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Abstract
Young A. Yoo1,*, Myoung Hee Kang2, Hyun Joo Lee3, Baek-hui Kim3, Jong Kuk Park6, Hyun Koo Kim4, Jun Suk Kim5, and Sang Cheul Oh5,*
1Brain Korea 21 Program for Biomedical Science; 2Graduate School of Medicine; Departments of 3Pathology and 4Thoracic and Cardiovascular Surgery; 5Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Korea University; and 6Laboratory of Radiation Tumor Physiology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
Y.A. Yoo and M.H. Kang contributed equally to this work.
*Corresponding Authors: Young A. Yoo and Sang Cheul Oh.
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.
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