Open AccessRAP80 regulates epithelial–mesenchymal transition related with metastasis and malignancy of cancer
Author(s) -
Park Song Yi,
Korm Sovannarith,
Chung Hee Jin,
Choi Su jin,
Jang JinJu,
Cho Sunhee,
Lim Yong Taik,
Kim Hongtae,
Lee JooYong
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12877
Subject(s) - gene knockdown , epithelial–mesenchymal transition , downregulation and upregulation , metastasis , cancer research , malignancy , cancer , biology , adenocarcinoma , lung cancer , medicine , pathology , cell culture , gene , genetics
Epithelial–mesenchymal transition ( EMT ) has been closely related with invasive and metastatic properties of cancer. Recently, the convergence of DNA damage response and EMT in cancer development has received a great amount of scientific attention. Here, we showed that EMT is induced by the downregulation of RAP 80, a well‐known regulator for DNA damage response. The knockdown of RAP 80 leads to EMT ‐like morphological changes and the increase of tumor sphere formation in non‐adhesive culture. Mechanistically, RAP 80 controls a reciprocal regulatory axis of ZEB 1 (for EMT activation) and miR200c (for EMT inhibition). The downregulation of RAP 80 increases ZEB 1 protein and decreases miR200c expression to activate EMT signaling in the form of drastic inhibitions of E‐cadherin, p16 and p21 expression. Using in vivo metastasis analysis, RAP 80 knockdown cells are shown to dramatically metastasize into the lung and generate more malignant phenotype compared to controls. Interestingly, the expression level of RAP 80 was positively correlated with the survival rate in lung adenocarcinoma and breast cancer patients. These findings indicate that RAP 80 is a critical gatekeeper in impeding EMT ‐induced metastasis and malignant phenotypes of cancer as well as preserving DNA integrity.