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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death [1]
These results indicated that Ras association domain family 1 isoform A (RASSF1A) was inactivated by methylation in hepatocellular carcinoma (HCC) cells
The relationship between Yes-associated protein (YAP) and AREG histoscores showed a significant positive correlation (P 1⁄4 0.001; r 1⁄4 0.408), whereas that between RASSF1A and YAP histoscores exhibited a significant negative correlation (P 1⁄4 0.043; r 1⁄4 À0.236; Supplementary Fig. S2). These results indicated that RASSF1A, YAP, and AREG (YAP signature) are involved in human multistep hepatocarcinogenesis
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death [1]. Several genetic and epigenetic alterations were shown to be related with hepatocarcinogenesis, including frequent promoter hypermethylation of several tumor suppressor genes, such as Ras association domain family 1 isoform A In HCC, epigenetic alterations, such as global DNA hypomethylation or CpG island hypermethylation, are critical mechanisms that affect the loss and gain of DNA methylation, respectively [3]. Inactivation of RASSF1A by DNA methylation has been shown to be involved in the development of many human cancers, Authors' Affiliations: 1Department of Pathology, 2Brain Korea 21 Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, and 3Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.
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