Dissection of signal transduction pathways as a tool for the development of targeted therapies of hepatocellular carcinoma.
Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis, relevant to preneoplastic lesions progression to full malignancy in rodent models, and evaluation of these changes in human hepatocellular carcinomas (HCCs). Activation of ERB receptor family, MAPK, JAK-STAT, beta-Catenin cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine decarboxylase, Cyclins and CDKs occurs in human and rodent hepatocarcinogenesis. This is associated with downregulation of the cell cycle inhibitors p16(INK4A) and p53 and TGF-beta/SMAD signaling. Oncosuppressor genes, including p16(INK4A), E-CAD, and DLC-1 are often hypermethylated in humans and rodents. Moreover, protection of cell cycle from p16(INK4A) inhibition by upregulation of CDC37, HSP90, and CRM1 correlates to HCC progression. A body of evidence indicates that inhibition of key genes of aforementioned signaling pathways by antisense or siRNA approaches or specific inhibitors restraints growth of in vitro cultured or in vivo xenografted HCCs. Efforts are currently dedicated to improve transduction efficiency. HCC cells may escape gene therapy by various mechanisms. Attempts to overcome this difficulty include discovery of new therapeutic targets, gene therapy directed to different molecular targets essential for tumor cell survival and specifically directed to HCC subtypes.
Calvisi
Diego F
DF
Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.
Pascale
Rosa M
RM
Feo
Francesco
F
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy*; D019175:DNA Methylation; D004195:Disease Models, Animal; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor / Q000502:physiology; D015316:Genetic Therapy; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy*; D011230:Precancerous Conditions / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
D014408:Biomarkers, Tumor