Abstract
Hepatocellular carcinoma (HCC) is a rapidly fatal disease with short life expectancy from the time of diagnosis. Therapies with pharmacological agents do not improve the prognosis of patients with unresectable HCC. This emphasizes the need to identify prognostic markers and targets for early diagnosis, chemoprevention, and treatment of the disease. Available evidence indicates that clinical outcome of HCC could reflect genetic predisposition to cancer development and progression. Numerous loci controlling HCC progression have been identified in rodents. In this review, we describe the results of preclinical studies on effector mechanisms of susceptibility/resistance genes, responsible for HCC progression, aimed at identifying new prognostic markers and therapeutic targets of this tumor. Highest c-Myc amplification, cell cycle deregulation, alterations of iNOS/IKK/NF-kB and Ras/ERK signaling, and deregulation of FoxM1 and Mybl2 occur in rapidly progressing dysplastic nodules and HCC, induced in genetic susceptible rat strains, compared to slowly progressing lesions of resistant rats. Notably, alterations of these molecular mechanisms in human HCC subtypes with poorer and better prognosis, are similar to those present in genetically susceptible and resistant rats, respectively, and may function as prognostic markers and putative therapeutic targets. Attempts to cure advanced HCC by molecular therapy with cell signaling inhibitors directed against specific targets have given contradictory results, limited therapeutic effects, and major adverse effects in some instances. To overcome these difficulties it is necessary to direct gene therapy to different molecular targets essential for the survival of tumor cells, according to HCC subtype and status. Thus, efforts are necessary to identify and test, in pre-clinical and clinical studies, new therapeutic targets for combined molecular treatments of HCC. This approach may lead to identification of numerous new prognostic markers, representing promising candidates for the identification of high risk patients who may benefit from new anticancer drugs against key components of signaling pathways.
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