A new, effective and high-yield approach for identifying liver tumor suppressors

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of death from cancer [1]. The major risk factors for development of HCC include chronic hepatitis B (HBV) and hepatitis C virus infection, high dietary exposure to fungal aflatoxins, and other disorders causing cirrhosis, such as hereditary hemochromatosis, α1-antityripsin deficiency, primary biliary cirrhosis, non-alcoholic steatohepatitis and alcoholic cirrhosis [2]. Despite significant improvements in our understanding of the pathogenesis of HCC over the past few decades, we still do not have a comprehensive understanding of the major molecular pathogenic processes involved in liver carcinogenesis.Current conceptions of carcinogenesis posit that a limited number of molecular alterations involving oncogene activation and tumor suppressor inhibition are responsible for the initiation of the cancer phenotype [3]. The 'cancer platform' concept proposes that most oncogenic molecules also have the inherent ability to activate tumor suppressor genes or pathways through oncogene-induced apoptosis or senescence, thus limiting their oncogenic effects in a homeostatic fashion. Oncogene activation is therefore generally only tumorigenic when it is coupled with inactivation or inhibition of oncogene-induced pro-apoptotic or senescence pathways [4].The specific effects that lead to inactivation of these pro-apoptotic or senescence pathways may impinge on major known tumor suppressors such as p53, but may also be due to effects on other genes and molecules within the p53 or other tumor suppressor pathways [5]. These effects may be mediated through epigenetic or genetic mechanisms. The known risk factors for HCC are associated with chronic inflammation or hepatocellular injury. These insults result in repeated cycles of hepatocyte injury, death and repair that eventually lead to the premature senescence of the liver [6]. Senescent hepatocytes lose the telomeric repeats that p