Sonic Hedgehog signaling pathway as a potential target to inhibit the progression of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated mortality worldwide. Hepatocarcinogenesis involves numerous interlinked factors and processes, including the Sonic hedgehog (Shh) signaling pathway, which participates in the carcinogenesis, progression, invasiveness, recurrence and cancer stem cell maintenance of HCC. The Shh signaling pathway is activated by ligands that bind to their receptor protein, Protein patched homolog (Ptch). The process of Shh ligand binding to Ptch weakens the inhibition of smoothened homolog (SMO) and activates signal transduction via glioma-associated oncogene homolog (Gli) transcription factors. The overexpression of Shh pathway molecules, including Shh, Ptch-1, Gli and SMO has been indicated in patients with HCC. It has also been suggested that the Shh signaling pathway exhibits cross-talk between numerous other signaling pathways. The inactivation of the Shh signaling pathway reduces HCC growth, increases radio-sensitivity and increases the beneficial effect of chemotherapy in HCC treatment. Therefore, inhibition of the Shh pathway may be an effective target therapy that can be used in the treatment of HCC.

Keywords: cancer stem cells; hepatocellular carcinoma; recurrence; sonic hedgehog signaling pathway.

Figure 1.

Shh signaling pathway in hepatocellular carcinoma. Left (Off state): Ptch inhibits SMO activation. The signaling from SMO to Gli is blocked. SuFu binds to Gli for protein degradation via the proteasome. Therefore, the expression of Hh signaling pathway target gene turns off. Right (On state): Shh ligand bind to their receptor, PTCH. The binding of Hh ligands to PTCH weakens the inhibition of SMO and activates signal transduction via GLI transcription factor, activating downstream gene expression in cell migration/invasion/transition (SNAIL, MMPs, CHSY1), cell cycle/tumor growth (cyclin B1, CDK, Bcl2) and cancer stem cell marker (CD133). Shh, Sonic hedgehog; Ptch, protein patched homolog; SMO, smoothened homolog; Gli, glioma associated oncogene homolog; EMT, epithelial-mesenchymal transition.