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.
Highlights
Hepatocellular carcinoma (HCC) is a major cause of mortality worldwide [1]
To determine whether Ras-association domain family 10 (RASSF10) is downregulated in HCC, we first measured the expression of RASSF10 mRNA in fresh HCC tissue and matching non-cancerous liver samples by quantitative real-time polymerase chain reaction
Low expression of RASSF10 was detected in 70.83% (204/288) of HCC tumors and 31.94% (92/288) of non-cancerous tissue samples (P < 0.001; Figure 1C). These results suggest that RASSF10 expression is downregulated in HCC
Summary
Hepatocellular carcinoma (HCC) is a major cause of mortality worldwide [1]. Of the approximately 782,500 new HCC cases annually, China accounts for nearly half [2, 3]. Genetic alterations and epigenetic modifications, especially DNA methylation, are both associated with HCC development and progression [4, 5]. HCC is likely to spread via hematogenous dissemination at an early stage [6]. Due to the absence of simple and effective diagnostic indicators and recognizable early symptoms, most HCC patients are diagnosed at an advanced stage, when surgery is no longer feasible, which results in a poor prognosis [7]. New strategies are urgently needed for early HCC diagnosis, metastasis inhibition and treatment
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