title: RASSF10 is an epigenetically inactivated tumor suppressor and independent prognostic factor in hepatocellular carcinoma.
abstract: Methylation of the Ras-association domain family 10 (RASSF10) promoter region correlates with clinicopathological characteristics and poor prognosis in several human cancers. Here, we examined RASSF10 expression in hepatocellular carcinoma (HCC) and its role in hepatocarcinogenesis. RASSF10 mRNA and protein levels were downregulated in both HCC cell lines and patient tissue samples. In patient tissues, low RASSF10 levels correlated with hepatocirrhosis, poor tumor differentiation, tumor thrombus and Barcelona Clinic Liver Cancer stage, and were indicative of increased tumor recurrence and reduced patient survival. Low RASSF10 expression was associated with promoter hypermethylation, which was in turn associated with polycyclic aromatic hydrocarbon and aflatoxin B1 exposure, but not DNA methyltransferase expression. Overexpression of RASSF10 in HCC cell lines suppressed cell growth and colony formation, and induced apoptosis by up- or down-regulating specific Bcl-2 family proteins. RASSF10 overexpression increased pro-apoptotic Bax and Bad levels, but decreased anti-apoptotic Bcl-2 and Bcl-xl expression. Overexpression also inhibited tumor formation in nude mice and reduced cell migration and invasion by inhibiting the epithelial-mesenchymal transition. RASSF10 knockdown promoted cell growth. Our results show that RASSF10 is frequently hypermethylated and down-regulated in HCC and can potentially serve as a useful biomarker predictive of HCC patient prognosis.
authors.affiliation: Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu, China.|Department of General Surgery, Changzhou Wujin People's Hospital, Changzhou, Jiangsu, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Pathology, Nantong University Affiliated Hospital, Nantong, Jiangsu, China.
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Liu
authors.affiliation: Department of Pathology, Nantong University Affiliated Hospital, Nantong, Jiangsu, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Surgical Comprehensive Laboratory, Nantong University Affiliated Hospital, Nantong, Jiangsu, China.
authors.forename: Yi-Bing
authors.initials: YB
authors.lastname: Guo
authors.affiliation: Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu, China.
authors.forename: Qin-Sheng
authors.initials: QS
authors.lastname: Mao
authors.affiliation: Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu, China.
authors.forename: Wan-Jiang
authors.initials: WJ
authors.lastname: Xue
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C548440:RASSF10 protein, human; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins
keywords: DNA methylation; RASSF10; biomarker; hepatocellular carcinoma; tumor suppressor