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RASSF1A-Mediated Regulation of AREG via the Hippo Pathway in Hepatocellular Carcinoma

Authors
 Ei Yong Ahn  ;  Ji Su Kim  ;  Gi Jeong Kim  ;  Young Nyun Park 
Citation
 MOLECULAR CANCER RESEARCH, Vol.11(7) : 748-758, 2013 
Journal Title
MOLECULAR CANCER RESEARCH
ISSN
 1541-7786 
Issue Date
2013
MeSH
Adaptor Proteins, Signal Transducing/metabolism* ; Adult ; Aged ; Amphiregulin ; Apoptosis/genetics ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/metabolism* ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; Cell Proliferation ; DNA Methylation/genetics ; Down-Regulation/genetics ; EGF Family of Proteins ; Female ; Gene Expression Regulation, Neoplastic ; Glycoproteins/genetics ; Glycoproteins/metabolism* ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism* ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism* ; Liver Neoplasms/pathology ; Male ; Middle Aged ; Phosphoproteins/metabolism* ; Protein-Serine-Threonine Kinases/metabolism ; Signal Transduction*/genetics ; Tumor Suppressor Proteins/metabolism* ; Up-Regulation/genetics
Keywords
Adaptor Proteins, Signal Transducing/metabolism* ; Adult ; Aged ; Amphiregulin ; Apoptosis/genetics ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/metabolism* ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; Cell Proliferation ; DNA Methylation/genetics ; Down-Regulation/genetics ; EGF Family of Proteins ; Female ; Gene Expression Regulation, Neoplastic ; Glycoproteins/genetics ; Glycoproteins/metabolism* ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism* ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism* ; Liver Neoplasms/pathology ; Male ; Middle Aged ; Phosphoproteins/metabolism* ; Protein-Serine-Threonine Kinases/metabolism ; Signal Transduction*/genetics ; Tumor Suppressor Proteins/metabolism* ; Up-Regulation/genetics
Abstract
Ras association domain family 1 isoform A (RASSF1A) is a tumor suppressor that is methylated in many human cancers, including hepatocellular carcinoma (HCC). RASSF1A has been shown to suppress tumors via activation of the Hippo tumor suppressor pathway, including mammalian STE20-like kinase (MST). Amphiregulin (AREG), a target gene for Yes-associated protein (YAP), is a known oncogenic component of the Hippo pathway; however, the tumor-suppressive effect of RASSF1A on AREG in regard to regulation of the Hippo pathway remains unclear in HCC. Overexpression of RASSF1A in HCC cells, which lack functional RASSF1A, significantly inhibited cell proliferation and induced apoptosis by activating the Hippo pathway. Consequently, overexpression of RASSF1A inhibited the oncogenic functions of YAP, leading to a significant reduction in AREG secretion via regulation of the Hippo pathway. In human specimens, greater expression of RASSF1A was observed in chronic hepatitis/cirrhosis than in HCC, whereas expression of YAP and AREG was higher in 81% and 86% of HCC than in corresponding chronic hepatitis/cirrhosis, respectively. Furthermore, RASSF1A protein gradually decreased as multistep hepatocarcinogenesis progressed from chronic hepatitis/cirrhosis dysplastic nodules toward HCC, whereas the protein expression of YAP and AREG gradually increased. These findings provide mechanistic insight into the regulation of YAP and AREG by RASSF1A in human multistep hepatocarcinogenesis.
Full Text
http://mcr.aacrjournals.org/content/11/7/748.long
DOI
10.1158/1541-7786.MCR-12-0665
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/87218
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