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Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer
Tumor metastasis is the major cause of poor prognosis and mortality in colorectal cancer (CRC). However, early diagnosis of highly metastatic CRC is currently difficult. In the present study, we screened for a novel biomarker, GDNF family receptor alpha 1 (GFRA1) based on the expression and methylat...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682896/ https://www.ncbi.nlm.nih.gov/pubmed/33175846 http://dx.doi.org/10.1371/journal.pgen.1009159 |
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author | Dong, Zhexu Dai, Lei Zhang, Yong Fang, Chao Shi, Gang Chen, Ye Li, Junshu Wang, Qin Fu, Jiamei Yu, Yan Wang, Wenshuang Cheng, Lin Liu, Yi Lin, Yi Wang, Yuan Wang, Qingnan Wang, Huiling Zhang, Hantao Zhang, Yujing Su, Xiaolan Zhang, Shuang Wang, Feng Qiu, Meng Zhou, Zongguang Deng, Hongxin |
author_facet | Dong, Zhexu Dai, Lei Zhang, Yong Fang, Chao Shi, Gang Chen, Ye Li, Junshu Wang, Qin Fu, Jiamei Yu, Yan Wang, Wenshuang Cheng, Lin Liu, Yi Lin, Yi Wang, Yuan Wang, Qingnan Wang, Huiling Zhang, Hantao Zhang, Yujing Su, Xiaolan Zhang, Shuang Wang, Feng Qiu, Meng Zhou, Zongguang Deng, Hongxin |
author_sort | Dong, Zhexu |
collection | PubMed |
description | Tumor metastasis is the major cause of poor prognosis and mortality in colorectal cancer (CRC). However, early diagnosis of highly metastatic CRC is currently difficult. In the present study, we screened for a novel biomarker, GDNF family receptor alpha 1 (GFRA1) based on the expression and methylation data in CRC patients from The Cancer Genome Altlas (TCGA), followed by further analysis of the correlation between the GFRA1 expression, methylation, and prognosis of patients. Our results show DNA hypomethylation-mediated upregulation of GFRA1 in invasive CRC, and it was found to be correlated with poor prognosis of CRC patients. Furthermore, GFRA1 methylation-modified sequences were found to have potential as methylation diagnostic markers of highly metastatic CRC. The targeted demethylation of GFRA1 by dCas9-TET1CD and gRNA promoted CRC metastasis in vivo and in vitro. Mechanistically, demethylation of GFRA1 induces epithelial-mesenchymal transition (EMT) by promoting AKT phosphorylation and increasing c-Jun expression in CRC cells. Collectively, our findings indicate that GFRA1 hypomethylation can promote CRC invasion via inducing EMT, and thus, GFRA1 methylation can be used as a biomarker for the early diagnosis of highly metastasis CRC. |
format | Online Article Text |
id | pubmed-7682896 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-76828962020-12-02 Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer Dong, Zhexu Dai, Lei Zhang, Yong Fang, Chao Shi, Gang Chen, Ye Li, Junshu Wang, Qin Fu, Jiamei Yu, Yan Wang, Wenshuang Cheng, Lin Liu, Yi Lin, Yi Wang, Yuan Wang, Qingnan Wang, Huiling Zhang, Hantao Zhang, Yujing Su, Xiaolan Zhang, Shuang Wang, Feng Qiu, Meng Zhou, Zongguang Deng, Hongxin PLoS Genet Research Article Tumor metastasis is the major cause of poor prognosis and mortality in colorectal cancer (CRC). However, early diagnosis of highly metastatic CRC is currently difficult. In the present study, we screened for a novel biomarker, GDNF family receptor alpha 1 (GFRA1) based on the expression and methylation data in CRC patients from The Cancer Genome Altlas (TCGA), followed by further analysis of the correlation between the GFRA1 expression, methylation, and prognosis of patients. Our results show DNA hypomethylation-mediated upregulation of GFRA1 in invasive CRC, and it was found to be correlated with poor prognosis of CRC patients. Furthermore, GFRA1 methylation-modified sequences were found to have potential as methylation diagnostic markers of highly metastatic CRC. The targeted demethylation of GFRA1 by dCas9-TET1CD and gRNA promoted CRC metastasis in vivo and in vitro. Mechanistically, demethylation of GFRA1 induces epithelial-mesenchymal transition (EMT) by promoting AKT phosphorylation and increasing c-Jun expression in CRC cells. Collectively, our findings indicate that GFRA1 hypomethylation can promote CRC invasion via inducing EMT, and thus, GFRA1 methylation can be used as a biomarker for the early diagnosis of highly metastasis CRC. Public Library of Science 2020-11-11 /pmc/articles/PMC7682896/ /pubmed/33175846 http://dx.doi.org/10.1371/journal.pgen.1009159 Text en © 2020 Dong et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Dong, Zhexu Dai, Lei Zhang, Yong Fang, Chao Shi, Gang Chen, Ye Li, Junshu Wang, Qin Fu, Jiamei Yu, Yan Wang, Wenshuang Cheng, Lin Liu, Yi Lin, Yi Wang, Yuan Wang, Qingnan Wang, Huiling Zhang, Hantao Zhang, Yujing Su, Xiaolan Zhang, Shuang Wang, Feng Qiu, Meng Zhou, Zongguang Deng, Hongxin Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer |
title | Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer |
title_full | Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer |
title_fullStr | Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer |
title_full_unstemmed | Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer |
title_short | Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer |
title_sort | hypomethylation of gdnf family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682896/ https://www.ncbi.nlm.nih.gov/pubmed/33175846 http://dx.doi.org/10.1371/journal.pgen.1009159 |
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