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. 2021 Jan 11;10(1):123. doi: 10.3390/cells10010123

Figure 1.

Figure 1

Hedgehog (Hh) signaling pathway contributes to hepatic carcinogenesis. The canonical Hh pathway starts from the Hh ligands binding to the 12-pass transmembrane protein patched 1 (PTCH1), which liberates SMO and further promotes the translocation of GLI into the nucleus. The non-canonical Hh pathway does not involve the ligand and receptor (PCTH1), and is operated in an SMO-independent fashion. In fact, it is activated by other factors, such as TGF-β. TGF-β binds to TGF-β receptor II and facilitates the phosphorylation of SMAD2/3, and then p-SMAD2/3 is translocated into the nucleus together with SMAD4. The GLI transcription factor may interact with the SMAD complex and co-transact GLI targeting genes although how SMAD and GLIs work together in co-transactivation of the targeting genes is unclear. These targeting genes are involved in chronic inflammation and its transformation to oncogenic initiation, together with the fibrogenic (TGF-β) and oncogenic (c-Myc, Wnt, Nanog) factors. Hh signaling plays a critical role in maintenance of stem-like properties (CD133, CD44 and Nanog) in onset of epithelial mesenchymal transition (EMT) and in HCC invasion and metastasis through Snail, Twist, Zeb-1 and MMPs, as well as in drug resistance through ABCC1 and TAP1. The Hh signaling is self-amplified through a positive feedback of its signaling molecules as targeting genes (PTCH1 and GLI1), and the activated cells produce more ligands under an oncogenic status.