MiR-19a promotes epithelial-mesenchymal transition through PI3K/AKT pathway in gastric cancer

Lü, Weidong; Zuo, Yun; Xu, Zhennan; Zhang, Min

doi:10.3748/wjg.v21.i15.4564

Cited by 55 publications

(50 citation statements)

References 36 publications

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“…Zhang et al reported that Wnt5a, through stimulation of the non-classical Wnt signaling pathway, mediates EMT during the metastasis of cancer cells, and may serve as a target for the inhibition of EMT and gastric cancer metastasis (32). Lu et al have shown that miRNA-19a, which is associated with cancer invasion and metastasis and is expressed highly in gastric cancer cell lines, induces EMT in gastric cancer cells by activating the PI3K/AKT signal pathway (33 (12). Previous study by Nam and colleagues on cancer cell EMT has shown that Sp1 plays crucial roles in the integrin α5-dependent induction of EMT and metastasis (8).…”

Section: Discussionmentioning

confidence: 99%

miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1

Shan

Hu³

et al. 2016

International Journal of Oncology

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Abstract. Sp1 plays critical roles in epithelial-mesenchymal transition (EMT) of certain cancer. However, few studies have indicated whether Sp1 is involved in the EMT of gastric cancer, and whether abnormal expression of Sp1 in gastric cancer EMT is regulated in a post-transcriptional manner, and the involvement of miRNAs in this regulation. In this study, we selected 20 cases of gastric cancers, their liver metastases and para-carcinoma tissues to examine the levels of Sp1 protein and mRNA by immunohistochemistry and fluorescent PCR, which showed that Sp1 was increased in gastric cancers and their metastases compared with adjacent tissues, but there was no difference in Sp1 mRNA between these three groups, suggesting changes in Sp1 may be attributed to inactivation of post-transcriptional regulation. We verified by a luciferase reporter system that miRNA-223 binds to 3'-UTR of Sp1 gene and inhibits its translation, in agreement with negative correlation between miRNA-223 and Sp1 protein levels in gastric cancer cells. By employing TGF-β1 to induce MGC-803, BGC-823 and SGC-7901, we successfully built cellular EMT model. Then, we overexpressed miRNA-223 in the model by using a lentiviral system, which diminished EMT indicators and suppressed proliferation and invasion ability, and induced apoptosis. Finally, we verified the specificity of the regulation pathway miRNA-223/Sp1/EMT. These findings suggest that low expression of miRNA-223 in gastric cancer cells is an important cause for EMT. miRNA-223 specifically regulates the EMT process of gastric cancer cells through its target gene Sp1. Overexpression of miRNA-223 in these cells inhibits EMT via the miRNA-223/Sp1/EMT pathway.

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Section: Discussionmentioning

confidence: 99%

miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1

Shan

Hu³

et al. 2016

International Journal of Oncology

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“…The proinvasive and prometastasis effects of sorafenib (antiangiogenic agent that inhibits tumor growth but promotes tumor invasion and metastasis in HCC) were assigned to activate PI3K/Akt/snail pathway (45). Overexpression of miR19a was also shown to activate PI3K/AKT signaling, and induced EMT in gastric cancers (43). Overexpression of mortalin was earlier shown to inactivate p53, activate telomerase, and antiapoptotic signaling through Raf/MEK/ERK pathway and inhibition of conformational change of Bax (17,18,38), and to mediate erythropoietin-induced growth of erythroid progenitor cells ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…4). PI3K-Akt signaling has been reported to regulate EMT through the transcription factor snail, a critical EMT mediator (43,44). The proinvasive and prometastasis effects of sorafenib (antiangiogenic agent that inhibits tumor growth but promotes tumor invasion and metastasis in HCC) were assigned to activate PI3K/Akt/snail pathway (45).…”

Section: Discussionmentioning

confidence: 99%

Stress Chaperone Mortalin Contributes to Epithelial-to-Mesenchymal Transition and Cancer Metastasis

Kaul

Ryu

et al. 2016

Cancer Research

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Mortalin/mthsp70 (HSPA9) is a stress chaperone enriched in many cancers that has been implicated in carcinogenesis by promoting cell proliferation and survival. In this study, we examined the clinical relevance of mortalin upregulation in carcinogenesis. Consistent with high mortalin expression in various human tumors and cell lines, we found that mortalin overexpression increased the migration and invasiveness of breast cancer cells. Expression analyses revealed that proteins involved in focal adhesion, PI3K-Akt, and JAK-STAT signaling, all known to play key roles in cell migration and epithelial-tomesenchymal transition (EMT), were upregulated in mortalinexpressing cancer cells. We further determined that expression levels of the mesenchymal markers vimentin (VIM), fibronectin (FN1), b-catenin (CTNNB1), CK14 (KRT14), and hnRNP-K were also increased upon mortalin overexpression, whereas the epithelial markers E-cadherin (CDH1), CK8 (KRT8), and CK18 (KRT18) were downregulated. Furthermore, shRNAmediated and pharmacologic inhibition of mortalin suppressed the migration and invasive capacity of cancer cells and was associated with a diminished EMT gene signature. Taken together, these findings support a role for mortalin in the induction of EMT, prompting further investigation of its therapeutic value in metastatic disease models. Cancer Res; 76(9);

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“…To our knowledge, the present study is the first to provide evidence that PITX1 expression is modulated through miR-19a-3p in GC. miR-19a is frequently overexpressed, promotes cell proliferation and the epithelial to mesenchymal transition, and inhibits cell apoptosis in lung carcinoma [36,37], osteosarcoma stem cells [38], colorectal cancer [39][40][41][42], cell renal cell carcinoma [43], oral squamous cell carcinoma [44], hepatocellular carcinoma cells [45], pancreatic cancer [46], GC [47,48], cholangiocarcinoma [49], breast cancer [50], bladder cancer [51], medulloblastoma [52], and cervical carcinoma [53]. Our findings are consistent with these data because they provide evidence that miR19a is a key regulator of the multistep processes of cancer development.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Downregulated PITX1 Modulated by MiR-19a-3p Promotes Cell Malignancy and Predicts a Poor Prognosis of Gastric Cancer by Affecting Transcriptionally Activated PDCD5

Qiao

Gong

Song

et al. 2018

Cell Physiol Biochem

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Background/Aims: PITX1 has been identified as a potential tumor-suppressor gene in several malignant tumors. The molecular mechanism underlying PITX1, particularly its function as a transcription factor regulating gene expression during tumorigenesis, is still poorly understood. Methods: The expression level and location of PITX1 were determined by quantitative reverse transcription PCR (qRT-PCR) and immunohistochemical staining in gastric cancer (GC). The effect of PITX1 on the GC cell proliferation and tumorigenesis was analyzed in vitro and in vivo. To explore how PITX1 suppresses cell proliferation, we used PITX1-ChIP-sequencing to measure genome-wide binding sites of PITX1 and assessed global function associations based on its putative target genes. ChIP-PCR, electrophoretic mobility shift assay, and promoter reporter assays examined whether PITX1 bound to PDCD5 and regulated its expression. The function of PDCD5 in GC cell apoptosis was further examined in vitro and in vivo. The relationship between the PITX1 protein level and GC patient prognosis was evaluated by the Kaplan-Meier estimator. Meanwhile, the expression level of miR-19a-3p, which is related to PITX1, was also detected by luciferase reporter assay, qRT-PCR, and western blotting. Results: The expression level of PITX1 was decreased in GC tissues and cell lines. Elevated PITX1 expression significantly suppressed the cell proliferation of GC cells and tumorigenesis in vitro and in vivo. PITX1 knockdown blocked its inhibition of GC cell proliferation. PITX1 bound to whole genomewide sites, with these targets enriched on genes with functions mainly related to cell growth and apoptosis. PITX1 bound to PDCD5, an apoptosis-related gene, during tumorigenesis, and cis-regulated PDCD5 expression. Increased PDCD5 expression in GC cells not only induced GC cell apoptosis, but also suppressed GC cell growth in vitro and in vivo. Moreover, PITX1 expression was regulated by miR-19a-3p. More importantly, a decreased level of PITX1 protein was correlated with poor GC patient prognosis. Conclusion: Decreased expression of PITX1 predicts shorter overall survival in GC patients. As a transcriptional activator, PITX1 regulates apoptosis-related genes, including PDCD5, during gastric carcinogenesis. These data indicate PDCD5 to be a novel and feasible therapeutic target for GC.

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MiR-19a promotes epithelial-mesenchymal transition through PI3K/AKT pathway in gastric cancer

Cited by 55 publications

References 36 publications

miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1

miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1

Stress Chaperone Mortalin Contributes to Epithelial-to-Mesenchymal Transition and Cancer Metastasis

Downregulated PITX1 Modulated by MiR-19a-3p Promotes Cell Malignancy and Predicts a Poor Prognosis of Gastric Cancer by Affecting Transcriptionally Activated PDCD5

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