Tumor Suppressor In Gastric Cancer Research Articles

Circular RNA_LARP4 inhibits cell migration and invasion of prostate cancer by targeting FOXO3A.

The importance of circular RNAs in malignant tumors causes more attention in researchers. Circular RNA_LARP4 is identified as a tumor suppressor in gastric cancer, but the role of circular RNA_LARP4 in prostate cancer (PCa) remains unclear. Our work aims to uncover whether and how circular RNA_LARP4 functions in the PCa development. Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was utilized to determine the level of circular RNA_LARP4 in PCa tissues and cell lines. The patients' prognosis was analyzed. Circular RNA_LARP4 lentivirus was constructed for transfection of PCa cells. Cell migrated and invaded ability was detected through wound healing assay and transwell assay. Western blot assay was performed to analyze the protein level of FOXO3A. The low circular RNA_LARP4 expression was associated with poor prognosis of PCa patients. The circular RNA_LARP4 was lowly expressed in PCa tissues compared with adjacent samples. The expression of circular RNA_LARP4 was downregulated in PCa cell lines. The cell migrated and invaded ability of PCa cells was inhibited after circular RNA_LARP4 was overexpressed. Furthermore, FOXO3A expression was increased via the overexpression of circular RNA_LARP4. Circular RNA_LARP4 could suppress cell migration and invasion of PCa by upregulating FOXO3A.

LINC00619 restricts gastric cancer progression by preventing microRNA-224-5p-mediated inhibition of OPCML

Several long intergenic noncoding RNAs (lincRNAs) have been linked to carcinogenesis; however, little is known about the role of LINC00619 in gastric cancer (GC). LINC00619 was identified among differentially expressed lncRNAs linked to gastric cancer based on microarray analysis and its relationships with miR-224-5p and opioid binding protein/cell adhesion molecule-like gene (OPCML) were investigated. LINC00619, miR-224-5p, and OPCML expression were measured in GC tissues and cells. Ectopic expression and depletion experiments were conducted to assess the effects of LINC00619, miR-224-5p and OPCML on cell proliferation, invasion, migration and apoptosis as well as their effects on the expression of apoptosis- and metastasis-related genes (Bcl-2, Bax, MMP-2 and MMP-9). Tumorigenicity in the nude mice was also examined. Gastric cancer was characterized by downregulation of LINC00619 and OPCML and upregulation of miR-224-5p. Additionally, we found that miR-224-5p could interact with both LINC00619 and OPCML. Upregulation of LINC00619, which binds to miR-224-5p, led to decreased miR-224-5p expression while increasing the expression of OPCML, a target gene of miR-224-5p. Overexpression of LINC00619 or OPCML or downregulation of miR-224-5p suppressed cell proliferation, invasion, migration and tumorigenicity while promoting apoptosis in GC. Our results indicated that LINC00619 functions as a tumor suppressor in GC by impairing miR-224-5p-mediated inhibition of OPCML.

LncRNA WT1-AS over-expression inhibits non-small cell lung cancer cell stemness by down-regulating TGF-\u03b21

BackgroundLncRNA WT1-AS is a recently identified potential tumor suppressor in gastric cancer. This study mainly explored the role of WT1-AS in non-small cell lung cancer (NSCLC).MethodsWT1-AS and TGF-β1 mRNA in two types of tissues of 74 NSCLC patients were detected by performing RT-qPCR experiments. WT1-AS and TGF-β1 expression vectors were established using the pcDNA3.1 vector. Protein concentration was measured by BCA assay. Mean values in this study were calculated using the data of three biological replicates of each experiment.ResultsWe found that WT1-AS was down-regulated, while TGF-β1 was upregulated in NSCLC tissues. Survival analysis showed that low levels of WT1-AS expression predicted poor survival of NSCLC patients. WT1-AS and TGF-β1 were inversely correlated in NSCLC tissues. Over-expression experiments revealed down-regulated TGF-β1 after WT1-AS over-expression, while TGF-β1 over-expression failed to affect WT1-AS. WT1-AS over-expression resulted in inhibited cancer cell stemness. TGF-β1 over-expression played an opposite role and attenuated the effects of TGF-β1 over-expression.ConclusionTherefore, WT1-AS over-expression may inhibit non-small cell lung cancer cell stemness by down-regulating TGF-β1.Trial registrationThe First Affiliated Hospital of Anhui Medical University Ethics committee approved this study (AHMU20101009).

MiR-30a suppresses metastasis of gastric adenocarcinoma via targeting FAPα.

Gastric cancer is one of the leading causes of death worldwide. MicroRNA-30a (miR-30a) has been demonstrated to be involved in several types of cancer development. We aimed to identify the molecular mechanism of miR-30a in gastric cancer. We investigated the expression of miR-30a in gastric cancer tissues by qRT-PCR. The role of miR-30a on the metastasis and proliferation of gastric cancer was evaluated by cell migration assay, CCK-8 assay and tumor peritoneal dissemination model. The target of miR-30a in gastric cancer was identified. We discovered that miR-30a was significantly downregulated in gastric cancer tissues compared with adjacent nonmalignant tissues. The expression of miR-30a was inversely correlated with progression of gastric cancer. Gain- and loss-of function revealed that miR-30a acted as a potent tumor suppressor in gastric cancer. Re-expressed miR-30a inhibited gastric cancer cells migration, knock down miR-30a have the opposite effects. Furthermore, overexpression of miR-30a suppressed tumor peritoneal dissemination in vivo. We identified that fibroblast activation protein α (FAPα) was a direct target of miR-30a. The relative expression of FAPα was significantly higher in gastric cancer tissues compared with adjacent nonmalignant tissues. Inhibition of FAPα could recapitulate the effects of miR-30a, and overexpression of FAPα could abrogate the effect of miR-30a. MiR-30a inhibited gastric cancer metastasis by targeting FAPα, suggesting that miR-30a may function as a novel tumor suppressor in gastric cancer.

DAXX inhibits cancer stemness and epithelial\u2013mesenchymal transition in gastric cancer

BackgroundDAXX is a transcription repressor that has been implicated in several types of cancers, but its role in the development of gastric cancer remains unknown.MethodsWe analysed the expression of DAXX in 83 pairs of gastric cancer samples, including neoplastic and adjacent tissues, and correlated the expression levels with clinical stages. We also investigated the molecular mechanisms by which DAXX downregulation promotes cancer growth using both in vitro and in vivo models.ResultsDAXX was downregulated in advanced gastric cancer samples. The expression of DAXX inversely correlates with that of cancer stem cell markers CD44 and Oct4 in gastric cancer lines. DAXX overexpression in gastric cancer cells inhibited migration, invasion and epithelial– mesenchymal transition (EMT). The inhibition of EMT was achieved through the repression of SNAI3, a key inducer of EMT, by recruiting HDAC-1 into the nucleus. Using a xenograft mouse model, we demonstrated that the MKN45 cells formed smaller tumours when DAXX was overexpressed. Wild-type AGS cells were not able to form tumours in nude mice, but in contrast, formed visible tumours when DAXX was silenced in the cells.ConclusionWe for the first time demonstrated that DAXX functions as a tumour suppressor in gastric cancer by inhibiting stem cell growth and EMT.

Circ PSMC3 inhibits prostate cancer cell proliferation by downregulating DGCR8.

The importance of circular RNAs in malignant tumors has attracted a lot of attention. Circular PSMC3 (CircPSMC3) is identified as a tumor suppressor in gastric cancer. The role of circPSMC3 in prostate cancer (PCa) remains unclear. Our study aims to uncover whether and how circPSMC3 functions in PCa development. Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was utilized to determine the level of circPSMC3 in PCa tissues and cell lines. The relation between circPSMC3 expression and patients' prognosis was analyzed as well. CircPSMC3 lentivirus was constructed and transfected into PCa cells. Cell migration and invasion abilities were detected through wound healing assay, transwell assay, and Matrigel assay, respectively. Western blot assay was performed to detect the protein level of DGCR8. CircPSMC3 was lowly expressed in PCa tissues compared with adjacent normal tissues. Low expression of circPSMC3 was significantly downregulated in PCa cell lines as well. The migration and invasion abilities of PCa cells were significantly inhibited after circPSMC3 was overexpressed in vitro. Furthermore, DGCR8 expression increased remarkably via the overexpression of circPSMC3. CircPSMC3 could suppress PCa cell migration and invasion by upregulating DGCR8.

Hypoxia Activates SOX5/Wnt/β-Catenin Signaling by Suppressing MiR-338-3p in Gastric Cancer.

MicroRNAs are known to be important in a variety of cancer types. The specific expression and roles of miR-338-3p in the context of gastric cancer, however, remains largely unknown. In this study, we found that miR-338-3p was expressed significantly lower in established/primary human gastric cancer cells than that in human gastric epithelial cells; miR-338-3p is also decreased in human gastric cancer tissues and was positively associated with the worse prognosis of patients with gastric cancer. Enforced expression of miR-338-3p could inhibit cell growth, survival, and proliferation, while inducing cell apoptosis. In addition, miR-338-3p negatively regulated SOX5 expression through directly binding to the 3′-untranslated region of SOX5, and an inverse correlation was found between miR-338-3p and SOX5 messenger RNA expression in gastric cancer tissues. Furthermore, miR-338-3p-induced inactivation of Wnt/β-catenin signaling was greatly abrogated by SOX5 upregulation. Finally, we found that hypoxic conditions were linked with reduced miR-338-3p expression in the context of gastric cancer. In conclusion, miR-338-3p acts as a tumor suppressor in gastric cancer, possibly by directly targeting SOX5 and blocking Wnt/β-catenin signaling. These findings might provide novel therapeutic targets for gastric cancer.

DERL3 functions as a tumor suppressor in gastric cancer

BackgroundGastric cancer is a common malignant tumor in the clinic with a high mortality rate, ranking the first among malignant tumors of the digestive system. Early gastric cancer exhibits no specific clinical symptoms and signs, and most of the patients were diagnosed as advanced gastric cancer. The prognosis is poor, and the 5-year overall survival rate is still lower than 30%, seriously threatening people’s life and health. However, the pathogenesis of gastric cancer is still unclear. MethodsThis study aimed to identify methylated differentially expressed genes in gastric cancer and to study the cellular functions and pathways that may be involved in its regulation, as well as the biological functions of key methylated differentially expressed genes. The gene expression data set and methylation data set of gastric cancer genes based on TCGA were analyzed to identify prognostic methylated genes. ResultsThis study showed that the methylation of the DERL3 promoter was correlated with the clinical analysis of tumors. Further studies were conducted on genes co-expressed with DERL3, whose functions and pathways to inhibit gastric cancer were adaptive immune response, T cell activation, immune response-regulating pathway, cell surface on molecules, and natural killer cell-mediated cytotoxicity. Finally, cell proliferation assay, cell scratch assay, and cell invasion assay confirmed that DERL3 as a tumor suppressor gene inhibited the malignant evolution of gastric cancer. ConclusionsThe analysis of key methylated differentially expressed genes helped elucidate the epigenetic regulation mechanism in the development of gastric cancer. DERL3, as a methylation biomarker, has a predictive and prognostic value in the accurate diagnosis and treatment of gastric cancer and provides potential targets for the precision treatment of gastric cancer. Trial RegistrationNot applicable.

TRIM58 suppresses the tumor growth in gastric cancer by inactivation of β-catenin signaling via ubiquitination

ABSTRACTObjective: To investigate and define the underlying molecular mechanism of tripartite motif-containing 58 (TRIM58) in regulating the tumor growth of gastric cancer (GC).Methods: TRIM58 expression in GC tissues and cells was detected by real-time PCR and Western blot, followed by lentiviral-induced overexpression or knockdown of TRIM58. Subsequently, CCK8, BrdU-ELISA, flow cytometry, immunoprecipitation, in vitro animal experiments and immunochemistry were performed to explore the function of TRIM58. Western blotting was used to detect β-catenin, C-myc, Cyclin D1, and survivin expression.Results: TRIM58 expression was significantly reduced in tumor tissues of GC patients and GC cell lines, whereas β-catenin, C-myc, Cyclin D1, and survivin were highly expressed. Overexpression of TRIM58 in GC cells resulted in decreases in β-catenin, C-myc, Cyclin D1, and survivin protein expression and significantly suppressed proliferation by preventing cell-cycle progression and promoting cell apoptosis. Conversely, TRIM58 knockdown resulted in the opposite effects. Furthermore, the effect of TRIM58 knockdown on GC cells was potently reversed by a β-catenin inhibitor, XAV939. Immunoprecipitations showed the interaction between TRIM58 and β-catenin, and TRIM58 overexpression significantly enhanced β-catenin degradation. In addition, we found a significant decrease in the growth and weight of tumors and an increase in tumor cell apoptosis in TRIM58-overexpression nude mice, which were also accompanied by reduced β-catenin expression.Conclusions: These data suggest that TRIM58 may function as a tumor suppressor in GC and potentially suppress the tumor growth of gastric cancer by inactivation of β-catenin signaling via ubiquitination.

STRA6 exerts oncogenic role in gastric tumorigenesis by acting as a crucial target of miR-873

BackgroundIncreasing evidence shows that stimulated by retinoic acid 6 (STRA6) participates in regulating multiple cancers. However, the biological roles of STRA6 in gastric cancer (GC) remain unknown. This study aimed to investigate the biological function of STRA6 and reveal the underlying mechanism of its dysregulation in GC.MethodsThe expression level of STRA6 was detected through quantitative real-time PCR and Western blot analysis. The effects of STRA6 on the proliferation of GC cells were studied through CCK-8 proliferation, colony formation and 5-ethynyl-2′-deoxyuridine (EdU) assays. The effects of STRA6 on migration and invasion were detected via wound healing and Transwell assays. Upstream miRNAs, which might regulate STRA6 expression, was predicted through bioinformatics analysis. Their interaction was further confirmed through dual-luciferase reporter assays and rescue experiments.ResultsSTRA6 was up-regulated in GC and enhanced the proliferation and metastasis of GC cells in vitro and in vivo. STRA6 knockdown could inhibit the Wnt/β-catenin signalling pathway. STRA6 was confirmed as an miR-873 target, which acted as a tumour suppressor in GC. Rescue assays showed that the repressing effect of miR-873 could be partially reversed by overexpressing STRA6.ConclusionsSTRA6 is down-regulated by miR-873 and plays an oncogenic role by activating Wnt/β-catenin signalling in GC.

LncRNA WT1-AS Inhibits Triple-Negative Breast Cancer Cell Migration and Invasion by Downregulating Transforming Growth Factor β1.

Background: Long noncoding RNA WT1-AS has been demonstrated as a potential tumor suppressor in gastric cancer. However, the functions of WT1-AS in other types of cancer remain unclear. Our study was therefore performed to explore the role of WT1-AS in triple-negative breast cancer (TNBC). Materials and Methods: Tissue specimens were obtained from 62 TNBC patients included in this study. A TNBC cell line BT-549 was used as the cell model of TNBC. Gene expression was detected by qPCR and Western blot. Overexpression experiments were used to analyze gene interactions. Transwell assays were used to explore the effects of transfections on cell invasion and migration. Results: We found that WT1-AS was downregulated in TNBC tissues than in nontumor tissues and decreased with increase in clinical stages. Transforming growth factor β1 (TGF-β1) was upregulated in TNBC tissues and inversely correlated with WT1-AS. TGF-β1 overexpression did not significantly affect WT1-AS in BT-549 cells, but WT1-AS negatively regulated the expression of TGF-β1. WT1-AS overexpression caused inhibited migration and invasion of TNBC cells. TGF-β1 overexpression showed opposite functions and reduced the effects of WT1-AS overexpression. Conclusion: WT1-AS may downregulate TGF-β to inhibit the migration and invasion of TNBC cells.

Downregulated miR-383-5p contributes to the proliferation and migration of gastric cancer cells and is associated with poor prognosis.

AimThe study aims to identify differentially expressed microRNAs (DEMs) in gastric cancer (GC) and explore the expression, prognosis and downstream regulation role of miR-383-5p in GC.MethodsThe GC miRNA-Seq and clinical information were downloaded from Firebrowse which stores integrated data sourced from The Cancer Genome Atlas database. The DEMs were identified with limma package in R software at the cut-off criteria of P < 0.05 and |log2 fold change| > 1.0 (|log2FC| > 1.0). The expression of miR-383-5p in GC cell lines and 54 paired GC tissues was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The overall survival curve of miR-383-5p and the association between its expression and clinicopathological features were explored. Wound healing and cell counting kit-8 assays were performed to investigate the capacity of miR-383-5p in cell proliferation and migration. The downstream target genes were predicted by bioinformatics tools (miRDB, TargetScan and starBase). The consensus target genes were selected for gene functional enrichment analysis by FunRich v3.0 software. The luciferase reporter assay was performed to verify the potential targeting sites of miR-383-5p on lactate dehydrogenase A (LDHA).ResultsA total of 21 down-regulated miRNAs (including miR-383-5p) and 202 up-regulated miRNAs were identified by analyzing GC miRNA-Seq data. Survival analysis found that patients with low miR-383-5p expression had a shorter survival time (median survival time 21.1 months) than those with high expression (46.9 months). The results of qRT-PCR indicated that miR-383-5p was downregulated in GC cell lines and tissues, which was consistent with miRNA-Seq data. The expression of miR-383-5p was significantly associated with tumor size and differentiation grade. Besides, overexpression of miR-383-5p suppressed GC cells proliferation and migration. A total of 49 common target genes of miR-383-5p were obtained by bioinformatics tools and gene functional enrichment analysis showed that these predicted genes participated in PI3K, mTOR, c-MYC, TGF-beta receptor, VEGF/VEGFR and E-cadherin signaling pathways. The data showed that expression of miR-383-5p was negatively correlated with target LDHA (r = −0.203). Luciferase reporter assay suggested that LDHA was a target of miR-383-5p.ConclusionThe present study concluded that miR-383-5p was downregulated and may act as a tumor suppressor in GC. Furthermore, its target genes were involved in important signaling pathways. It could be a prognostic biomarker and play a vital role in exploring the molecular mechanism of GC.

Exosomal miR-1246 in serum as a potential biomarker for early diagnosis of gastric cancer.

Gastric cancer (GC) patients are usually diagnosed in advanced stages which results in high mortality. This study aimed to identify novel circulating miRNAs as biomarkers for the early detection of GC. Candidate miRNA was identified after integrated analysis of two Gene Expression Omnibus (GEO) datasets and clinical serum samples. Exosomes extracted were verified using transmission electron microscopy (TEM) and western blot. The expressions of miRNAs were tested through qRT-PCR. Receiver operating characteristic curve (ROC) analysis was used to explore the diagnostic utility of miRNAs. RNA pull-down assay was used to find RNA binding proteins (RBPs) which transport candidate miRNA into exosomes. Bioinformatics analysis of candidate miRNA was conducted using DAVID and Cytoscape. After integrated analysis of two GEO datasets, six circulating miRNAs were found to be consistently upregulated in GC patients. Then, qRT-PCR demonstrated that serum miR-1246 was the one with the largest fold change. Studies in vitro revealed that elevated serum miR-1246 was tumor-derived by being packaged into exosomes with the help of ELAVL1. Thereafter, we discovered that exosomal miR-1246 expressions in serum could differentiate GC patients with TNM stage I from healthy controls (HCs) and patients with benign diseases (BDs) with area under the curve (AUC) of 0.843 and 0.811, respectively. Bioinformatics analysis revealed miR-1246, as a tumor suppressor in GC, could regulate several signaling pathways. Circulating exosomal miR-1246 was a potential biomarker for the early diagnosis of GC.

MicroRNA-1297 inhibits proliferation and promotes apoptosis in gastric cancer cells by downregulating CDC6 expression.

Gastric cancer (GC), one of the most common malignant tumors and the second most common leading cause of cancer-related death worldwide, is a biologically heterogeneous disease accompanied by various genetic and epigenetic alterations. However, the molecular mechanisms underlying this disease are complex and not completely understood. Increasing studies have shown that aberrant microRNA (miRNA) expression is associated with GC tumorigenesis and growth. MiR-1297 has been confirmed to be a cancer suppressor in diverse tumors in humans. However, to date, the function and mechanism of miR-1297 in GC have not been determined. Here, we found that the expression of miR-1297 was significantly reduced in GC tissues or GC cell lines compared with paracarcinoma normal tissue or normal cell lines. Exogenic overexpression of miR-1297 in GC cell lines can inhibit cell proliferation and colony formation and induce apoptosis, and inhibition of miR-1297 in GC cell lines can promote cell proliferation and colony formation, and reduce apoptosis in vitro. We further confirmed that miR-1297 acted as a tumor suppressor through targeting cell division control protein 6 (CDC6) in GC. Moreover, the inverse relationship between miR-1297 and CDC6 was verified in GC cell lines. Our results indicated that miR-1297 is a potent tumor suppressor in GC, and its antiproliferative and gene-regulatory effects are, in part, mediated through its downstream target gene, CDC6. These findings implied that miR-1297 might be used as a novel therapeutic target of GC.

MTSS1 inhibits metastatic potential and induces G2/M phase cell cycle arrest in gastric cancer.

Background: Metastasis suppressor 1 (MTSS1), a potential metastasis suppressor gene associated with tumor progression, may play an important role in cancer development. Our previous study demonstrated that MTSS1 was downregulated significantly when gastric cancer (GC) progressed and metastasized, suggesting that MTSS1 may be involved in the physiopathologic mechanism of GC.Purpose: The objective of this study was to evaluate the effect of MTSS1 expression on the biological behavior of gastric cancer cell both in vitro and in vivo.Materials and methods: The gain-and-loss function of MTSS1 in GC cells were analyzed after transfection with pEGFP-N1-MTSS1 and ShRNA431. Proliferation and invasion abilities were measured by means of plate clone formation assay and transwell assay. To further explore the underlying mechanism of MTSS1-induced tumor restrain, cell cycle distribution was analyzed using flow cytometry.Results: The results revealed that overexpression of MTSS1 significantly reduced proliferation, migration and invasion of GC cells in vivo and in vitro, while downregulation of MTSS1 had the opposite biological manifestations. Moreover, overexpression of MTSS1 induced accumulation of GC cells in G2/M phase, increased phosphorylated Cdc2 expression and decreased Cdc25C and cyclinB1 levels, suggesting MTSS1 could cause G2/M cell cycle arrest.Conclusion: Our data provided insight into an important role for MTSS1 in suppressing tumor cell proliferation, invasion and migration, indicating that MTSS, as a functional tumor suppressor in GC, could be a potential therapeutic target to prevent GC metastasis.

Consistency analysis of microRNA-arm expression reveals microRNA-369-5p/3p as tumor suppressors in gastric cancer.

The 5p and 3p arms of microRNA (miRNA) are typically generated from the same precursor, and one arm influences protein output, while the other has a short half‐life. However, a few miR‐5p/3p pairs have been reported to co‐exist in cancer cells. Here, we performed a genome‐wide analysis of miRNA expression in gastric cancer (GC) cells to systematically investigate the co‐expression profile of miR‐5p/3p in gastric tumorigenesis. We discovered that only 41 miR‐5p/3p pairs out of 1749 analyzed miRNA were co‐expressed. Specifically, abnormal expression of miR‐369‐5p and miR‐369‐3p was correlated with GC progression. Importantly, both in vitro and in vivo assays revealed that miR‐369‐5p and miR‐369‐3p exhibited tumor‐suppressive roles by regulating jun proto‐oncogene and v‐akt murine thymoma viral oncogene homolog 1 function in GC cells, respectively. Moreover, we observed that miR‐369 was inactivated in GC tissues due to DNA methylation. We also showed that inhibition of miR‐369‐5p/3p attenuated the effect of azacitidine (AZA) treatment on suppressing cell growth and invasion. These results suggest that the therapeutic efficacy of AZA in GC is at least partly attributable to miR‐369 activation. Overall, our findings provide convincing evidence that both the 5p and 3p arms of miRNA co‐expressed in GC and DNA methylation‐induced miR‐369 signaling contribute to GC progression.

TMEM100 expression suppresses metastasis and enhances sensitivity to chemotherapy in gastric cancer.

The gene encoding transmembrane protein 100 (TMEM100) was first discovered to be transcribed by the murine genome. It has been recently proven that TMEM100 contributes to hepatocellular carcinoma and non-small-cell lung carcinoma (NSCLC). This study investigates the impact of TMEM100 expression on gastric cancer (GC). TMEM100 expression was remarkably downregulated in GC samples compared to the surrounding non-malignant tissues (p < 0.01). Excessive TMEM100 expression prohibited the migration and invasion of GC cells without influencing their growth. However, TMEM100 knockdown restored their migration and invasion potential. Additionally, TMEM100 expression restored the sensitivity of GC cells to chemotherapeutic drugs such as 5-fluouracil (5-FU) and cisplatin. In terms of TMEM100 modulation, it was revealed that BMP9 rather than BMP10, is the upstream modulator of TM3M100. HIF1α downregulation modulated the impact of TMEM100 on cell migration, chemotherapy sensitivity and invasion in GC cells. Eventually, the in vivo examination of TMEM100 activity revealed that its upregulation prohibits the pulmonary metastasis of GC cells and increases the sensitivity of xenograft tumors to 5-FU treatment. In conclusion, TMEM100 serves as a tumor suppressor in GC and could be used as a promising target for the treatment of GC and as a predictor of GC clinical outcome.

Effects of microRNA-378 on epithelial-mesenchymal transition, migration, invasion and prognosis in gastric carcinoma by targeting BMP2.

Gastric cancer (GC) is a common malignancy. Recent studies have suggested that microRNAs are crucial factors in tumorigenesis. Thus, we investigated the effect of miR-378 on GC metastasis and further explored the underlying mechanism. Quantitative Real-time polymerase chain reaction (qRT-PCR) was carried out to measure the miR-378 expressions in GC and adjacent normal tissue samples. MiR-378 expressions in human GC cells were determined using qRT-PCR and Western blots. Moreover, transwell assays were conducted to measure the invasion and migration capacities of GC cells. Additionally, the regulating effects on BMP2 by miR-378 were assessed by luciferase reporter assays and western blots. Western blot was also carried out to observe the protein expressions of epithelial-mesenchymal transition (EMT) related genes. MiR-378 expressions in GC tissues were downregulated. In the meantime, reduced miR-378 expression was associated with poor prognosis and malignant clinicopathologic features of GC patients. MiR-378 overexpression repressed GC cell invasion, migration and EMT. Furthermore, BMP2 was a direct target of miR-378 and implicated in miR-378-mediated suppressive functions in GC invasion, migration and EMT. We showed that miR-378 served as a tumor suppressor in GC via modulating BMP2, suggesting that miR-378/BMP2 axis might be therapeutic targets and promising biomarkers for GC treatment.

CircLMTK2 acts as a novel tumor suppressor in gastric cancer.

Recently, circRNAs have been found to play regulatory roles in cancer. In the present study, we aimed to investigate the characteristics and effect of circLMTK2, and its potential role as a novel biomarker in cases of gastric cancer (GC). About 111 pairs of clinical tissues from patients were collected for circLMTK2 expression investigation. Afterward, the relationship of circLMTK2 expression level and clinical features, such as survival, tumor size and so on, were analyzed, along with a multivariate Cox hazards analysis. Finally, malignant biological properties, like cell viability and mobility, were explored in cell line MGC-803. We found that circLMTK2 was a stable circRNA generated from the back-spliced Exon 10 and Exon 11 of the LMTK2 gene in GC cells. CircLMTK2 expression was significantly down-regulated in gastric carcinoma tissue specimens (P<0.001) compared with its expression in paired normal tissues. Furthermore, a Kaplan–Meier analysis revealed that lower levels of circLMTK2 expression were associated with decreased overall survival (OS) (P<0.001), and a multivariate Cox hazards analysis showed that high circLMTK2 expression was an independent factor for OS. Afterward, overexpression of circLMTK2 was performed in gastric cancer cell line MGC-803, and results indicated that malignant biological properties were inhibited by circLTMK2 overexpression. The present study showed the first evidence that circLMTK2 was down-regulated in GC, suggesting it as a novel biomarker for prognosis, and also as a therapeutic target in treatment of GC.

RN181 is a tumour suppressor in gastric cancer by regulation of the ERK/MAPK-cyclin D1/CDK4 pathway.

RN181, a RING finger domain‐containing protein, is an E3 ubiquitin ligase. However, its biological function and clinical significance in cancer biology are obscure. Here, we report that RN181 expression is significantly down‐regulated in 165 tumour tissues of gastric carcinoma (GC) versus adjacent non‐tumour tissues, and inversely associated with tumour differentiation, tumour size, clinical stage, and patient's overall survival. Alterations of RN181 expression in GC cells by retrovirus‐transduced up‐regulation and down‐regulation demonstrated that RN181 functions as a tumour suppressor to inhibit growth of GC in both in vitro culture and in vivo animal models by decreasing tumour cell proliferation and increasing tumour cell apoptosis. Cell cycle analysis revealed that RN181 controls the cell cycle transition from G1 to S phase. Mechanistic studies demonstrated that RN181 inhibits ERK/MAPK signalling, thereby regulating the activity of cyclin D1–CDK4, and consequently controlling progression in the cell cycle from G1 to S phase. Restoring CDK4 in GC cells rescued the inhibitory phenotype produced by RN181 in vitro and in vivo, suggesting a dominant role of CDK4 in control of the tumour growth by RN181. Importantly, RN181 expression is inversely correlated with the expression of cyclin D1 and CDK4 in GC clinical samples, substantiating the role of the RN181–cyclin D1/CDK4 pathway in control of the tumour growth of GC. Our results provide new insights into the pathogenesis and development of GC and rationale for developing novel intervention strategies against GC by disruption of ERK/MAPK–cyclin D1/CDK4 signalling. In addition, RN181 may serve as a novel biomarker for predicting clinical outcome of GC. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.