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RASSF10 is an epigenetically inactivated tumor suppressor and independent prognostic factor in hepatocellular carcinoma

2015; Impact Journals LLC; Volume: 7; Issue: 4 Linguagem: Inglês

10.18632/oncotarget.6654

1949-2553

Fei Wang, Ying Feng, Peng Li, Kun Wang, Liang Feng, Yifei Liu, Hua Huang, Yibing Guo, Qin‐Sheng Mao, Wan‐Jiang Xue,

Ferroptosis and cancer prognosis

// Fei Wang 1,* , Ying Feng 1,* , Peng Li 1 , Kun Wang 1,4 , Liang Feng 1 , Yi-Fei Liu 2 , Hua Huang 2 , Yi-Bing Guo 3 , Qin-Sheng Mao 1 and Wan-Jiang Xue 1 1 Department of General Surgery,Nantong University Affiliated Hospital, Nantong, Jiangsu, China 2 Department of Pathology,Nantong University Affiliated Hospital, Nantong, Jiangsu, China 3 Department of Surgical Comprehensive Laboratory, Nantong University Affiliated Hospital, Nantong, Jiangsu, China 4 Department of General Surgery, Changzhou Wujin People's Hospital, Changzhou, Jiangsu, China * These authors have contributed equally to this work Correspondence to: Wan-Jiang Xue, email: // Qin-Sheng Mao, email: // Keywords : RASSF10, hepatocellular carcinoma, DNA methylation, tumor suppressor, biomarker Received : June 05, 2015 Accepted : December 04, 2015 Published : December 18, 2015 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.