Promoted Gastric Cancer Cell Migration Research Articles

TRIM37 promotes cell invasion and metastasis by regulating SIP1-mediated epithelial-mesenchymal transition in gastric cancer.

BackgroundTripartite motif containing 37 (TRIM37) has been demonstrated to function importantly during the progression of various cancers. However, the role of TRIM37 in gastric cancer (GC) remains elusive.Materials and methodsTRIM37 mRNA and protein expressions were determined by qRT-PCR, Western blot, and immunohistochemical staining in GC specimens. The effects of TRIM37 on GC cells behavior were evaluated by transwell assays in vitro and metastasis assay in vivo, respectively. Besides, qRT-PCR, Western blot, and immunofluorescence staining were employed to detect the expressions of TRIM37 and epithelial–mesenchymal transition (EMT)-related markers.ResultsThe present study revealed that TRIM37 mRNA or protein expression was significantly increased in GC tissues compared with that in paracancerous control tissues, and its aberrant overexpression was closely associated with clinical metastasis and poor prognosis in patients with GC. TRIM37 knockdown significantly suppressed GC cells migration and invasion in vitro, as well as metastasis in vivo. Inversely, TRIM37 overexpression exerted the opposite effects. Mechanistic studies suggested that SIP1-mediated EMT might be responsible for TRIM37-facilitated GC cells migration and invasion.ConclusionOur findings revealed that high TRIM37 expression was associated with clinical metastasis and poor survival in patients with GC. TRIM37 promoted GC cells migration and invasion via EMT, mediated by the transcription factor SIP1, thus providing a candidate target for GC treatment.

Ubiquitin-like modifier activating enzyme 2 promotes cell migration and invasion through Wnt/β-catenin signaling in gastric cancer.

AIMTo investigate the function and mechanism of ubiquitin-like modifier activating enzyme 2 (Uba2) in progression of gastric cancer (GC) cells.METHODSUba2 level in patients with GC was analyzed by Western blotting and immunohistochemistry. MTT and colony formation assays were performed to examine cell proliferation. Flow cytometry was used for cell cycle analysis. Wound healing and Transwell assays were conducted to examine the effects of Uba2 on migration and invasion. Expression levels of cell cycle-related proteins, epithelial-mesenchymal transition (EMT) biomarkers, and involvement of the Wnt/β-catenin pathway was assessed by Western blotting. Activation of the Wnt/β-catenin pathway was confirmed by luciferase assay.RESULTSUba2 expression was higher in GC than in normal tissues. Increased Uba2 expression was correlated with tissue differentiation, Lauren’s classification, vascular invasion, and TNM stage, as determined by the analysis of 100 GC cases (P < 0.05). Knock-down of Uba2 inhibited GC cell proliferation, induced cell cycle arrest, and altered expression of cyclin D1, P21, P27, and Bcl-2, while up-regulation of Uba2 showed the opposite effects. The wound healing and Transwell assays showed that Uba2 promoted GC cell migration and invasion. Western blotting revealed alterations in EMT biomarkers, suggesting the role of Uba2 in EMT. Furthermore, the luciferase reporter assay indicated the involvement of the Wnt/β-catenin signaling pathway as a possible modulator of Uba2 oncogenic functions.CONCLUSIONUba2 plays a vital role in GC cell migration and invasion, possibly by regulating the Wnt/β-catenin signaling pathway and EMT.

SIRT1 suppresses the migration and invasion of gastric cancer by regulating ARHGAP5 expression

Gastric cancer (GC) ranks among the top five malignant tumors worldwide by the incidence and mortality rate. However, the mechanisms underlying its progression are poorly understood. In this study, we investigated the role of SIRT1, a class III deacetylase, in the invasion and metastasis of GC. Here, we found that knockdown of SIRT1 promoted GC cell migration and invasion in vitro and metastasis in vivo. Forced expression of SIRT1 in GC cells had the opposite effects. Then, we used mRNA microarray to identify the target genes that are regulated by SIRT1 and found that ARHGAP5 was downregulated by SIRT1. The results of the mRNA microarray were confirmed in several GC cell lines. Furthermore, SIRT1 inhibited the expression of ARHGAP5 by physically associating with transcription factor c-JUN and deacetylating and inhibiting the transcriptional activity of c-JUN. Then the expression dynamics and clinical significance of ARHGAP5 were analyzed using clinical samples and database. The expression of ARHGAP5 was increased in GC, and positively correlated with tumor size, tumor infiltration, lymph node metastasis, and clinical stage. And multivariate analyses indicated that ARHGAP5 served as an independent prognostic marker of GC. In addition, the biological effects of ARHGAP5 in SIRT1-mediated inhibition of GC migration and invasion were investigated using both in vitro and in vivo models. Silencing of ARHGAP5 considerably inhibited the migration and invasion of GC, and ARHGAP5 was found to be involved in the SIRT1-mediated inhibition of GC migration and invasion. Our results indicate that SIRT1 suppresses migration and invasion of GC by downregulating ARHGAP5 through an interaction with c-JUN, and these phenomena represent a novel mechanism of the antitumor action of SIRT1.

DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer

DNA methyltransferase 3A (DNMT3A) has been recognised as a key element of epigenetic regulation in normal development, and the aberrant regulation of DNMT3A is implicated in multiple types of cancers, especially haematological malignancies. However, its clinical significance and detailed functional role in solid tumours remain unknown, although abnormal expression has gained widespread attention in these cancers. Here, we show that DNMT3A isoform b (DNMT3Ab), a member of the DNMT3A isoform family, is critical for directing epithelial–mesenchymal transition (EMT)-associated metastasis in gastric cancer (GC). DNMT3Ab is positively linked to tumour-node-metastasis (TNM) stage, lymph node metastasis and poor prognosis in GC patients. Overexpression of DNMT3Ab promotes GC cell migration and invasion as well as EMT through repression of E-cadherin. Meanwhile, DNMT3Ab promotes lung metastasis of GC in vivo. Mechanistic studies indicate that DNMT3Ab mediates the epigenetic inaction of the E-cadherin gene via DNA hypermethylation and histone modifications of H3K9me2 and H3K27me3. Depletion of DNMT3Ab effectively restores the expression of E-cadherin and reverses TGF-β-induced EMT by reducing DNA methylation, H3K9me2 and H3K27me3 levels at the E-cadherin promoter. Importantly, DNMT3Ab cooperated with H3K9me2 and H3K27me3 contributes to the transcriptional regulation of E-cadherin in a Snail-dependent manner. Further, gene expression profiling analysis indicates that multiple metastasis-associated genes and oncogenic signalling pathways are regulated in response to DNMT3Ab overexpression. These results identify DNMT3Ab as a crucial regulator of metastasis-related genes in GC. Targeting the DNMT3Ab/Snail/E-cadherin axis may provide a promising therapeutic strategy in the treatment of metastatic GC with high DNMT3Ab expression.

MiR-93-5p/IFNAR1 axis promotes gastric cancer metastasis through activating the STAT3 signaling pathway

Aberrant expression of microRNAs (miRNAs) plays an important role in gastric cancer (GC) development. miR-93-5p has shown opposing functions in different types of cancers, but the exact expression pattern and molecular mechanism of miR-93-5p in GC development remain to be elucidated. Here, we reported that miR-93-5p expression was increased in GC tissues compared with the adjacent normal tissues and that its overexpression was correlated with distant metastasis and poor survival in GC patients. miR-93-5p knockdown inhibited the migration, invasion and proliferation of GC cells in vitro and in vivo, while its overexpression displayed an opposite result. Using an mRNA microarray, we found that miR-93-5p significantly downregulated IFNAR1 expression in GC cells, which was further identified as a direct target of miR-93-5p. IFNAR1 knockdown promoted GC cell migration and invasion, but its restoration could rescue GC cell migration and invasion induced by miR-93-5p overexpression. Moreover, miR-93-5p-IFNAR1 axis increased MMP9 expression via STAT3 pathway in GC cells. Taken together, we reveal that miR-93-5p overexpression is associated with the poor survival of GC patients and miR-93-5p-IFNAR1 axis promotes GC metastasis through activation of STAT3 pathway.

MAGI1 inhibits migration and invasion via blocking MAPK/ERK signaling pathway in gastric cancer.

ObjectiveTo explore the association of membrane-associated guanylate kinase inverted 1 (MAGI1) with gastric cancer (GC) and the related molecular mechanisms.MethodsThe reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) were utilized to measure the MAGI1 expression level in GC tissues. Quantitative real-time PCR and Western blotting were used to ensure the MAGI1 expression in GC cell lines. Small hairpin RNA (shRNA) was applied for knockdown of endogenous MAGI1 in GC cells. MTT assay and colony formation assay, scratch wounding migration assay and transwell chamber migration assay, as well as transwell chamber invasion assay were employed respectively to investigate the GC cell proliferation, migration and invasion in MAGI1-knockdown and control GC cells. The potential molecular mechanism mediated by MAGI1 was studied using Western blotting and RT- PCR.ResultsRT-PCR and IHC verified MAGI1 was frequently expressed in matched adjacent noncancerous mucosa compared with GC tissues and the expression of MAGI1 was related to clinical pathological parameters. Functional assays indicated that MAGI1 knockdown significantly promoted GC cell migration and invasion. Further mechanism investigation demonstrated that one pathway of MAGI1 inhibiting migration and invasion was mainly by altering the expression of matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT)-related molecules via inhibiting MAPK/ERK signaling pathway.ConclusionsMAGI1 was associated with GC clinical pathological parameters and acted as a tumor suppressor via inhibiting of MAPK/ERK signaling pathway in GC.

MicroRNA-940 promotes tumor cell invasion and metastasis by downregulating ZNF24 in gastric cancer

Growing evidence indicates that microRNA (miRNA) plays a vital role in progression and metastasis of gastric cancer (GC). However, the underlying mechanism of miRNA-mediated metastasis has not been fully understood. Recently, miRNA-940 (miR-940) was found to be overexpressed in GC, which correlated with malignant progression and poor survival. Mechanistically, we found that miR-940 promoted GC cell migration, invasion, and metastasis in vivo by directly and functionally repressing the expression of Zinc Finger Transcription Factor 24 (ZNF24). Importantly, upregulation of ZNF24 could re-inhibit miR-940-induced migration and invasion. Hence, we demonstrated the oncogenic role of miR-940 in GC, finding that miR-940 promoted GC progression by directly downregulating ZNF24 expression, and targeting miR-940 could serve as a novel strategy for future GC therapy.

Coronin3 regulates gastric cancer invasion and metastasis by interacting with Arp2

Coronin3 expression is increased in gastric cancer (GC) tissues and can promote GC invasion and metastasis. However, the mechanisms underlying Coronin3 function in GC remain unclear. In this study, we aimed to explore the interacting molecules essential for the tumor-promoting effects of Coronin3 in GC. Using mass spectrometric analysis, functional studies, and immunohistochemistry, we found that Arp2 interacted with Coronin3, and ectopic expression of Arp2 promoted GC cell migration and invasion, while Arp2 knockdown suppressed whole-cell motility and attenuated the Coronin3-mediated upregulation of cell migration and invasion. In addition, both proteins correlated with the metastatic status of GC patients. Furthermore, survival analyses demonstrated that both Coronin3 and Arp2 correlated with overall GC patient survival, and the combination of Coronin3 and Arp2 most accurately predicted GC patient prognosis. Combined, these data demonstrate that Coronin3 can regulate GC invasion and metastasis through Arp2, and the combination of Coronin3 and Arp2 provides a potential marker for predicting GC prognosis.

Signal transducer and activator of transcription 3 signaling upregulates fascin via nuclear factor-κB in gastric cancer: Implications in cell invasion and migration

Fascin protein plays important roles in tumor metastasis and is prognostically relevant to human gastric cancer (GC). However, its role in the development and progression of GC has not been comprehensively investigated. In the present study, results revealed that upregulation of fascin by interleukin-6 promotes GC cell migration and invasion in a signal transducer and activator of transcription 3 (STAT3)-dependent manner in MKN45 cells. Furthermore, STAT3 directly regulated fascin expression and nuclear factor-κB (NF-κB) bound to the fascin promoter in a STAT3-dependent and Notch-independent manner. Therefore, results demonstrate that STAT3 and NF-κB are required for upregulation of fascin and for cell migration and invasion in MKN45 cells. Effects of the treatments on cell signaling were detected by qPCR, western blot analysis and chromatin immunoprecipitation (ChIP) assay. Cell migration and invasion were analyzed using in vitro scratch wound healing assay, transwell and Matrigel assays, and xenograft model. In addition, the STAT3-NF-κB-fascin signaling axis is identified as a therapeutic target for blocking GC cell invasion and migration.