of cancers. Interestingly, miRNAs have also been found in fragile genomic sites that are associated with increased cancer risk. These micro RNAs regulate the expression of several genes that play a crucial role in the transition of normal oral mucosa through dysplasia to malignancy. The aim of this review is to recapitulate the current understanding of the many miRNAs that have been identified, the genes that they target and the role that they play in the carcinogenic pathway. The review also highlights the prospective role of miRNAs in the diagnosis, prognosis and treatment of oral cancers.

Background microRNAs (miRNAs) have been verified as molecular targets for regulating tumor proliferation, invasion, and metastasis in tumor progression. However, the relationship between miRNAs and cellular energy metabolism in breast cancer still needs to be clarified. This study aimed to investigate the role of miR‐429 in breast cancer progression. Methods Bioinformatic analyses were employed to detect the relationship between miR‐429 and cancer‐related signaling pathways. We used a Kaplan‐Meier curve to analyze survival rate in patients with high or low expression of miR‐429. We used real‐time quantitative PCR (RT‐qPCR) to detect the expression of miR‐429 in different cell lines. Sh‐con, over‐miR‐429, miR‐429 inhibitor, and sh‐inhibitor control were transfected. Colony formation and EDU assay were used to detect the proliferation of transfected cells. Wound healing and transwell assays were performed to detect the mobility and invasion ability of transfected cells. Western blot assay was used to detect relative protein expression in transfected cells and different tissues. Bioinformatic analyses were conducted to detect the target proteins expression in different breast cancer databases. Dual luciferase reporter assay was used to confirm the binding site between miR‐429 and fibronectin 1 (FN1). Results The results of our study indicate that MiR‐429 and its target genes are associated with cancer‐related signaling pathways and that higher miR‐429 expression corresponds with a better prognosis. When miR‐429 was overexpressed, the proliferation, invasion of MDA‐MB‐231 were inhibited. MiR‐429 was able to suppress the Wnt/β‐catenin signaling pathway, and FN1 overexpression could rescue the influence of over‐miR‐429. Conclusions The results of our study suggest that miR‐429 suppresses the proliferation and invasion of breast cancer via inhibiting the Wnt/β‐catenin signaling pathway., We report that increasing lines of evidence indicate the role of miRNAs in gene regulation in relation to tumor development. The aim of this study was to elucidate the undefined function and mechanism of miR‐429 in the proliferation, metastasis, and invasion in breast cancer. Overexpression of miR‐429 contributed to a notable impairment of proliferation, invasion, and epithelial‐to‐mesenchymal transition (EMT) in vitro. miR‐429 suppressed proliferation and invasion of breast cancer via inhibiting the Wnt/β‐catenin signaling pathway.

The phenomenon of enhanced invasion and metastasis of residual tumor cells has been observed in an increasing number of patients receiving chemoradiotherapy recently, and tumor metastasis will undoubtedly limit patient prognosis. However, the key mechanism by which chemoradiotherapy affects the invasion and metastasis of tumor cells remains unclear. Studies have shown that chemoradiotherapy may directly act on tumor cells and alter the tumor microenvironment, or induce cell apoptosis and autophagy to promote tumor cell survival and metastasis. In this review, we summarize the potential mechanisms by which chemoradiotherapy may affect the biological behavior of tumor cells and open up new avenues for reducing tumor recurrence and metastasis after treatment. These insights will improve the efficacy of chemoradiotherapy.

Invasion and metastasis correspond to the foremost cause of cancer-related death, and the molecular networks behind these two processes are extremely complex and dependent on the intra-and extracellular conditions along with the prime of the premetastatic niche. Currently, several studies suggest an association between the levels of HOX genes expression and cancer cell invasion and metastasis, which favour the formation of novel tumour masses. The deregulation of HOX genes by HMGA2/TET1 signalling and the regulatory effect of noncoding RNAs generated by the HOX loci can also promote invasion and metastasis, interfering with the expression of HOX genes or other genes relevant to these processes. In this review, we present five molecular mechanisms of HOX deregulation by which the HOX clusters products may affect invasion and metastatic processes in solid tumours. The work was financed by FEDER (Fundo Europeu de Desenvolvimento Regional) funds through the COMPETE 2020 Operational Programme for Competitiveness and Internationalisa-tion (POCI), Portugal 2020, and by Portuguese funds through FCT (Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior) in the framework of the project POCI-01-0145-FEDER-030562 (PTDC/BTM-TEC/30562/2017). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Background: Cancer cells undergoing invasion and metastasis possess a phenotype with attenuated glycolysis, but enhanced fatty acid oxidation (FAO). Calcium (Ca2+)-mediated signaling pathways are implicated in tumor metastasis and metabolism regulation. Stromal-interaction molecule 1 (STIM1) triggered store-operated Ca2+ entry (SOCE) is the major route of Ca2+ influx for non-excitable cells including hepatocellular carcinoma (HCC) cells. However, whether and how STIM1 regulates the invasion and metastasis of HCC via metabolic reprogramming is unclear. Methods: The expressions of STIM1 and Snail1 in the HCC tissues and cells were measured by immunohistochemistry, Western-blotting and quantitative PCR. STIM1 knockout-HCC cells were generated by CRISPR-Cas9, and gene-overexpression was mediated via lentivirus transfection. Besides, the invasive and metastatic activities of HCC cells were assessed by transwell assay, anoikis rate in vitro and lung metastasis in vivo. Seahorse energy analysis and micro-array were used to evaluate the glucose and lipid metabolism. Results: STIM1 was down-regulated in metastatic HCC cells rather than in proliferating HCC cells, and low STIM1 levels were associated with poor outcome of HCC patients. During tumor growth, STIM1 stabilized Snail1 protein by activating the CaMKII/AKT/GSK-3β pathway. Subsequently, the upregulated Snail1 suppressed STIM1/SOCE during metastasis. STIM1 restoration significantly diminished anoikis-resistance and metastasis induced by Snail1. Mechanistically, the downregulated STIM1 shifted the anabolic/catabolic balance, i.e., from aerobic glycolysis towards AMPK-activated fatty acid oxidation (FAO), which contributed to Snail1-driven metastasis and anoikis-resistance. Conclusions: Our data provide the molecular basis that STIM1 orchestrates invasion and metastasis via reprogramming HCC metabolism.

In recent years, circular RNAs (circRNAs) have been revealed to have important roles in carcinogenesis. Metastasis is the leading cause of lung adenocarcinoma (LUAC) death. However, the contributions of circRNA to the metastasis of LUAC remain largely unknown. Based on circBase data and our biobank tissues, we identified circCRIM1 (a circRNA derived from exons 2, 3 and 4 of the CRIM1 gene, hsa_circ_0002346) as having a significantly decreased expression in LUAC samples compared with matched normal control samples. Both in vivo and in vitro experiments revealed that circCRIM1 suppresses the invasion and metastasis of LUAC. In vitro precipitation of circRNAs, luciferase reporter assay, and biotin‐coupled microRNA capture were carried out to investigate the Ago2‐dependent interaction of circCRIM1 and microRNA (miR)‐93/miR‐182. Mechanistically, we found that circCRIM1 could promote the expression of leukemia inhibitory factor receptor, a well‐known tumor suppressor, by sponging miR‐93 and miR‐182. In the clinical and pathological analyses, the downregulation of circCRIM1 in LUAC was significantly correlated with lymphatic metastasis and TNM stage, which served as an independent risk factor for the overall survival of patients with LUAC. Our study showed that circCRIM1 inhibits the invasion and metastasis of lung adenocarcinoma cancer cells, which makes it a potential therapeutic target.

Hanahan and Weinberg introduced the “hallmarks of cancer” and typified essential biological abilities acquired by human cancer. Since then, a growing understanding of hallmark principles associated with breast cancer has assisted knowledge-based therapeutics development; however, despite the rapidly increasing number of targeted therapeutics, enduring disease-free responses for most forms of breast cancer is rare. Invasion and metastasis are the most defining feature of breast cancer malignancy and the leading cause of patient mortality. Hence, we propose a modified hallmarks model adapted to breast cancer, in which invasion and metastasis are shifted to the center of attention, thereby emphasizing it as a potentially superior therapeutic target. Although the scientific community highly appreciates the importance of the invasion and metastasis hallmark, as can be demonstrated by the growing number of publications on breast cancer metastasis, very few clinical trials concentrate on testing anti-metastasis inhibitors and even fewer trials focus on inhibitors for breast cancer metastasis. Here, we discuss the obstacles of applying research on invasion and metastasis therapeutics into the clinic and present current developments that could provide a potential solution to this dilemma.

Background The design of the combination of ferulic acid, ligustrazine and tetrahydropalmatine (FLT) is inspired by the Chinese herbal prescription Foshou San. Previous work has shown that FLT inhibited endometriosis growth in rat autograft models. However, the mechanism behind this is unclear. MMP/TIMP signaling is considered as the vital pathway of metastasis and invasion in endometriosis. In this study, we aim to disclose effects of FLT on MMP/TIMP signaling in invasion and metastasis during endometrial cells and xenograft endometriosis. Methods In vivo, effect of FLT on endometriosis was evaluated in a xenogeneic mice model. In vitro, cell viability assay was performed with an IC50 measurement of FLT in hEM15A and HEC1-B cells. The effect of FLT on invasion and metastasis was analyzed in scratch wound and transwell assay. Gene and protein expression of MMP/TIMP signaling were detected by qPCR and Western blotting. Results In xenograft endometriosis, FLT reduced ectopic volume without effect on weight. FLT inhibitory effects on cell growth exhibited a dose-dependent manner in hEM15A and HEC1-B cells. IC50s of FLT in hEM15A cells were 839.30 ± 121.11 or 483.53 ±156.91 μg·ml−1 after the treatment for 24 or 48 h, respectively. In HEC1-B cells, IC50 values of 24 or 48 h were 625.20 ± 59.52 or 250.30 ± 68.12 μg·ml−1. In addition, FLT significantly inhibited invasion and metastasis in scratch wound and transwell assay. Furthermore, FLT inactivated MMP/TIMP signaling with decreasing expression of MMP-2/9, and an enhancing expression of TIMP-1. Conclusions MMP/TIMP inactivation is a reasonable explanation for the inhibition of FLT on invasion and metastasis in endometriosis. This result reveals a potential mechanism on the role of FLT in endometriosis and may benefit for its further application.

Prostate cancer (PCa) is the most common solid tumor in men. While patients with local PCa have better prognostic survival, patients with metastatic PCa have relatively high mortality rates. Existing diagnostic methods for PCa rely on tissue biopsy and blood prostate-specific antigen (PSA) detection; however, the PSA test does not detect aggressive PCa. Liquid biopsy is a promising technique to overcome tumor heterogeneity in diagnosis, provide more comprehensive information, and track tumor progression over time, allowing for the development of treatment options at all stages of PCa. Exosomes containing proteins and nucleic acids are potential sources of tumor biomarkers. Accumulating evidence indicates that exosomes play important roles in cell communication and tumor progression and are suitable for monitoring PCa progression and metastasis. In this review, we summarize recent advances in the use of exosomal proteins and miRNAs as biomarkers for monitoring PCa invasion and metastasis and discuss their feasibility in clinical diagnosis.

The overactivation of Wnt/β-catenin signaling is a hallmark of colorectal cancer (CRC) development. We identified the cell adhesion molecule L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. The overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis and liver metastasis, and L1 is exclusively localized in the invasive areas of human CRC tissue. A number of genes are induced after L1 transfection into CRC cells by a mechanism involving the cytoskeletal protein ezrin and the NF-κB pathway. When studying the changes in gene expression in CRC cells overexpressing L1 in which ezrin levels were suppressed by shRNA to ezrin, we discovered the collagen-modifying enzyme lysyl hydroxylase 2 (PLOD2) among these genes. We found that increased PLOD2 expression was required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis and liver metastasis, since the suppression of endogenous PLOD2 expression, or its enzymatic activity, blocked the enhanced tumorigenic properties conferred by L1. The mechanism involved in increased PLOD2 expression by L1 involves ezrin signaling and PLOD2 that affect the SMAD2/3 pathway. We found that PLOD2 is localized in the colonic crypts in the stem cell compartment of the normal mucosa and is found at increased levels in invasive areas of the tumor and, in some cases, throughout the tumor tissue. The therapeutic strategies to target PLOD2 expression might provide a useful approach for CRC treatment.

As a CRISPR-Cas9-based tool to help scientists to investigate gene functions, Cancer Dependency Map genes (CDMs) include an enormous series of loss-of-function screens based on genome-scale RNAi. These genes participate in regulating survival and growth of tumor cells, which suggests their potential as novel therapeutic targets for malignant tumors. By far, studies on the roles of CDMs in gastric adenocarcinoma (GA) are scarce and only a small fraction of CDMs have been investigated. In the present study, datasets of the differentially expressed genes (DEGs) were extracted from the TCGA-based (The Cancer Genome Atlas) GEPIA database, from which differentially expressed CDMs were determined. Functions and prognostic significance of these verified CDMs were evaluated using a series of bioinformatics methods. In all, 246 differentially expressed CDMs were determined, with 147 upregulated and 99 downregulated. Ten CDMs (ALG8, ATRIP, CCT6A, CFDP1, CINP, MED18, METTL1, ORC1, TANGO6, and PWP2) were identified to be prognosis-related and subsequently a prognosis model based on these ten CDMs was constructed. In comparison with that of patients with low risk in TCGA training, testing and GSE84437 cohort, overall survival (OS) of patients with high risk was significantly worse. It was then subsequently demonstrated that for this prognostic model, area under the ROC (receiver operating characteristic) curve was 0.771 and 0.697 for TCGA training and testing cohort respectively, justifying its reliability in predicting survival of GA patients. With the ten identified CDMs, we then constructed a nomogram to generate a clinically practical model. The regulatory networks and functions of the ten CDMs were then explored, the results of which demonstrated that as the gene significantly associated with survival of GA patients and Hazard ratio (HR), PWP2 promoted in-vitro invasion and migration of GA cell lines through the EMT signaling pathway. Therefore, in conclusion, the present study might help understand the prognostic significance and molecular functions of CDMs in GA.

Objective: Recent studies have shown that tumor-associated macrophages (TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer (GC) cells through the Kindlin-2 pathway. However, the mechanism needs to be clarified. Methods: THP-1 monocytes were induced by PMA/interleukin (IL)-4/IL-13 to establish an efficient TAM model in vitro and M2 macrophages were isolated via flow cytometry. A dual luciferase reporter system and chromatin immunoprecipitation (ChIP) assay were used to investigate the mechanism of transforming growth factor beta 2 (TGF beta 2) regulating Kindlin-2 expression. Immunohistochemistry was used to study the relationships among TAM infiltration in human GC tissues, Kindlin-2 protein expression, clinicopathological parameters and prognosis in human GC tissues. A nude mouse oncogenesis model was used to verify the invasion and metastasis mechanisms in vivo. Results: We found that Kindlin-2 expression was upregulated at both mRNA and protein levels in GC cells cocultured with TAMs, associated with higher invasion rate. Kindlin-2 knockdown reduced the invasion rate of GC cells under coculture condition. TGF beta 2 secreted by TAMs regulated the expression of Kindlin-2 through the transcription factor NF-kappa B. TAMs thus participated in the progression of GC through the TGF beta 2/NF-kappa B/Kindlin-2 axis. Kindlin-2 expression and TAM infiltration were significantly positively correlated with TNM stage, and patients with high Kindlin-2 expression had significantly poorer overall survival than patients with low Kindlin-2 expression. Furthermore, Kindlin-2 promoted the invasion of GC cells in vivo. Conclusions: This study elucidates the mechanism of TAMs participating in GC cell invasion and metastasis through the TGF beta 2/NF-kappa B/Kindlin-2 axis, providing a possibility for new treatment options and approaches.

Background Abnormal microRNAs (miRNAs) expression is closely related to the development and poor prognosis of pancreatic ductal adenocarcinoma (PDAC). We aimed to elucidate the invasive mechanism and clinical significance of miR‐10b in PDAC. Methods The RNA sequence data of pancreatic cancer were extracted from the TCGA database. R packages were performed to analyze the differential expression of RNAs. TargetScan, picTar, and miRanda were used to predict the target gene of miRNA. The expression level of the selected candidate was tested by western blot and RT‐PCR in PDAC cells and tissues. Scrape and Transwell assays were determined the effect of candidate molecules on cell migration and invasion. The gain of function and loss of function was achieved by co‐culture with mimics and vector. Luciferase reporters were generated based on the psiCHECK2 vector. The relative luciferase activity was measured with the Dual‐Luciferase Reporter Assay System and Infinate M200 PRO microplate reader. Results Based on the TCGA data and bioinformatics analysis, we obtained seven differentially expressed miRNAs. Both TCGA data and our center clinical date indicated that miR‐10b was contributed to the poor survival of PDAC. Based on the target gene prediction database, we found that E2F7 was a target mRNA of miR‐10b. In subsequent experiments in molecular biology, miR‐10b expression was downregulated in PDAC cells and tissues, while E2F7 was upregulated. Scrape and Transwell assay indicated that miR‐10b could inhibit the invasion and migration of PDAC. MiR‐10b was confirmed to be by the E2F7 targeting site by dual‐luciferase report. Moreover, rescue experiments prove that miR‐10b could inhibit the invasion and migration of PDAC cells by regulating E2F7 expression. Conclusion Our results suggest that miR‐10b could inhibit the progression of PDAC by regulating E2F7 expression and acts as an independent prognostic risk factor for PDAC., Acquired the miRNA sequencing dataset and corresponding clinical records of PDAC from TCGA. Differentially expressed miRNA analysis and survival analysis indicated miR‐10b was PDAC progression associated miRNA. And E2F7 was a potential target of miR‐10b. And miR‐10b may inhibit PDAC cell migration and invasion by targeting E2F7.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, with typically extensive intraperitoneal implantation leading to poor prognosis. Our previous study preliminarily demonstrated β-hCG can promote tumorigenesis in immortalized nontumorigenic ovarian epithelial cells. In this study, the roles and mechanisms of β-hCG in regulating EOC proliferation and metastasis were thoroughly explored. First, histologically, β-hCG was aberrantly overexpressed in human EOC metastatic tissues, and significantly correlated with FIGO stage, tumor size, differentiation, histologic grade and high grade serous ovarian carcinoma (HGSOC) (P

// Jie Wang 1, * , Han Cai 1, * , Yue Xia 1, * , Shiying Wang 2 , Likai Xing 1 , Chao Chen 1 , Yong Zhang 1 , Jie Xu 1 , Peihao Yin 1 , Yiming Jiang 1 , Ronghua Zhao 3 , Qingshong Zuo 1 and Teng Chen 1, 4 1 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China 2 Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China 3 Department of Medical, Virogin Biotech Ltd., Vancouver, British Columbia V6S 2L9, Canada 4 Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Shanghai 200062, China * These authors have contributed equally to this work Correspondence to: Teng Chen, email: 13801842406@163.com Qingshong Zuo, email: zqsadsl123@sina.com Keywords: bufalin; gastric cancer; invasion and metastasis; Wnt/ASCL2 signaling; EMT Received: September 28, 2017 Accepted: January 02, 2018 Epub: January 11, 2018 Published: May 04, 2018 ABSTRACT Achaete-scute-like 2 (ASCL2) is a transcription factor containing a basic helix-loop-helix (bHLH) domain and is a downstream target of Wnt signaling in intestinal stem cells. Bufalin is the primary active ingredient in Chan Su, a traditional Chinese medicine obtained from the skin and parotid venom glands of toads. The purpose of this study was to research the anti-invasion and anti-metastasis activity of bufalin in gastric cancer and to identify the potential mechanism. Bufalin inhibited gastric cancer cell invasion and metastasis, suppressed cancer cell colony formation, and inhibited the growth of subcutaneous xenografted tumors in nude mice. Furthermore, bufalin inhibited ASCL2 expression and down-regulated the expression of invasion-related genes such as MMP2, MMP9, and vimentin, thereby suppressing epithelial-mesenchymal transition (EMT) in gastric cancer. A Wnt signaling inhibitor (XAV939) down-regulated invasion and the expression of ASCL2, β-catenin, and vimentin but up-regulated E-cadherin expression. In nude mice, bufalin inhibited the tumorigenic behavior of gastric cancer cells, induced cancer cell apoptosis, and regulated invasion-related gene expression. Together, our results suggest that bufalin arrests invasion and metastasis and that its mechanism of action may involve down-regulating Wnt/ASCL2 expression.

BACKGROUND Previous research showed that Jin-Fu-An decoction has a significant effect on lung cancer. However, it remains unclear whether p120ctn and its transcription factor Kaiso play a role in lung cancer cell proliferation, adhesion, migration, and metastasis. MATERIAL AND METHODS Proliferation inhibition was detected by CCK-8 assay. The migration and invasion were detected using Transwell assay. The location and expression of p120ctn and Kaiso were monitored by immunofluorescence staining. The expression changes of p120ctn, its isoform 1A, its S288 phosphorylation, and Kaiso were measured by Western blot assay. RESULTS The lung cancer cell line H1650 administered Jin-Fu-An decoction had significantly reduced the growth in dose-dependent and time-dependent manners. Migration and metastasis were significantly inhibited by application of Jin-Fu-An decoction in a dose-dependent manner. Additionally, Jin-Fu-An decoction decreased the expressions of p120ctn, its isoform 1A, and its S288 phosphorylation, but the protein level of Kaiso was elevated. CONCLUSIONS Jin-Fu-An decoction inhibits the proliferation, adhesion, migration, and metastasis though down-regulation of p120ctn or its isoform 1A expression, mediating the up-regulation of Kaiso. The underlying mechanism of Jin-Fu-An decoction might involve targeting the lower expression of p120ctn S288 phosphorylation, which suggests that Jin-Fu-An decoction may be a potential therapeutic measure as prevention and control of recurrence and metastasis of lung cancer.

// Zhao Yang 1, * , Jin He 2, * , Peng Gao 1 , Yi Niu 1 , Jie Zhang 3 , Lei Wang 3 , Meiyue Liu 1 , Xiaomei Wei 1 , Chunling Liu 3 , Chao Zhang 1 , Wei Wang 1 , Jiayi Du 3 , Hongmin Li 3 , Wanning Hu 1 and Guogui Sun 1 1 Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan, China 2 Department of Hepatobiliary Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Cencer, Tianjin, China 3 Department of Pathology, North China University of Science and Technology Affiliated People's Hospital, Tangshan, China * These authors share co-first authorship Correspondence to: Wanning Hu, email: wanning_hu2008@sina.com Guogui Sun, email: guogui_sun2013@163.com Keywords: lung cancer; microRNAs; invasion and metastasis; gene therapy Received: July 27, 2017 Accepted: November 14, 2017 Published: December 08, 2017 ABSTRACT MicroRNAs (miRNAs) are key regulators of multiple cancers, including non-small cell lung carcinoma (NSCLC). The aim of this study was to determine the expression pattern of miR-769-5p in NSCLC and to investigate its biological role during tumorigenesis. We showed that miR-769-5p was significantly downregulated and predicted poor prognosis in NSCLC compared with corresponding normal tissues. We then investigated its function and found that miR-769-5p significantly inhibited cell proliferation, migration and invasion in vitro and reduced tumor growth and metastasis in vivo . Furthermore, we explored the molecular mechanisms by which miR-769-5p contributes to NSCLC suppression and identified TGFBR1 as a direct target gene of miR-769-5p. Finally, we showed that TGFBR1 had opposite effects to those of miR-769-5p on lung cancer cells, suggesting that miR-769-5p might inhibit lung tumorigenesis by silencing TGFBR1. Taken together, our results demonstrated that miR-769-5p plays a pivotal role in NSCLC by inhibiting cell proliferation, migration and invasion by targeting TGFBR1.

Invasion and metastasis are crucially important factors in the survival of malignant tumors. Epithelial-mesenchymal transition (EMT) is an early step in metastatic progression and the presence of cancer stem cells is closely related to tumor survival, proliferation, metastasis, and recurrence. Herein we report that ectopic overexpression of microRNA 26b (miR-26b) in colorectal cancer (CRC) cell lines promoted EMT and stem cell-like phenotypes in vitro. Furthermore, miR-26b directly targeted and suppressed multiple tumor suppressors, including phosphatase and tensin homolog (PTEN) and wingless-type MMTV integration site family member 5A (WNT5A). Notably, miR-26b is markedly upregulated in tumor samples from patients with lymphatic metastases. These results indicate that miR-26b promotes CRC metastasis by downregulating PTEN and WNT5A, and may represent a therapeutic target for metastatic CRC.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a mortality rate that closely parallels its incidence rate, and a better understanding of the molecular and cellular mechanisms associated with the invasion and distant metastasis is required. Heat shock factor 1 (HSF1) is a very highly conserved factor in eukaryotes that regulates the protective heat shock response. Here, we show that HSF1 is abnormally activated in pancreatic cancer. The knockdown of HSF1 impaired the invasion and migration and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells in vitro; however, the upregulation of HSF1 showed the opposite effects. In vivo, the pharmacological inhibition of HSF1 significantly reduced the tumor burden, decreased the incidence of invasion, and prolonged the overall survival of transgenic mice harboring the spontaneous pancreatic cancer. We suggest that the loss of AMP‐activated protein kinase (AMPK) activation mediates the abnormal activation of HSF1 based on the findings that phospho‐HSF1 (p‐HSF1) was highly expressed in human PDAC tissues with a low expression of p‐AMPK and that in those tissues with a high p‐AMPK expression, the level of p‐HSF1 was decreased. The in vivo and in vitro activation of AMPK impaired the activity of HSF1, and HSF1 mediated the effects of the AMPK knockdown‐induced pancreatic cancer invasion and migration. Our study revealed a novel mechanism by which the loss of AMPK activation amplifies the activity of HSF1 to promote the invasion and metastasis of pancreatic cancer.

// Xiupeng Zhang 1 , Haijing Zhou 1 , Yong Zhang 2 , Lin Cai 1 , Guiyang Jiang 1 , Ailin Li 3 , Yuan Miao 1 , Qingchang Li 1 , Xueshan Qiu 1 and Enhua Wang 1 1 Department of Pathology, College of Basic Medicine Science and First Affiliated Hospital of China Medical University, Shenyang, China 2 Department of Pathology, Cancer Hospital of China Medical University, Shenyang, China 3 Department of Radiotherapy, First Affiliated Hospital of China Medical University, Shenyang, China Correspondence to: Yuan Miao, email: cmumiaoyuan@163.com Keywords: ZNF452, NSCLC, AKT signaling, proliferation, invasion and metastasis Received: January 17, 2017 Accepted: February 24, 2017 Published: March 21, 2017 ABSTRACT ZNF452 is a zinc-finger protein family member which contains an isolated SCAN (SRE-ZBP, CTfin51, AW-1 and Number 18 cDNA) zinc-finger domain. Despite the SCAN N-terminus domain is known to play a role in transcriptional regulation of genes involved in cell survival and differentiation, there are no precise cellular functions that have been assigned to ZNF452. In the present study, we found that either endogenous or exogenous ZNF452 was overexpressed in the cytoplasm of NSCLC cells and positive ratio of ZNF452 in NSCLC samples (50.8%, 93/183) was significantly higher than that in normal lung tissues (22.4%, 13/58, P

// Changjiang Luo 1, * , Yunyi Yao 2, * , Zeyuan Yu 1 , Huinian Zhou 1 , Lingyun Guo 1 , Junqiang Zhang 1 , Hongtai Cao 1 , Genyuan Zhang 1 , Yumin Li 1 , Zuoyi Jiao 1 1 Department of General Surgery, Lanzhou University Second Hospital and Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, Gansu, 730030, China 2 Department of Medical Technology and Key Laboratory of Biotechnology for Laboratory Medicine of Suzhou, Suzhou Vocational Health College, Suzhou, Jiangsu, 215009, China * These authors contributed equally to this work Correspondence to: Zuoyi Jiao, email: jiaozy@lzu.edu.cn Yumin Li, email: liym@lzu.edu.cn Keywords: UBE2T, ubiquitination, gastric cancer, tumor apoptosis, invasion and metastasis Received: October 28, 2016 Accepted: February 22, 2017 Published: March 06, 2017 ABSTRACT Ubiquitin-conjugating enzymes (E2 enzymes) such as UBE2T target proteins for degradation via the proteasome. Here, we examined the effects of UBE2T on the progression of gastric cancer. UBE2T was highly expressed in gastric tumors and gastric cancer cells. siRNA-mediated suppression of UBE2T inhibited gastric cancer cell proliferation and colony formation by promoting cell cycle arrest at G2/M phase and increasing apoptosis. Suppression of UBE2T also attenuated the invasive and metastatic abilities of gastric cancer cells by altering expression of epithelial-mesenchymal transition (EMT)-related factors. A xenograft model in which nude mice were injected with UBE2T knockdown human gastric cancer cells confirmed that suppression of UBE2T also decreased tumor formation and growth in vivo . Expression levels of CCND1, Phospho-GSK3B, WNT family members, and MYC were all affected by UBE2T knockdown. These results suggest that UBE2T plays a critical role in gastric cancer, and that it may serve as a useful prognostic biomarker and therapeutic target in gastric cancer patients.

Myricetin (3, 5, 7, 3', 4', 5'-hexahydroxyflavone) is a natural flavonol compound found in a large variety of plants, including berries, oranges, grapes, herbs, teas, and wine. In the last decade, a convergence of evidence has demonstrated that myricetin has good biological activity as an anti-tumor, anti-inflammatory, and anti-oxidation agent. In studies involving various types of cancer cells, myricetin has been shown to suppress cancer cell invasion and metastasis, to induce cell cycle arrest and apoptosis of cancer cells, and to inhibit their proliferation. These findings have raised interest in myricetin as a potential tumor inhibitor in human patients. In this review, evidence of myricetin's anti-tumor activity and its underlying molecular mechanisms published in the last decade are summarized.

Background Triple Negative Breast cancer (TNBC) is incurable cancer with higher rates of relapse and shorter overall survival compared with other subtypes of breast cancer. Cellular retinoic acid binding protein 2 (CRABP2) belongs to fatty acid binding protein (FABP) family which binds with all-trans retinoic acid (RA). Previous studies from the database have reported the patients with high expression of CRABP2 showed different prognosis in ER+ and ER− breast cancer. However, its biological role and exact mechanism in breast cancer remain unknown. This aim of this study was to explore how CRABP2 regulated invasion and metastasis based on the estrogen receptor-α (herein called ER) status in breast cancer. Methods Immunohistochemical staining method was used to analyze the expression of CRABP2 in human breast cancer tissues. Lentivirus vector-based shRNA technique was used to test the functional relevance of CRABP2 knockdown in breast tumors. Tail vein injection model was used to examine the lung metastasis. Co-immunoprecipitation, Western blotting, immunofluorescence, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were conducted to investigate the underlying mechanism that influenced the ER to the regulation of CRABP2 to Lats1. Results We observed that knockdown of CRABP2 promotes EMT, invasion and metastasis of ER+ breast cancer cells in vitro and in vivo, whereas overexpression of CRABP2 yields the reverse results. In ER+ mammary cancer cells, the interaction of CRABP2 and Lats1 suppress the ubiquitination of Lats1 to activate Hippo pathway to inhibit the invasion and metastasis of ER+ mammary cancer. However, in ER− mammary cancer cells, the interaction of CRABP2 and Lats1 promote the ubiquitination of Lats1 to inactivate Hippo pathway to promote the invasion and metastasis of ER− mammary cancer. Conclusions Our findings indicate that CRABP2 can suppress invasion and metastasis of ER+ breast cancer and promote invasion and metastasis of ER− breast cancer by regulating the stability of Lats1 in vitro and in vivo, and it provides new ideas for breast cancer therapy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1345-2) contains supplementary material, which is available to authorized users.

Background: Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide with a very high recurrence rate and very dismal prognosis. Diagnosis and treatment in HCC remain difficult, and the identification of new therapeutic targets is necessary for a better outcome of HCC treatment. AMP-Activated Protein Kinase (AMPK) is an essential intracellular energy sensor that plays multiple roles in cellular physiology and the pathological development of chronic diseases. Recent studies have highlighted the important regulation of AMPK in HCC. This review aims to comprehensively and critically summarize the role of AMPK in HCC. Methods: Original studies were retrieved from NCBI database with keywords including AMPK and HCC, which were analyzed with extensive reading. Results: Dysregulation of the kinase activity and expression of AMPK was observed in HCC, which was correlated with survival of the patients. Loss of AMPK in HCC cells may proceed cell cycle progression, proliferation, survival, migration, and invasion through different oncogenic molecules and pathways. Conclusions: We identified several AMPK activators which may possess potential anti-HCC function, and discussed the clinical perspective on the use of AMPK activators for HCC therapy.

Numerous esophageal squamous cell carcinoma (ESCC) patients exhibit tumor recurrence following radical resection. Invasion and metastasis are key factors in poor prognosis following esophagectomy. In the present study, two‑dimensional gel electrophoresis (2-DE) and matrix‑assisted laser desorption/ionization time-of-flight mass spectrometry were used to define patterns of protein expression in ESCC tissues at different pathological stages. The expression levels of identified proteins were determined by immunohistochemistry and western blotting. A total of fifteen protein spots with >2-fold differences were observed when comparing results of 2-DE for stage III and stage I ESCC tissue sample. A total of 12 proteins were identified by mass spectrometry analysis and database searches. The results of immunohistochemistry and western blotting demonstrated expression levels of tropomyosin 3 (TPM3) were higher in stage III ESCC tissue compared with stage I (P

// Nan Xie 1, 3, * , Cheng Wang 2, 3, * , Zehang Zhuang 2, 3 , Jinson Hou 2, 3 , Xiqiang Liu 2, 3 , Yue Wu 2, 3 , Haichao Liu 2, 3 , Hongzhang Huang 2, 3 1 Department of Oral Pathology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China 2 Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China 3 Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China * These authors have contributed equally to this work Correspondence to: Hongzhang Huang, email: drhuang52@163.com Keywords: tongue squamous cell carcinoma, tumor budding, miR-320a, Suz12, invasion and metastasis Received: June 06, 2016 Accepted: August 15, 2016 Published: August 25, 2016 ABSTRACT We aimed to determine the specific miRNA profile of tumor budding cells and investigate the potential role of miR-320a in invasion and metastasis of tongue squamous cell carcinoma (TSCC). We collected tumor budding cells and paired central tumor samples from five TSCC specimens with laser capture microdissection and examined the specimens using a miRNA microarray. The specific miRNA signature of tumor budding cells was identified. We found that miR-320a was dramatically decreased in tumor budding cells. Knockdown of miR-320a significantly enhanced migration and invasion of TSCC cell lines. Suz12 was shown to be a direct target of miR-320a. Similar results were also observed in nude mouse models. Multivariate analysis indicated that miR-320a was an independent prognostic factor. Kaplan–Meier analysis demonstrated that decreased miR-320a and high intensity of tumor budding were correlated with poor survival rate, especially in the subgroup with high-intensity tumor budding and low expression of miR-320a. We concluded that decreased expression of miR-320a could promote invasion and metastasis of tumor budding cells by targeting Suz12 in TSCC. A combination of tumor budding and miR-320a may serve as an index to identify an aggressive sub-population of TSCC cells with high metastatic potential.

Activator protein‐1 (AP‐1) is a transcriptional factor that regulates the expression of various genes associated with tumor invasion and migration. The purpose of our study was to assess the therapeutic effects of a novel selective AP‐1 inhibitor, T‐5224, in preventing lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) in an orthotopic mouse model. We assessed the effect of T‐5224 on HNSCC cell invasion, migration, proliferation, and MMP activity by carrying out an in vitro study using an invasion assay, scratch assay, WST‐8 assay, and gelatin zymography. We also observed morphological changes in HNSCC cells by time‐lapse microscopy. Furthermore, cervical lymph node metastasis was assessed using an orthotopic tumor model of human oral squamous cell carcinoma cells (HSC‐3‐M3) injected in the tongue of a BALB/c nude mouse. T‐5224 (150 mg/kg) or vehicle was given orally every day for 4 weeks. Animals were killed and assessed for lymph node metastasis by H&E staining of resected lymph nodes. T‐5224 significantly inhibited the invasion, migration, and MMP activity of HNSCC cells in a dose‐dependent manner; there was no significant influence on cell proliferation. The antimetastatic effect of T‐5224 was also confirmed in our animal study. The rate of cervical lymph node metastasis in the model was 40.0% in the T‐5224‐treated group (n = 30) versus 74.1% in the vehicle‐treated group (n = 27; P < 0.05). In conclusion, T‐5224 inhibited the invasion and migration of HNSCC cells in vitro, and prevented lymph node metastasis in head and neck cancer in an animal model.

Musashi2-Numb interaction plays a vital role in the progression of myeloid leukemia. However, its potential role in solid cancers has rarely been reported. We investigated the coordinate function of Musashi2-Numb in the development of pancreatic cancer (PC) in vitro and vivo. Both Musashi2 protein and mRNA levels were higher in PC tissues than that in paired normal pancreas (P

SOX2 is a transcription factor related to the maintenance of stem cells in a pluripotent state. Podoplanin is a type of transmembrane sialoglycoprotein, which plays an important role in tumor progression and metastasis. This study aims to determine association of SOX2 and podoplanin expression in the progression of oral squamous cell carcinomas and to elucidate the association between two proteins. Methodology: The immunohistochemical expression of SOX2 and podoplanin were evaluated in 60 cases of primary oral squamous cell carcinomas. The correlation between the SOX2 and podoplanin expression and the clinicopathological features of the tumors and the patient outcomes were assessed. Results: The expression of SOX2 was seen in 38/60 (63%) of the cases and the expression for podoplanin was seen in 45/60 (75%) cases. There was a significant inverse correlation between the expression of SOX2 and podoplanin with the tumor grade (p=0.002 and p=0.017, respectively). There was a high expression of SOX2 in 9/13 cases that presented with disease free survival. Survival analysis showed that a high expression of SOX2 correlated positively (p=0.043) with the disease-free survival. There was a significant positive association between the pattern of SOX2 and podoplanin expression (p=0.002). Conclusion: A high expression of SOX2 was associated with better disease-free survival. The expression of podoplanin was associated with the degree of differentiation of the tumors. Analysis of these biomarkers can aid in the prognosis and treatment of oral squamous cell carcinomas.

Increasing numbers of studies have confirmed that long noncoding RNA (lncRNA) play a critical role in epithelial ovarian cancer (EOC) progression. However, the potential function of the lncRNA tumor protein translationally controlled 1 (TPT1) antisense RNA 1 (TPT1‐AS1) in EOC is unclear. In this study, we aimed to uncover the biological roles and regulatory mechanisms of TPT1‐AS1 in EOC progression and metastasis. First, TPT1‐AS1 expression was significantly higher in EOC metastatic tissue and cell lines than in their respective control counterparts. In addition, ectopic TPT1‐AS1 expression was strongly associated with unfavorable EOC clinicopathological features, including FIGO stage, tumor size and tumor differentiation. TPT1‐AS1 overexpression remarkably induced cell proliferation, migration and invasion, and significantly attenuated cell adhesion ability in vitro and facilitated nude mouse subcutaneous xenograft growth and intraperitoneal metastasis in vivo, while the downregulation of TPT1‐AS1 expression produced the opposite effect in vitro. Mechanistically, TPT1‐AS1 was proven to be primarily distributed in EOC cell nuclei and positively modulated TPT1 promoter activity and transcription. Moreover, the oncogenic effects of TPT1‐AS1 could be reversed by TPT1 depletion, and the PI3K/AKT signaling pathway downstream of TPT1 was also altered. These results suggested that TPT1‐AS1 induced EOC tumor growth and metastasis through TPT1 and downstream PI3K/AKT signaling and that TPT1‐AS1 may be a promising therapeutic target for EOC.

Jiawei Foshou San (JFS) is the new formula originated from classic Foshou San formula, composed with ligustrazine, ferulic acid, and tetrahydropalmatine. Previously JFS inhibited the growth of endometriosis (EMS) with unclear mechanism, especially in metastasis, invasion, and epithelial–mesenchymal transition. In this study, network pharmacology was performed to explore potential mechanism of JFS on EMS. Through compound–compound target and compound target–EMS target networks, key targets were analyzed for pathway enrichment. MMP–TIMP were uncovered as one cluster of the core targets. Furthermore, autologous transplantation of EMS rat’s model were used to evaluate in vivo effect of JFS on invasion, metastasis and epithelial–mesenchymal transition. JFS significantly suppressed the growth, and reduced the volume of ectopic endometrium, with modification of pathologic structure. In-depth study, invasion and metastasis were restrained after treating with JFS through decreasing MMP-2 and MMP-9, increasing TIMP-1. Meanwhile, JFS promoted E-cadherin, and attenuated N-cadherin, Vimentin, Snail, Slug, ZEB1, ZEB2, Twist. In brief, anti-EMS effect of JFS might be related to the regulation of epithelial–mesenchymal transformation, thereby inhibition of invasion and metastasis. These findings reveal the potential mechanism of JFS on EMS and the benefit for further evaluation.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks effective targeted therapies. In the present study, we revealed that the expression of miR-30a was significantly decreased in TNBC, and TNBC patients with low expression of miR-30a were associated with high histological grade and more lymph node metastasis. Moreover, we found that miR-30a suppressed TNBC cell epithelial-mesenchymal transition (EMT), as demonstrated by the overexpression of miR-30a which increased the expression of epithelial marker E-cadherin but decreased the expression of mesenchymal markers N-cadherin and vimentin. Furthermore, we demonstrated that overexpression of miR-30a significantly suppressed TNBC cell invasion and migration, as well as inhibited tumor growth and metastasis in vivo. More importantly, RTK-like orphan receptor 1 (ROR1) was predicted as the direct target of miR-30a, which was subsequently confirmed by luciferase assays. Forced expression of miR-30a in TNBC cells decreased ROR1 expression, whereas the overexpression of ROR1 reversed the suppressive effects of miR-30a in TNBC cell migration and invasion. Collectively, this study indicated that miR-30a functions as a tumor-metastasis suppressor miRNA in TNBC by directly targeting ROR1 and that miR-30a may serve as a novel therapeutic target for TNBC.

Increasing number of studies have indicated aberrant microRNA (miRNA) expression could affect normal biological progress in non-small cell lung cancer (NSCLC) cells. This study was performed to evaluate the biologic functions of microRNA-224 (miR-224) in NSCLC. Real-time PCR was performed to evaluate the expression of miR-224 and Homeobox D10 (HOXD10) in NSCLC cell lines and tissues. Transwell assays were performed to investigate the function of miR-224 on NSCLC cell migration and invasion. Moreover, western blotting and luciferase assays were used to investigate HOXD10 as miR-224 downstream targets. miR-224 is increased in NSCLC metastatic tissues and cell lines. Increased miR-224 expression promoted NSCLC cell migration and invasion, while low miR-224 expression suppressed NSCLC cell migration and invasion. Furthermore, HOXD10 was targeted directly by miR-224 in NSCLC cells. Moreover, we found that HOXD10 was a functional target and influenced tumour-inductive functions of miR-224 on progression of NSCLC. These findings suggest that miR-224 may be used in the treatment of NSCLC. Targeting this novel strategy, miR-224/HOXD10 axis may be helpful as promising biomarker and therapeutic method to control NSCLC cell metastasis.

As the most common metastatic disease of abdomen pelvic cavity cancer, peritoneal carcinomatosis (PC) renders significant negative impact on patient survival and quality of life. Invasive peritoneal exfoliated cancer cells (PECCs) preferentially select the omentum as a predominant target site for cancer cell colonization and proliferation compared with other tissues in the abdominal cavity. The precise pathogenic mechanism remains to be determined. As omental milky spots (MSs) are the major implantation site for malignant cells in peritoneal dissemination, researches on mechanisms of PC have been mainly focused on MS, primitive lymphoid tissues with unique structural features, and functional characteristics. To date, extensive biophysical and biochemical methods have been manipulated to investigate the MS exact function in the peritoneal cavity. This review summarized MS as hotbeds for PECC. The anatomical distribution was briefly described first. Then, MS histology was systematically reviewed, including morphological features, cellular constituents, and histological staining methods. At last, the roles of MS in PC pathological process were summarized with special emphasis on the distinct roles of macrophages.

// Zhongling Luo 1 , Xu Zhang 1 , Weiqi Zeng 1 , Juan Su 1 , Keda Yang 2 , Lixia Lu 1 , Chuan Bian Lim 3 , Wen Tang 4 , Lisha Wu 5 , Shuang Zhao 1 , Xuekun Jia 1 , Cong Peng 1 , Xiang Chen 1 1 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China 2 Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China 3 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA 4 Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China 5 Institute of Medical Science Research, Xiangya Hospital, Central South University, Changsha, Hunan, China Correspondence to: Cong Peng, e-mail: pengchongpeng@hotmail.com Xiang Chen, e-mail: chenxiangck@126.com Keywords: TRAF6, melanoma, invasion and metastasis, Basigin, ubiquitination Received: September 07, 2015 Accepted: January 02, 2016 Published: January 12, 2016 ABSTRACT TRAF6 plays a crucial role in the regulation of the innate and adaptive immune responses. Although studies have shown that TRAF6 has oncogenic activity, the role of TRAF6 in melanoma is unclear. Here, we report that TRAF6 is overexpressed in primary as well as metastatic melanoma tumors and melanoma cell lines. Knockdown of TRAF6 with shRNA significantly suppressed malignant phenotypes including cell proliferation, anchorage-independent cell growth and metastasis in vitro and in vivo . Notably, we demonstrated that Basigin (BSG)/CD147, a critical molecule for cancer cell invasion and metastasis, is a novel interacting partner of TRAF6. Furthermore, depletion of TRAF6 by shRNA reduced the recruitment of BSG to the plasma membrane and K63-linked ubiquitination, in turn, which impaired BSG-dependent MMP9 induction. Taken together, our findings indicate that TRAF6 is involved in regulating melanoma invasion and metastasis, suggesting that TRAF6 may be a potential target for therapy or chemo-prevention in melanoma.

miR-101 is considered to play an important role in hepato-cellular carcinoma (HCC), but the underlying molecular mechanism remains to be elucidated. Here, we aimed to confirm whether Girdin is a target gene of miR-101 and determine the tumor suppressor of miR-101 through Girdin pathway. In our previous studies, we firstly found Girdin protein was overexpressed in HCC tissues, and it closely correlated to tumor size, T stage, TNM stage and Edmondson-Steiner stage of HCC patients. After specific small interfering RNA of Girdin was transfected into HepG2 and Huh7.5.1 cells, the proliferation and invasion ability of tumor cells were significantly inhibited. In this study, we further explored the detailed molecular mechanism of Girdin in HCC. Interestingly, we found that miR-101 significantly low-expressed in HCC tissues compared with that in matched normal tissues while Girdin had a relative higher expression, and miR-101 was inversely correlated with Girdin expression. In addition, after miR-101 transfection, the proliferation, migration and invasion abilities of HepG2 cells were weakened. Furthermore, we confirmed that Girdin is a direct target gene of miR-101. Finally we confirmed Talen-mediated Girdin knockout markedly suppressed cell proliferation, migration and invasion in HCC while down-regulation of miR-101 significantly restored the inhibitory effect. Our findings suggested that miR-101/Girdin axis could be a potential application of HCC treatment.

Diagnostics and therapies have shown evident advances. Tumour surgery, chemotherapy and radiotherapy are the main techniques in treat cancers. Targeted therapy and drug resistance are the main focus in cancer research, but many molecular intracellular mechanisms remain unknown. Src homology region 2-containing protein tyrosine phosphatase 2 (Shp2) is associated with breast cancer, leukaemia, lung cancer, liver cancer, gastric cancer, laryngeal cancer, oral cancer and other cancer types. Signalling pathways involving Shp2 have also been discovered. Shp2 is related to many diseases. Mutations in the ptpn11 gene cause Noonan syndrome, LEOPARD syndrome and childhood leukaemia. Shp2 is also involved in several cancer-related processes, including cancer cell invasion and metastasis, apoptosis, DNA damage, cell proliferation, cell cycle and drug resistance. Based on the structure and function of Shp2, scientists have investigated specific mechanisms involved in cancer. Shp2 may be a potential therapeutic target because this phosphatase is implicated in many aspects. Furthermore, Shp2 inhibitors have been used in experiments to develop treatment strategies. However, conflicting results related to Shp2 functions have been presented in the literature, and such results should be resolved in future studies.

// Tianshu Li 1, 2 , Heng Lu 1 , Debarati Mukherjee 1 , Satadru K. Lahiri 1 , Chao Shen 1, 3 , Lin Yu 1 , Jihe Zhao 1 1 Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA 2 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA 3 College of Life Sciences, Wuhan University, Wuhan, China Correspondence to: Jihe Zhao, e-mail: Jihe.Zhao@ucf.edu Keywords: KLF8, EGFR, microRNA141, invasion and metastasis, breast cancer Received: March 17, 2015 Accepted: May 14, 2015 Published: May 27, 2015 ABSTRACT Kruppel-like factor 8 (KLF8) is a dual transcriptional factor critical for breast cancer progression. Epidermal growth factor receptor (EGFR) is frequently overexpressed in aggressive such as triple-negative breast cancer and associated with poor clinical outcomes. Here we report a novel KLF8-EGFR signaling axis in breast cancer. We identified a highly correlated co-overexpression between KLF8 and EGFR in invasive breast cancer cells and patient tumor samples. Overexpression of KLF8 in the non-tumorigenic MCF-10A cells induced the expression of EGFR, whereas knockdown of KLF8 from the MDA-MB-231 cells decreased it. Promoter activation and binding assays indicated that KLF8 promotes the EGFR expression by directly binding its gene promoter. We also revealed that KLF8 directly represses the promoter of miR141 and miR141 targets the 3′-untranslational region of EGFR transcript to inhibit EGFR translation. Treatment with the EGFR inhibitor AG1478 or overexpression of miR141 blocked the activity of ERK downstream of EGFR and inhibited KLF8-depndent cell invasiveness, proliferation and viability in cell culture and invasive growth and lung metastasis in nude mice. Conversely, overexpression of an inhibitory sponge of miR141 led to the opposite phenotypes. Taken together, these findings demonstrate a novel KLF8 to miR141/EGFR signaling pathway potentially crucial for breast cancer malignancy.

The incidence rate of head and neck squamous cell carcinoma (HNSCC) has steadily increased over the past decade. However, treatment options for metastatic HNSCC are often limited and the 5‐year survival rate has remained static. Therefore, the development and assessment of more efficient but less toxic therapeutic strategies is an unmet need for treatment of more extensive HNSCC. Here, we report that CYT997, a novel microtubule‐disrupting agent, exerts strong activity in inhibiting HNSCC cell invasion and metastasis. The loss of invasion capacity by CYT997 was accompanied by an associated increase in cell adhesion and the reversal of epithelial‐mesenchymal transition (EMT). Increased expression of E‐cadherin protein and decreased expression of Vimentin protein became evident in HNSCC cells following CYT997 exposure, which were consistently observed in HNSCC xenografts from the mice receiving CYT997. Moreover, the capacity of invasive HNSCC cells to form pulmonary metastases was significantly blocked with CYT997 treatment, indicating that the diminishment of EMT traits contributes to CYT997‐suppressed metastasis. Intriguingly, CYT997 impaired intracellular ATP levels in HNSCC cells, at least in part, through its inhibitory effect on the mitochondrial protein IF1. The addition of ATP attenuated CYT997‐induced suppression of cell invasion, coupled with down‐regulation of E‐Cadherin and up‐regulation of Vimentin. These findings support a critical role of ATP levels in cell invasion and metastasis under the influence of CYT997. Collectively, our data unveil the mechanism involved in mediating CYT997 action, and provide preclinical rationale for possible clinical application of CYT997 as a novel therapeutic strategy against aggressive HNSCC.

The long-term survival rate of hepatocellular carcinoma (HCC) is poor. One of the reasons for the poor rate of survival is the high rate of recurrence caused by intrahepatic metastas is that adversely affects long-term outcome. Many studies have indicated that microRNAs play an important role in HCC, but there has been no research of clonal origins on recurrent HCC (RHCC) by analzing microRNAs. In the present study, we found that miR-483-5p was significantly upregulated in RHCC tissues of short-term recurrence (≤ 2 years) by miRNA microarray screening, and can significantly promote migration and invasion of HCC cells in vitro and increase intrahepatic metastasis in nude mice in vivo. Furthermore, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM), which significantly suppressed migration and invasion of HCC cells, was a direct target of miR-483-5p, and the re-introduction of ALCAM expression could antagonize the promoting effects of miR-483-5p on the capacity of HCC cells for migration and invasion. In addition, expression level of ALCAM was negatively correlated with microvascular invasion and tumor size recognized as prognostic factors. The cases which were negative for ALCAM expression had shorter time to recurrence than positive cases, and univariate and multivariate survival analyses showed that ALCAM was an independent risk factor of HCC recurrence. qRT-PCR and Western blotting showed that the expression of EMT related genes (MMP-2, MMP-9, E-caherin and vimentin) significantly changed as a result of interfering or overexpression of ALCAM, and ALCAM was significantly associated with EMT in HCC. These results suggest that the miR-483-5p/ALCAM axis is an important regulator in invasion and metastasis and biomarker for recurrence risk assessment of HCC.

Background Pancreatic cancer is a lethal disease in part because of its potential for aggressive invasion and metastasis. Lipoxin A4 (LXA4) is one of the metabolites that is derived from arachidonic acid and that is catalyzed by 15-lipoxygenase (15-LOX), and it has recently been reported to exhibit anti-cancer effects. However, the role of LXA4 in pancreatic cancer remains to be elucidated. Methods Pancreatic cell lines were treated with vehicle or LXA4, and the invasive capacity was then assessed by Transwell assays. The expression of epithelial and mesenchymal markers was determined by western blotting and immunofluorescence. Anti-TGF-β1 neutralizing antibody and exogenous recombinant human TGF-β1 (rhTGF-β1) were used to study the effect of LXA4 on the TGF-β signaling. A liver metastasis model was applied to investigate the effect of LXA4 in vivo. The correlation between the Lipoxin effect score (LES) and the clinical-pathological features of pancreatic cancer was also analyzed. Results We found that in patients with pancreatic cancer, low LES was correlated with aggressive metastatic potential. The LXA4 activity, which was mediated by the LXA4 receptor FPRL1, could significantly suppress invasion capacity and mesenchymal phenotypes. The expression and autocrine signaling pathway activity of TGF-β1 were also downregulated by LXA4. In the liver metastasis model in nude mice, the stable analog of LXA4, BML-111, could inhibit the metastasis of pancreatic cancer cells. Conclusion Our results demonstrated that LXA4 could reverse mesenchymal phenotypes, which attenuated invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancer, which may provide a new strategy to prevent the metastasis of pancreatic cancer.

Human carcinoembryonic antigen (CEA) is the prototypic member of a family of highly related cell surface glycoproteins that includes carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) and others. CEACAM6 (formerly NCA), which belongs to the immunoglobulin superfamily, is a cell adhesion protein of the CEA family. It is normally expressed on the epithelial surfaces and on the surface of myeloid cells (CD66c). CEACAM6 is a multi-functional glycoprotein that mediates homotypic binding with other CEA family members and heterotypic binding with integrin receptors. It functions by organizing tissue architecture and regulating different signal transduction, while aberrant expression leads to the development of human malignancies. It was first discovered in proliferating cells of adenomas and hyperplastic polyps in comparison to benign colonic tissue when overexpressed on the surface of various cell types in model systems. CEACAM6 functions as a pan-inhibitor of cell differentiation and cell polarization, and it also causes distortion of tissue architecture. Moreover, overexpression of CEACAM6 modulates cancer progression through aberrant cell differentiation, anti-apoptosis, cell growth and resistance to therapeutic agents. In addition, CEACAM6 overexpression in multiple malignancies promotes cell invasion and metastasis, thereby representing an acquired advantage of tumor cells directly responsible for an invasive phenotype. This review focuses on the findings supporting the mechanisms of actions linking the oncogenic potential of CEACAM6 to the onset of cancer progression and pathogenesis, especially in breast cancer, and to validating CEACAM6 as a target to pave the way towards the design of efficient therapeutic strategies against breast cancer.

Background/Aims: Hepatocellular carcinoma (HCC) is a major threat to human health. The condition carries a high risk of death; 45% of new cases occur in China. Surgical resection is the first choice for treatment of HCC, but 30.9% of patients experience recurrence within 6 months after the operation. To improve patient survival, we must determine how to reduce the probability of recurrence and metastasis and elucidate the underlying mechanism of disease. We therefore studied the effect of somatostatin octapeptide (octreotide) on the invasion and metastasis of HCC. Methods: The migration and invasion cytological tests were used to detect the effect of octreotide on liver cancer cells (SK-Hep-1 and HepG2). PEBP1 RNAi was used to knockdown expression. Invasion and metastasis were measured with transwell migration and wound-healing assays. Western blotting was used to detect changes in levels of PEBP1 and invasion pathway proteins after octreotide treatment. The effect of octreotide was studied in vivo by establishing a pulmonary metastasis model using SK-Hep-1 cells in nude mice. In-vivo bioluminescence imaging and hematoxylin and eosin staining of lung tissue were used to verify the results. Results: Increasing concentrations of octreotide were progressively more effective in halting the invasion and metastasis of liver cancer cells. Octreotide may upregulate PEBP1, TIMP-2, and E-cadherin while downregulating MMP-2 and Twist to inhibit cell invasion and metastasis. And downregulation of PEBP1 would also change the expression of MMP-2, TIMP-2 and Twist. The in-vivo experiments showed no cancer cell metastasis in 4 of the 6 mice in the octreotide-treatment group, while all of the mice in the control group displayed pulmonary metastasis of human HCC cells. And the survival period of the mice in the octreotide-treatment group was significantly prolonged. Conclusions: Octreotide may weaken invasion and metastasis through the upregulation of PEBP1. Octreotide may reduce the risk of recurrence and metastasis after surgery for liver cancer.

// Xiao-Hong Liao 1, 2, 3, * , Ye Zhang 1, * , Wen-Jie Dong 1, 2, 3 , Zhi-Min Shao 1, 2, 3, 4, 5 and Da-Qiang Li 1, 2, 3, 4, 5 1 Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China 2 Department of Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China 3 Cancer Institute, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China 4 Department of Breast Surgery, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China 5 Key Laboratory of Breast Cancer in Shanghai, Shanghai Medical College, Fudan University, Shanghai 200032, China * These authors contributed equally to this work Correspondence to: Zhi-Min Shao, email: zhimingshao@yahoo.com Da-Qiang Li, email: daqiangli1974@fudan.edu.cn Keywords: breast cancer, invasion and metastasis, protein-protein interaction, MORC2, proline-rich domain Received: April 13, 2017 Accepted: June 05, 2017 Published: June 16, 2017 ABSTRACT MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling protein with emerging roles in the regulation of DNA damage response and gene transcription, but its mechanistic role in breast cancer development and progression remains unexplored. Here, we show that MORC2 promoted breast cancer invasion and metastasis and these effects depended on a proline-rich domain (PRD) within its carboxy-terminal region spanning residues 601–734. Induced expression of wild-type MORC2 did not significantly affect cell proliferation and cell-cycle progression, but promoted breast cancer cell migration and invasion in vitro and metastatic lung colonization in vivo . The PRD domain was dispensable for the protein stability and subcellular localization of MORC2, but depletion of the PRD domain substantially suppressed MORC2-mediated migration, invasion, and metastasis. Proteomic and biochemical analyses further demonstrated that wild-type MORC2, but not PRD deletion mutant, interacted with catenin delta 1 (CTNND1), a cadherin-associated protein that participates in tumor invasion and metastasis. Moreover, knockdown of endogenous CTNND1 by short hairpin RNAs suppressed the migratory and invasive potential of MORC2-expressing cells. Taken together, these results suggest that MORC2 promotes breast cancer invasion and metastasis through its PRD domain-mediated interaction with CTNND1.

Background Our previous study showed that GATA6 plays important roles in cholangiocarcinoma (CCA) cell invasion and metastasis. However, the regulation mechanism of GATA6 in CCA is not clear. In this study, we studied the potential function of miR-124 in CCA and the mechanism of GATA6 regulation. Methods The expression levels of miR-124 and GATA6 in cancerous tissues from 57 CCA patients was detected by RT-PCR and IHC. The impact of miR-124 on GATA6 expression in CCA cells was evaluated using cell transfection, xenotransplantation into nude mice and a luciferase reporter assay. Results miR-124 was decreased in 57 cancerous tissue samples compared with 38 matched paracancerous samples. The miR-124 level was inversely associated with lymph node involvement and distant metastasis. miR-124 significantly inhibited invasion and migration of CCA cells in vitro. Furthermore, miR-124 inhibited CCA cell metastasis in nude mice. miR-124 inhibited the luciferase activity of reporter genes containing the wild-type GATA6 3′-UTR, which was abrogated by mutation of the binding site. The protein levels of GATA6 were negatively regulated by miR-124. miR-124 expression was inversely associated with GATA6 in 57 cancerous samples. The miR-124-induced suppression of CCA invasion was abrogated by remedial expression of GATA6. GATA6 expression was decreased by miR-124 overexpression in liver masses from nude mice. Conclusions Our data suggested that miR-124 decreases GATA6 expression by targeting its 3′-UTR, which in turn inhibits CCA invasion and metastasis. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3166-z) contains supplementary material, which is available to authorized users.

Distant metastasis to specific target organs is responsible for over 90% of breast cancer-related deaths, but the underlying molecular mechanism is unclear. Mounting evidence suggests that the interplay between breast cancer cells and the target organ microenvironment is the key determinant of organ-specific metastasis of this lethal disease. Here, we highlight new findings and concepts concerning the emerging role of the tumor microenvironment in breast cancer metastasis; we also discuss potential therapeutic intervention strategies aimed at targeting components of the tumor microenvironment.