Dissection of Signal Transduction Pathways as a Tool for the Development of Targeted Therapies of Hepatocellular Carcinoma

Abstract

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.

hsa-miR-191 Is a Candidate Oncogene Target for Hepatocellular Carcinoma Therapy

“…The pathways most influenced were mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (P < 0.0007), transforming growth factor-β (TGF-β; P < 0.01), and MAPK/c-Jun NH 2 -terminal kinase (P < 0.03). Those pathways are important for human hepatocarcinogenesis (24) and are part of the control of cellular proliferation and differentiation. Because the inhibition of miR-191 led to changes in those pathways, we Figure 3B shows overlap of genes from populations of mRNA upregulated 2-fold or more after miR-191 inhibition (from the Affymetrix GeneChip), predicted targets of miR-191 (from the union of TargetScan and Miranda), and genes in affected pathways (from KEGG and NetPath).…”

“…TGF-β and MAPK pathways were found to be most affected. These pathways play a significant role in hepatocarcinogenesis (24). The TGF-β pathway regulates cell proliferation, differentiation, and adhesion (36).…”

Nitidine chloride inhibits hepatocellular carcinoma cell growth in vivo through the suppression of the JAK1/STAT3 signaling pathway

“…STAT3 can stimulate endothelial cell migration and differentiation and lead to tumor VEGF overproduction by direct transcriptional activation (20)(21)(22). The JAK1-STAT3 pathway plays a crucial role in cell survival, angiogenesis, immune evasion and inflammatory responses through the activation of STAT3, causing cyclin D1, cyclin-dependent kinase (CDK)4, Bcl-2, Bax and vascular endothelial growth factor gene transcription (23)(24)(25)(26). Thus, the JAK1-STAT3 signaling pathway as a target for intervention is expected to become a novel method for the treatment of HCC.…”

Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

“…The complexity of molecular changes of HCC predicts the impossibility to cure HCC development by interfering with only one signaling pathway. To overcome this difficulty and the occurrence of resistance to therapy, networked biologic therapies have been proposed [140,143,144] in which a combination of non-cytotoxic interventions must be performed to interrupt the damage. These interventions may be directed to interfere with different cell survival pathways, enhance apoptosis, block angiogenesis and extrahepatic fibrosis, induce the lysis of tumor cells, stimulate antitumor immunity, decrease HBV and HCV replication, etc.…”