title: Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer.
abstract: Activation of sonic hedgehog (Shh) signaling has been implicated in progression of a variety of tumors. In this study, we elucidated a role for Shh in the invasion of gastric tumors and determined the mechanism by which Shh is regulated. Immunohistochemical analysis of 178 primary human gastric tumor biopsies indicated that Shh expression was positively correlated with lymph node metastasis, high lymphatic vessel density, and poor prognosis. In mouse xenograft models of human gastric cancer, enforced expression of Shh significantly enhanced the incidence of lung metastasis compared with nonexpressing controls. Mechanistic investigations revealed that phosphoinositide 3-kinase (PI3K)/Akt inhibition blocked Shh-induced epithelial-mesenchyme transition, the activity of matrix metalloproteinase 9 (MMP-9), and lymphangiogenesis, reducing tumor invasiveness and metastasis. Taken together, our findings establish that Shh signaling promotes the metastasis of gastric cancer through activation of the PI3K/Akt pathway, which leads to mesenchymal transition and MMP-9 activation. These findings offer preclinical validation of Shh as a candidate therapeutic target for treatment of metastatic gastric cancers.
authors: Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, Korea. ydanbi@korea.ac.kr
authors: Young A
authors: YA
authors: Yoo
authors: Myoung Hee
authors: MH
authors: Kang
authors: Hyun Joo
authors: HJ
authors: Lee
authors: Baek-hui
authors: BH
authors: Kim
authors: Jong Kuk
authors: JK
authors: Park
authors: Hyun Koo
authors: HK
authors: Kim
authors: Jun Suk
authors: JS
authors: Kim
authors: Sang Cheul
authors: SC
authors: Oh
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D053823:Hedgehog Proteins / Q000032:analysis / Q000502:physiology*; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013274:Stomach Neoplasms / Q000473:pathology*
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9