Sonic Hedgehog Pathway Promotes Metastasis and Lymphangiogenesis via Activation of Akt, EMT, and MMP-9 Pathway in Gastric Cancer

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 tumo...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2011-11, Vol.71 (22), p.7061-7070
Main Authors: YOO, Young A, MYOUNG HEE KANG, HYUN JOO LEE, KIM, Baek-Hui, JONG KUK PARK, HYUN KOO KIM, JUN SUK KIM, SANG CHEUL OH
Format: Article
Language:English
Subjects:
Adult
Aged
Animals
Antineoplastic agents
Biological and medical sciences
Cell Line, Tumor
Epithelial-Mesenchymal Transition
Female
Gastroenterology. Liver. Pancreas. Abdomen
Hedgehog Proteins - analysis
Hedgehog Proteins - physiology
Humans
Lymphangiogenesis
Lymphatic Metastasis
Male
Matrix Metalloproteinase 9 - physiology
Medical sciences
Mice
Mice, Inbred BALB C
Middle Aged
Pharmacology. Drug treatments
Phosphatidylinositol 3-Kinases - physiology
Proto-Oncogene Proteins c-akt - physiology
Signal Transduction - physiology
Stomach Neoplasms - pathology
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumors
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-11-1338