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Molecular Mechanisms Underlying Hepatocellular Carcinoma
INSERM, U871, 69003 Lyon; Université Lyon 1, IFR62 Lyon-Est, 69008 Lyon, France
Hospices Civils de Lyon, Hôtel Dieu, Service d’hépatologie et de gastroentérologie, 69002 Lyon, France
* Author to whom correspondence should be addressed.
Received: 14 August 2009; in revised form: 3 November 2009 / Accepted: 9 November 2009 / Published: 9 November 2009
Abstract: Hepatocarcinogenesis is a complex process that remains still partly understood. That might be explained by the multiplicity of etiologic factors, the genetic/epigenetic heterogeneity of tumors bulks and the ignorance of the liver cell types that give rise to tumorigenic cells that have stem cell-like properties. The DNA stress induced by hepatocyte turnover, inflammation and maybe early oncogenic pathway activation and sometimes viral factors, leads to DNA damage response which activates the key tumor suppressive checkpoints p53/p21Cip1 and p16INK4a/pRb responsible of cell cycle arrest and cellular senescence as reflected by the cirrhosis stage. Still obscure mechanisms, but maybe involving the Wnt signaling and Twist proteins, would allow pre-senescent hepatocytes to bypass senescence, acquire immortality by telomerase reactivation and get the last genetic/epigenetic hits necessary for cancerous transformation. Among some of the oncogenic pathways that might play key driving roles in hepatocarcinogenesis, c-myc and the Wnt/β-catenin signaling seem of particular interest. Finally, antiproliferative and apoptosis deficiencies involving TGF-β, Akt/PTEN, IGF2 pathways for instance are prerequisite for cancerous transformation. Of evidence, not only the transformed liver cell per se but the facilitating microenvironment is of fundamental importance for tumor bulk growth and metastasis.
Keywords: hepatocellular carcinoma; stem cells; cellular stress; senescence; oncogenes; tumor suppressors
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MDPI and ACS Style
Merle, P.; Trepo, C. Molecular Mechanisms Underlying Hepatocellular Carcinoma. Viruses 2009, 1, 852-872.
Merle P, Trepo C. Molecular Mechanisms Underlying Hepatocellular Carcinoma. Viruses. 2009; 1(3):852-872.
Merle, Philippe; Trepo, Christian. 2009. "Molecular Mechanisms Underlying Hepatocellular Carcinoma." Viruses 1, no. 3: 852-872.