Hedgehog signaling pathway in colorectal cancer: function, mechanism, and therapy

Figures & data

Figure 1 The sketch of Hedgehog (Hh) signaling pathway. The Hh signaling pathway contains three Hh homologs: Sonic Hh, Indian Hh, and Desert Hh. (A) When the ligand is absent (“Off” state), the patched (Ptc) receptor inhibits the downstream protein Smoothened (SMO). Henceforth, glioma-associated oncogene homolog (Gli) proteins are sequestered by Suppressor of Fused (SuFu). The Hh pathway is, generally, inhibited at “Off” state. (B) After activation of the Hh ligand, Hh proteins are released from the signaling cell. Hh then subsequently binds (“On” state) to PtcH, removing the inhibition and further activating SMO. SMO then regulates the downstream transduction molecules of Gli proteins (Gli1, Gli2, and Gli3). Gli proteins are subsequently transferred to the nuclei and they exert their transduction functions.

Table 1 Mutations that are correlated in colorectal carcinogenesis

Gene	Chromosomal location	Type of mutation	Prevalence (%)	Function of gene product
KRAS	12p12	Point mutation (codons 12, 13 of exon 2)	40	Cell proliferation and survival
PIK3CA	3q26	Point mutations (E545K on exon 9, H1047R on exon 20)	15–30	Cell proliferation and survival
CDK8	13q12	Gene amplification	10–15	β-Catenin activation
EGFR	7p12	Gene amplification	5–15	Cell proliferation and survival
BRAF	7q34	Point mutations activating kinase activity (most commonly V600E)	5–10	Cell proliferation and survival
CMYC	8q24	Gene amplification	5–10	Cell proliferation and survival
CCNE1	19q12	Gene amplification	5	Cell proliferation and survival
NRAS	1p13	Point mutation	<5	Cell proliferation and survival
CTNNB1	3p22	Stabilizing point mutations and in-frame deletions near N terminus	<5	Regulation of Wnt pathway target genes that promote tumor growth and invasion
ERBB2 (HER2)	17q21	Gene amplification	<5	Cell proliferation and survival
MYB	6q22-q23	Gene amplification	<5	Stimulates growth of intestinal stem cells