Survival-Related lncRNA Landscape Analysis Identifies LINC01614 as an Oncogenic lncRNA in Gastric Cancer

Background: Long non-coding RNAs (lncRNAs) reportedly play important roles in biomarker and tumorigenesis of gastric cancer (GC). This study aimed to determine the potential application of prognostic lncRNA signature and identified the role of LINC01614 in carcinogenesis in GC.Material and Methods: Data accessed from the Cancer Genome Atlas database was used to construct a lncRNA signature. Joint effect analysis of the signature and clinical parameters was performed to verify the clinical value of the signature. Co-expression analysis was conducted for prognostic lncRNAs and protein-coding genes. Moreover, the relative expression of LINC01614 was validated in GC tissues and cell lines. In vitro and in vivo experiments were conducted to analyze the biological functions of the newly identified gene in GC cells.Results: A seven-lncRNA (LINC01614, LINC01537, LINC01210, OVAAL, LINC01446, CYMP-AS1, and SCAT8) signature was identified as a promising prognostic signature in GC. Results indicated that the seven-lncRNA was involved in tumorigenesis and progression pathways. LINC01614 expression was identified and found to be upregulated in GC tissues and cells. The study findings revealed that LINC01614 promoted cell proliferation, migration, invasion, and epithelial-mesenchymal transition. Knockdown of LINC01614 arrested cell cycle distribution at the G2/M phase. Further, LINC01614 also promoted tumor growth in vivo.Conclusion: We developed an independent seven-lncRNA biomarker for prognostic prediction and identified LINC01614 as an oncogenic lncRNA in GC.

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Knockdown of ARK5 Expression Suppresses Invasion and Metastasis of Gastric Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000478685 ◽

2017 ◽

Vol 42 (3) ◽

pp. 1025-1036 ◽

Cited By ~ 12

Author(s):

Dehu Chen ◽

Guiyuan Liu ◽

Ning Xu ◽

Xiaolan You ◽

Haihua Zhou ◽

...

Keyword(s):

Gastric Cancer ◽

Western Blot ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Invasion And Metastasis ◽

Ags Cells ◽

Mesenchymal Transition

Background/Aims: Gastric cancer (GC) is a common and lethal malignancy, and AMP-activated protein kinase-related kinase 5 (ARK5) has been discovered to promote cancer metastasis in certain types of cancer. In this study, we explored the role of ARK5 in GC invasion and metastasis. Methods: ARK5 and epithelial-mesenchymal transition (EMT)-related markers were determined by immunohistochemistry and western blot in GC specimens. Other methods including stably transfected against ARK5 into SGC7901 and AGS cells, western blot, migration and invasion assays in vitro and nude mice tumorigenicity in vivo were also employed. Results: The results demonstrated that ARK5 expression was increased and positively correlated with metastasis, EMT-related markers and poor prognosis in patients with GC. Knockdown of ARK5 expression remarkably suppressed GC cells invasion and metastasis via regulating EMT, rather than proliferation in vitro and in vivo. And knockdown of ARK5 expression in GC cells resulted in the down-regulation of the mTOR/p70S6k signals, Slug and SIP1. Conclusion: The elevated ARK5 expression was closely associated with cancer metastasis and patient survival, and it seemed to function in GC cells migration and invasion via EMT alteration, together with the alteration of the mTOR/p70S6k signals, Slug and SIP1, thus providing a potential therapeutic target for GC.

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Pleckstrin-2 as a Prognostic Factor and Mediator of Gastric Cancer Progression

Gastroenterology Research and Practice ◽

10.1155/2021/5527387 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Jun Wang ◽

Zhigang He ◽

Bo Sun ◽

Wenhai Huang ◽

Jianbin Xiang ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

In Vivo Studies ◽

Vimentin Expression ◽

Mesenchymal Transition ◽

Gastric Cancer Patients

Pleckstrin-2 (PLEK2) is a crucial mediator of cytoskeletal reorganization. However, the potential roles of PLEK2 in gastric cancer are still unknown. PLEK2 expression in gastric cancer was examined by western blotting and real-time PCR. Survival analysis was utilized to test the clinical impacts of the levels of PLEK2 in gastric cancer patients. In vitro and in vivo studies were used to estimate the potential roles played by PLEK2 in modulating gastric cancer proliferation, self-renewal, and tumourigenicity. Bioinformatics approaches were used to monitor the effect of PLEK2 on epithelial-mesenchymal transition (EMT) signalling pathways. PLEK2 expression was significantly upregulated in gastric cancer as compared with nontumour samples. Kaplan-Meier plotter analysis revealed that gastric cancer patients with higher PLEK2 levels had substantially poorer overall survival compared with gastric cancer patients with lower PLEK2 levels. The upregulation or downregulation of PLEK2 in gastric cancer cell lines effectively enhanced or inhibited cell proliferation and proinvasive behaviour, respectively. Additionally, we also found that PLEK2 enhanced EMT through downregulating E-cadherin expression and upregulating Vimentin expression. Our findings demonstrated that PLEK2 plays a potential role in gastric cancer and may be a novel therapeutic target for gastric cancer.

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Circular RNA CDR1as Inhibits the Metastasis of Gastric Cancer through Targeting miR-876-5p/GNG7 Axis

Gastroenterology Research and Practice ◽

10.1155/2021/5583029 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Jiajia Jiang ◽

Rong Li ◽

Junyi Wang ◽

Jie Hou ◽

Hui Qian ◽

...

Keyword(s):

Gastric Cancer ◽

Epithelial Mesenchymal Transition ◽

Circular Rna ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Luciferase Reporter Gene ◽

Mesenchymal Transition ◽

Underlying Mechanisms

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

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METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer

Molecular Cancer ◽

10.1186/s12943-019-1065-4 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 49

Author(s):

Ben Yue ◽

Chenlong Song ◽

Linxi Yang ◽

Ran Cui ◽

Xingwang Cheng ◽

...

Keyword(s):

Gastric Cancer ◽

Epithelial Mesenchymal Transition ◽

Luciferase Reporter ◽

Mesenchymal Transition ◽

Qrt Pcr ◽

Rna Immunoprecipitation ◽

E Cadherin

Abstract Background As one of the most frequent chemical modifications in eukaryotic mRNAs, N6-methyladenosine (m6A) modification exerts important effects on mRNA stability, splicing, and translation. Recently, the regulatory role of m6A in tumorigenesis has been increasingly recognized. However, dysregulation of m6A and its functions in tumor epithelial-mesenchymal transition (EMT) and metastasis remain obscure. Methods qRT-PCR and immunohistochemistry were used to evaluate the expression of methyltransferase-like 3 (METTL3) in gastric cancer (GC). The effects of METTL3 on GC metastasis were investigated through in vitro and in vivo assays. The mechanism of METTL3 action was explored through transcriptome-sequencing, m6A-sequencing, m6A methylated RNA immunoprecipitation quantitative reverse transcription polymerase chain reaction (MeRIP qRT-PCR), confocal immunofluorescent assay, luciferase reporter assay, co-immunoprecipitation, RNA immunoprecipitation and chromatin immunoprecipitation assay. Results Here, we show that METTL3, a major RNA N6-adenosine methyltransferase, was upregulated in GC. Clinically, elevated METTL3 level was predictive of poor prognosis. Functionally, we found that METTL3 was required for the EMT process in vitro and for metastasis in vivo. Mechanistically, we unveiled the METTL3-mediated m6A modification profile in GC cells for the first time and identified zinc finger MYM-type containing 1 (ZMYM1) as a bona fide m6A target of METTL3. The m6A modification of ZMYM1 mRNA by METTL3 enhanced its stability relying on the “reader” protein HuR (also known as ELAVL1) dependent pathway. In addition, ZMYM1 bound to and mediated the repression of E-cadherin promoter by recruiting the CtBP/LSD1/CoREST complex, thus facilitating the EMT program and metastasis. Conclusions Collectively, our findings indicate the critical role of m6A modification in GC and uncover METTL3/ZMYM1/E-cadherin signaling as a potential therapeutic target in anti-metastatic strategy against GC.

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Calcium Binding Protein S100A16 Expedites Proliferation, Invasion and Epithelial-Mesenchymal Transition Process in Gastric Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.736929 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xiaoying You ◽

Min Li ◽

Hongwei Cai ◽

Wenwen Zhang ◽

Ye Hong ◽

...

Keyword(s):

Gastric Cancer ◽

Calcium Binding ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

Binding Protein ◽

Transition Process ◽

Calcium Binding Protein ◽

Mesenchymal Transition

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system, listed as the second cause of cancer-related deaths worldwide. S100 Calcium Binding Protein A16 (S100A16) is an acidic calcium-binding protein associated with several types of tumor progression. However, the function of S100A16 in GC is still not very clear. In this study, we analyzed S100A16 expression with the GEPIA database and the UALCAN cancer database. Meanwhile, 100 clinical GC samples were used for the evaluation of its role in the prognostic analysis. We found that S100A16 is significantly upregulated in GC tissues and closely correlated with poor prognosis in GC patients. Functional studies reveal that S100A16 overexpression triggers GC cell proliferation and migration both in vivo and in vitro; by contrast, S100A16 knockdown restricts the speed of GC cell growth and mobility. Proteomic analysis results reveal a large S100A16 interactome, which includes ZO-2 (Zonula Occludens-2), a master regulator of cell-to-cell tight junctions. Mechanistic assay results indicate that excessive S100A16 instigates GC cell invasion, migration, and epithelial-mesenchymal transition (EMT) via ZO-2 inhibition, which arose from S100A16-mediated ZO-2 ubiquitination and degradation. Our results not only reveal that S100A16 is a promising candidate biomarker in GC early diagnosis and prediction of metastasis, but also establish the therapeutic importance of targeting S100A16 to prevent ZO-2 loss and suppress GC metastasis and progression.

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Circular RNA circFGD4 suppresses gastric cancer progression via modulating miR-532-3p/APC/β-catenin signalling pathway

Clinical Science ◽

10.1042/cs20191043 ◽

2020 ◽

Author(s):

Xinglong Dai ◽

Jianjun Liu ◽

Xiong Guo ◽

Anqi Cheng ◽

Xiaoya Deng ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Viability ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Luciferase Reporter ◽

Circular Rnas ◽

Mesenchymal Transition ◽

Potential Biomarker

Background: Mounting evidence has displayed critical roles of circular RNAs (circRNAs) in multiple cancers. The underlying mechanisms by which circFGD4 contributed to gastric cancer (GC) are still unclear. Methods: The levels and clinical values of circFGD4 in GC patients were detected and analysed by quantitative real-time PCR. The biological roles of circFGD4 in GC were assessed in vitro and in vivo experiments. Dual-luciferase reporter, fluorescence in situ hybridization, RNA immunoprecipitation, biotin-coupled RNA pull-down, and TOP/Flash and FOP/Flash reporter gene assays were employed to evaluate the effects of circFGD4 on miR-532-3p-mediated adenomatous polyposis coli (APC)/β-catenin signalling in GC cells. Results: circFGD4 expression was down-regulated the most in human GC tissues and cell lines. Low expression of circFGD4 was correlated with poor tumour differentiation, lymphatic metastasis, and poor prognosis of GC patients. circFGD4 suppressed GC cell viability, colony formation, migration, induced epithelial-mesenchymal transition (EMT) and tumorigenesis and metastasis in vivo. Next, we validated that circFGD4 acted as a sponge of miR-532-3p to relieve the tumour-promoting effects of miR-532-3p on its target APC. The mechanistic analysis demonstrated that the circFGD4 suppressed GC cell viability, migration, and EMT by modulating the miR-532-3p/APC axis to inactivate the β-catenin signalling. Conclusion: circFGD4 suppressed GC progression through sponging miR-532-3p and enhancing APC expression to inactivate the β-catenin signalling. Thus circFGD4 provides a novel potential biomarker and valuable therapeutic strategy for GC.

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The YAP1–NMU Axis Is Associated with Pancreatic Cancer Progression and Poor Outcome: Identification of a Novel Diagnostic Biomarker and Therapeutic Target

Cancers ◽

10.3390/cancers11101477 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1477 ◽

Cited By ~ 4

Author(s):

Yoo ◽

Lee ◽

Jun ◽

Noh ◽

Lee ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

The Cancer Genome Atlas ◽

Mesenchymal Transition ◽

Tumor Group ◽

Cancer Genome Atlas

Yes-associated protein (YAP)-1 is highly upregulated in pancreatic cancer and associated with tumor progression. However, little is known about the role of YAP1 and related genes in pancreatic cancer. Here, we identified target genes regulated by YAP1 and explored their role in pancreatic cancer progression and the related clinical implications. Analysis of different pancreatic cancer databases showed that Neuromedin U (NMU) expression was positively correlated with YAP1 expression in the tumor group. The Cancer Genome Atlas data indicated that high YAP1 and NMU expression levels were associated with poor mean and overall survival. YAP1 overexpression induced NMU expression and transcription and promoted cell motility in vitro and tumor metastasis in vivo via upregulation of epithelial–mesenchymal transition (EMT), whereas specific inhibition of NMU in cells stably expressing YAP1 had the opposite effect in vitro and in vivo. To define this functional association, we identified a transcriptional enhanced associate domain (TEAD) binding site in the NMU promoter and demonstrated that YAP1–TEAD binding upstream of the NMU gene regulated its transcription. These results indicate that the identified positive correlation between YAP1 and NMU is a potential novel drug target and biomarker in metastatic pancreatic cancer.

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The POU2F1/miR-4490/USP22 axis regulates cell proliferation and metastasis in gastric cancer

Cellular Oncology ◽

10.1007/s13402-020-00553-1 ◽

2020 ◽

Vol 43 (6) ◽

pp. 1017-1033 ◽

Cited By ~ 1

Author(s):

Yizhi Xiao ◽

Side Liu ◽

Jiaying Li ◽

Weiyu Dai ◽

Weimei Tang ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Cell Cycle Progression ◽

Epithelial Mesenchymal Transition ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Aberrant Expression ◽

Mesenchymal Transition

Abstract Purpose Growing evidence indicates that aberrant expression of microRNAs contributes to tumor development. However, the biological role of microRNA-4490 (miR-4490) in gastric cancer (GC) remains to be clarified. Methods To explore the function of miR-4490 in GC, we performed colony formation, EdU incorporation, qRT-PCR, Western blotting, in situ hybridization (ISH), immunohistochemistry (IHC), flow cytometry, ChIP and dual-luciferase reporter assays. In addition, the growth, migration and invasion capacities of GC cells were evaluated. Results We found that miR-4490 was significantly downregulated in primary GC samples and in GC-derived cell lines compared with normal controls, and that this expression level was negatively correlated with GC malignancy. Exogenous miR-4490 expression not only reduced cell cycle progression and proliferation, but also significantly inhibited GC cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, we found that miR-4490 directly targets USP22, which mediates inhibition of GC cell proliferation and EMT-induced metastasis in vitro and in vivo. Moreover, we found through luciferase and ChIP assays that transcription factor POU2F1 can directly bind to POU2F1 binding sites within the miR-4490 and USP22 promoters and, by doing so, modulate their transcription. Spearman’s correlation analysis revealed a positive correlation between USP22 and POU2F1 expression and negative correlations between miR-4490 and USP22 as well as miR-4490 and POU2F1 expression in primary GC tissues. Conclusion Based on our results we conclude that miR-4490 acts as a tumor suppressor, and that the POU2F1/miR-4490/USP22 axis plays an important role in the regulation of growth, invasion and EMT of GC cells.

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Silencing of UBE2D1 Inhibited Cell Migration in Gastric Cancer, Decreasing Ubiquitination of SMAD4

10.21203/rs.3.rs-409052/v1 ◽

2021 ◽

Author(s):

Honghu Xie ◽

Yu He ◽

Yugang Wu ◽

Qicheng Lu

Keyword(s):

Gastric Cancer ◽

Cell Migration ◽

Mouse Model ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Early Stage ◽

Transforming Growth Factor Β ◽

Mesenchymal Transition

Abstract Background: Gastric cancer (GC) is the second leading cause of cancer-related deaths. Because it is hard to diagnose at early stage, the overall 5 years survival rate is lower than 25%. High migration is the main hallmark of malignant cells at advanced stage of GC. Thus, it is urgent to find biomarkers for early diagnosis and more effective therapy of GC.Methods: In this study, silencing and overexpression lentiviruses targeting the ubiquitin-conjugating enzyme E2 D1 (UBE2D1), transwell, wound healing, and pulmonary metastasis mouse model were applied to analyze the function of UBE2D1 in vitro and in vivo. Real-time PCR and immunohistochemistry were used to elucidate the level of UBE2D1 in GC samples.Results: Silencing of UBE2D1 inhibited cell migration and the levels of Epithelial-mesenchymal transition (EMT) makers (MMP2 and MMP9) in AGS and MKN45 cells. Silencing of UBE2D1 inhibited cell metastasis in mouse model. On the contrary, UBE2D1 overexpression increased cell migration and the levels of MMP2 and MMP9 in MGC-803 cells. Further, silencing of UBE2D1 decreased the ubiquitination level of mothers against decapentaplegic homolog 4 (SMAD4), and the increase of cell migration induced by UBE2D1 overexpression could be reversed by SMAD4.Conclusion: Silencing of UBE2D1 inhibited cell migration through transforming growth factor β (TGF-β)/SMAD4 signaling pathway in GC.

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Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A

PPAR Research ◽

10.1155/2021/6663782 ◽

2021 ◽

Vol 2021 ◽

pp. 1-20

Author(s):

Rui Kong ◽

Nan Wang ◽

Wei Han ◽

Wen Bao ◽

Jie Lu

Keyword(s):

Cell Cycle ◽

Colon Cancer ◽

Epithelial Mesenchymal Transition ◽

Epigenetic Therapy ◽

Cell Cycle Distribution ◽

Peroxisome Proliferator ◽

Antitumor Effects ◽

Mesenchymal Transition

Peroxisome proliferator-activated receptor alpha (PPARA) is the molecular target of fibrates commonly used to treat dyslipidemia and diabetes. Recently, the potential role of PPARA in other pathological conditions, such as cancers, has been recognized. Here, using bioinformatics analysis, we found that PPARA was expressed at relatively low levels in pancancers, and Kaplan-Meier analyses revealed that high PPARA protein expression was correlated with better survival of patients with colon cancer. In vitro experiments showed that fenofibrate regulated cell cycle distribution, promoted apoptosis, and suppressed cell proliferation and epithelial mesenchymal transition by activating PPARA. PPARA activation inhibited DNMT1 activity and abolished methylation-mediated CDKN2A repression. Downregulation of cyclin-CDK complexes led to the restoration of CDKN2A, which caused cell cycle arrest in the G1 phase via regulation of the CDKN2A/RB/E2F pathway. Finally, we demonstrated that fenofibrate administration inhibited tumor growth and DNMT1 activity in vivo. The PPARA agonist, fenofibrate, might serve as an applicable agent for epigenetic therapy of colon cancer patients.

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