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

Figure 1 Cell cycle protection from inhibition by P16^INK4A through the CDC37-HSP90 complex and CRM1 transporter protein. P16^INK4A forms complexes with CDK4 and CDK6 which, as a consequence, cannot by activated by Cyclin D1 and cannot phosphorylate pRb. The chaperons CDC37 and HSP90 form complexes with CDKs protecting them from inactivation by P16^INK4A. CRM1 forms a complex with E2F4, a P16^INK4A effector, transporting it outside of the nucleus, thus inactivating P16^INK4A.

Figure 2 Schematic representations of the activated RAS-MAPK, RASSF1A/NORE1A, and Dab2IP/ASK1 pathways, iNOS signalling, and FOXM1-related pathways involved in the dysregulation of cell growth and apoptosis in HCC. Active Ha-RAS (GTP-RAS) triggers the MAPK pathway leading to activation of ERK1/2. Active ERK can down-regulate DUSP1 by phosphorylation at ser296 allowing the formation of the SKP2/CSK1/DUSP1 complex, which facilitates DUSP1 ubiquitination and proteasomal degradation. In addition, ERK may further contribute to DUSP1 proteolysis via induction of its target FOXM1, leading to transcriptional activation of SKP2 and CKS1. These mechanisms result in decreased inhibition of ERK by DUSP1 (blunt arrow). Moreover, FOXM1 favors the growth of neoplastic cells by targeting genes involved in G₂← M transition, genomic instability, angiogenesis, NF-κB activation, and anti-apoptosis. iNOS activates IKK that allows proteasomal degradation of the NF-κB inhibitor, IkB-α. This results in NF-κB activation. iNOS also activates Ha-RAS, thus triggering the MAPK pathway leading to activation of ERK1/2. NF-κB activation by ERK may occur through AURORA-A (AURKA) which inhibits IkB-α. NF-κB activates various antiapoptotic genes (XIAP, cIAP1, BCL-xL) and inhibits the proapoptotic gene JNK. The inhibition of RAS activation by DAB2IP leads to the activation of ASK1, whereas active RAS favors the formation of the RASSF1-NORE1A complex. Both the ASK1 and RASSF1-NORE1A complexes trigger pro-apoptotic pathways. ASK1: Apoptosis signal-regulating kinase 1; BCL-Xl: BCL2-related protein, long isoform; CDC37: Cell division cycle 37; CKS1: CDC28 protein kinase 1b; cIAP: Iinhibitor-of-apoptosis protein 1; DAB2: Disabled homolog 2; DAB2IP: DAB2-interacting protein; DUSP1: Dual-specificity phosphatase 1; EPO: Erythropoietin; ERK: Extracellular signal-regulated kinase; GLI1: Glioblastoma associated oncogene 1; HIF-1α: Hypoxia-inducible factor 1 α; HSP90: Heat shock protein 90; HXK II: Hexokinase II; IKK: Inhibitor of kB kinase; iNOS: Inducible nitric oxide synthase; MST1: Mammalian sterile twenty kinase 1; NEK2: NIMA-related kinase 2; NF-κB: Nuclear factor-κB; NORE1A: Novel RAS effector 1A; RASSF1A: RAS association domain family 1A; RKIP: RAF kinase inhibitory protein; SKP2: S-phase kinase-associated protein 2; VEGF-α: Vascular endothelial growth factor α; XIAP: Inhibitor of apoptosis, X-linked. Pointed and blunt arrows indicate activation and inhibition, respectively.