Emerging signaling pathways in hepatocellular carcinoma

Abstract

Signaling pathways have become a major source of targets for novel therapies in hepatocellular carcinoma (HCC). Survival benefits achieved with sorafenib, a multikinase inhibitor, are unprecedented and underscore the importance of improving our understanding of how signaling networks interact in transformed cells. Numerous signaling modules are de-regulated in HCC, including some related to growth factor signaling (e.g., IGF, EGF, PDGF, FGF, HGF), cell differentiation (WNT, Hedgehog, Notch), and angiogenesis (VEGF). Intracellular mediators such as RAS and AKT/MTOR may also play a role in HCC development and progression. Different molecular mechanisms have been shown to induce aberrant pathway activation. These include point mutations, chromosomal aberrations, and epigenetically driven down-regulation. The use of novel molecular technologies such as next-generation sequencing in HCC research has enabled the identification of novel pathways previously underexplored in the HCC field, such as chromatin remodeling and autophagy. Considering recent failures of molecular therapies in advanced clinical trials (e.g., sunitinib, brivanib), survey of these and other new pathways may provide alternative therapeutic targets.

Keywords: Cascade; Chromatin remodeling; HDAC; Hippo; Liver cancer.

Fig. 1

Emerging signaling pathways in hepatocellular carcinoma. Chromatin remodelling: Deacetylation (Ac) of histones within the nucleosomes by HDACs results in DNA condensation, restricting transcriptional activation. On the other hand, chromatin remodelling complexes, including ARID1/2, lead to transcriptional activation by facilitating access for the transcription machinery through nucleosome restructuring. Notch signaling: Binding of protein ligands to the extracellular domain of NOTCH receptors (NOTCH-R) induces photolytic cleavage of the receptor, releasing its intracellular domain (NOTCH-ICD), which then enters the nucleus and modifies expression of its target genes (e.g., HES, HEY, and SOX9). Hedgehog (Hh) signaling: In the presence of Hh ligands, PTCH releases its inhibitory effect on SMO, which is in a complex with COS-2 and FU, allowing the nuclear translocation of the transcription factor GLI. Hippo signaling: Upon stimulation, the upstream regulators of hippo pathway (e.g., FAT, NF2, and FDM6) activate the kinase complexes MST1/2-SVA1 and Lats1/2-Mob1, resulting in phosphorylation of the transcription factor YAP and preventing its nuclear translocation. Lymphotoxins and microbiota: The recognition of microbial ligands (LPS/PAMPs) by TLKRs (e.g., TLK4) on the hepatic stellate cells leads to activation of NF-kβ signaling and the consequent production of proinflammatory molecules, including cytokines and TNF-α.