Hedgehog, WNT, FGF and BMP signaling pathways network together during embryogenesis, tissue regeneration, and
carcinogenesis. Aberrant activation of Hedgehog signaling pathway leads to pathological consequences in a variety of human
tumors, such as
gastric cancer and
pancreatic cancer. Endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), surgical
gastrectomy and
chemotherapy are therapeutic options for
gastric cancer; however, prognosis of advanced
gastric cancer patient is still poor. Here, Hedgehog signaling pathway in human
gastric cancer and its clinical applications will be reviewed. Human SHH, IHH, DHH (Hedgehog homologs), HHAT (Hedgehog
acyltransferase), HHIP (Hedgehog-interacting
protein), DISP1, DISP2, DISP3 (Dispatched homologs), PTCH1, PTCH2 (Patched homologs), SMO (Smoothened homolog), KIF27, KIF7 (Costal-2 homologs), STK36 (Fused homolog), SUFU (SuFu homolog), DZIP1 (Iguana homolog), GLI1, GLI2 and GLI3 (Cubitus interruptus homologs) are implicated in the Hedgehog signaling. PTCH1, FOXM1 and CCND2 are direct transcriptional targets of Hedgehog signaling. Hedgehog signaling activation leads to cell proliferation through cell cycle regulation. SHH regulates growth and differentiation within gastric mucosa through autocrine loop and FOXL1-mediated epithelial-mesenchymal interaction. SHH is implicated in stem/progenitor cell restitution of damaged gastric mucosa during
chronic infection with Helicobacter pylori. SHH up-regulation, IHH upregulation and HHIP down-regulation lead to aberrant activation of Hedgehog signaling through PTCH1 to GLI1 in
gastric cancer. Small molecule compounds targeted to SMO (KADD-cyclopamine, SANT1-4, Cur61414) as well as humanized anti-SHH
antibodies are potent anti-
cancer drugs for
gastric cancer. Cocktail of Hedgehog inhibitors would be developed as novel
therapeutics for
gastric cancer. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of Hedgehog signaling genes would be utilized for genetic screening of
gastric cancer, while
cDNA-PCR, microarray and ELISA detecting aberrant Hedgehog signaling activation would be utilized for therapeutic optional choice. Genetic screening and precise selection of therapeutic options would contribute to the realization of
personalized medicine.