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Polymorphisms in genes related to epithelial-mesenchymal transition and risk of non-small cell lung cancer.

ABSTRACT: The epithelial-mesenchymal transition (EMT) process is a crucial step for tumor invasion and metastasis. Previous research investigating EMT has mostly focused on its role in cancer progression. Recent studies showed that EMT and EMT-driving transcription factor (EMT-TF) expression are early events in lung cancer pathogenesis, implying a potential association between EMT and lung cancer risk. In this study, we examined whether genetic variants in EMT-related genes are associated with risk of non-small cell lung cancer (NSCLC). We used data from a genome-wide association study of 1482 NSCLC cases and 1544 healthy controls as the discovery phase, in which we analyzed 1602 single-nucleotide polymorphisms (SNPs) within 159 EMT-related genes. We then validated the significant SNPs in another 5699 cases and 5815 controls from the National Cancer Institute lung cancer genome-wide association study. Cumulative effects were evaluated for validated SNPs, and a gene-based test was performed to explore gene-level association with disease risk. In the discovery phase, 174 SNPs demonstrated significant associations with NSCLC risk. In the validation phase, seven SNPs mapped to EGFR, NOTCH3, ADGRF1 and SMAD3 were confirmed. Cumulative effect analysis of the significant SNPs demonstrated increasing risk with the number of unfavorable genotypes in the discovery and validation datasets. Gene-based analysis implicated ADGRF1, NOTCH3 and CDH1 as significant for NSCLC risk. Functional prediction revealed several potential mechanisms underlying these associations. Our results suggest that EMT-related gene variants may be involved in susceptibility to NSCLC; if confirmed, they might help identify higher-risk individuals.

SUBMITTER: Xie K

PROVIDER: S-EPMC5862248 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Polymorphisms in genes related to epithelial-mesenchymal transition and risk of non-small cell lung cancer.

Xie Kunlin K Ye Yuanqing Y Zeng Yong Y Gu Jian J Yang Hushan H Wu Xifeng X

Carcinogenesis 20171001 10

The epithelial-mesenchymal transition (EMT) process is a crucial step for tumor invasion and metastasis. Previous research investigating EMT has mostly focused on its role in cancer progression. Recent studies showed that EMT and EMT-driving transcription factor (EMT-TF) expression are early events in lung cancer pathogenesis, implying a potential association between EMT and lung cancer risk. In this study, we examined whether genetic variants in EMT-related genes are associated with risk of non ...[more]

PMID: 28968839

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Project description:BackgroundTwist-related protein 1 (TWIST1) plays an essential role in the carcinogenesis and metastasis of NSCLC. Our aims were to identify the molecule at the downstream of TWIST1 and to evaluate its potential as a diagnostic and a prognostic marker in NSCLC.MethodsThe functional genes at the downstream of TWIST1 were obtained via microarray gene expression analyses in the NSCLC cell line. The expression levels of synaptotagmin 7 (SYT7) in a cohort of patients with NSCLC (n = 154) were examined using immunohistochemistry staining and assessed by Kaplan-Meier survival analysis and Cox regression analysis. The effects of SYT7 on the tumorigenesis and metastasis of NSCLC were measured in NSCLC cells. In vivo xenograft lung cancer models were used to study the tumorigenesis role of SYT7.FindingsWe discovered that SYT7 is significantly altered by TWIST1 expression. We further confirmed that SYT7 protein was significantly higher in NSCLC than that in the adjacent normal lung tissue, and higher SYT7 expression was associated with poor survival of NSCLC patients. The protein level of SYT7 was positively correlated with TWIST1 in NSCLC tissue. Functional experiments indicated that SYT7 promoted proliferation, invasion, and metastasis and inhibited cell apoptosis of NSCLC cells in vitro. In vivo experiments showed that shSYT7 inhibited the xenograft tumor growth of NSCLC cells. Knocking down of SYT7 increased the expression of E-cadherin and decreased the level of N-cadherin and Vimentin in cultured cells.InterpretationOur data indicate that SYT7 is an important promoter for EMT and tumor progression in NSCLC. FUND: This project was supported by grants from the Major Scientific and Technological Innovation Project of Shandong Province (2018CXGC1212), Science and Technology Foundation of Shandong Province (2014GSF118084, 2016GSF121043), Medical and Health Technology Innovation Plan of Jinan City (201805002) and the National Natural Science Foundation of China (81372333).

Project description:The aim of the present study was to investigate whether miR?203 can inhibit transforming growth factor?? (TGF??)?induced epithelial?mesenchymal transition (EMT), and the migration and invasion ability of non?small cell lung cancer (NSCLC) cells by targeting SMAD3. In the present study, the expression levels of miR?203, SMAD3 mRNA and protein in NSCLC tissues were examined, as well as their corresponding paracancerous samples. The miR?203 mimics and miR?203 inhibitor were transfected into the H226 cell line. RT?qPCR was used to assess the expression levels of E?cadherin, Snail, N?cadherin and vimentin mRNA, and western blotting was performed to detect the expression levels of p?SMAD2, SMAD2, p?SMAD3, SMAD3 and SMAD4. The cell migration and invasion abilities were detected by Transwell assays. The target site of SMAD3 was predicted by the combined action between miR?203 and dual luciferase. The results revealed that the RNA levels of miR?203, compared with paracancerous tissues, were decreased in NSCLC tissues, while SMAD3 mRNA and protein levels were upregulated, and miR?203 inhibited SMAD3 expression. Induction of TGF?? led to decreased E?cadherin mRNA levels, upregulation of Snail, N?cadherin and vimentin mRNA levels (P<0.05), and significant increase in cell migration and invasion, whereas transfection of miR?203 mimics reversed the aforementioned results (P<0.05). Conversely, miR?203 inhibitor could further aggravate the aforementioned results (P<0.05). Western blot results revealed that transfection of miR?203 mimics significantly reduced the protein expression of SMAD3 and p?SMAD3 (P<0.05). Furthermore, the results of the Dual?Luciferase assay revealed that miR?203 inhibited SMAD3 expression by interacting with specific regions of its 3'?UTR. Overall, a novel mechanism is revealed, in which, miR?203 can inhibit SMAD3 by interacting with specific regions of the 3'?UTR of SMAD3, thereby restraining TGF???induced EMT progression and migration and invasion of NSCLC cells.

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Polymorphisms in genes related to epithelial-mesenchymal transition and risk of non-small cell lung cancer.

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Polymorphisms in genes related to epithelial-mesenchymal transition and risk of non-small cell lung cancer.

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