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

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 22; pp. 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: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.11.2011
• 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; Enzyme; Akt protein kinase; Metalloendopeptidases; Activation; Malignant tumor; Metastasis; Stomach cancer; Gelatinase B; Cell signaling; Peptidases; Regulation(control); Hedgehog protein; Hydrolases; Digestive diseases; Lymphangiogenesis; Cancer; Gastric disease
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-1338

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.