Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer

Young A. Yoo, Myoung Hee Kang, Hyun Joo Lee, Baek-Hui Kim, Jong Kuk Park, Hyun Koo Kim, Jun Suk Kim, Sang Cheul Oh

Research output: Contribution to journalArticle

196 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7061-7070
Number of pages10
JournalCancer Research
Volume71
Issue number22
DOIs
Publication statusPublished - 2011 Nov 15

Fingerprint

Lymphangiogenesis
Hedgehogs
Matrix Metalloproteinase 9
Stomach Neoplasms
Neoplasm Metastasis
1-Phosphatidylinositol 4-Kinase
Neoplasms
Stomach
Lymphatic Vessels
Mesoderm
Heterografts
Lymph Nodes
Biopsy
Lung
Incidence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. / Yoo, Young A.; Kang, Myoung Hee; Lee, Hyun Joo; Kim, Baek-Hui; Park, Jong Kuk; Kim, Hyun Koo ; Kim, Jun Suk; Oh, Sang Cheul.

In: Cancer Research, Vol. 71, No. 22, 15.11.2011, p. 7061-7070.

Research output: Contribution to journalArticle

Yoo, Young A. ; Kang, Myoung Hee ; Lee, Hyun Joo ; Kim, Baek-Hui ; Park, Jong Kuk ; Kim, Hyun Koo ; Kim, Jun Suk ; Oh, Sang Cheul. / Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. In: Cancer Research. 2011 ; Vol. 71, No. 22. pp. 7061-7070.
@article{0fb70735cf7640c8aaf74a287c2443a3,
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.",
author = "Yoo, {Young A.} and Kang, {Myoung Hee} and Lee, {Hyun Joo} and Baek-Hui Kim and Park, {Jong Kuk} and Kim, {Hyun Koo} and Kim, {Jun Suk} and Oh, {Sang Cheul}",
year = "2011",
month = "11",
day = "15",
doi = "10.1158/0008-5472.CAN-11-1338",
language = "English",
volume = "71",
pages = "7061--7070",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "22",

}

TY - JOUR

T1 - Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer

AU - Yoo, Young A.

AU - Kang, Myoung Hee

AU - Lee, Hyun Joo

AU - Kim, Baek-Hui

AU - Park, Jong Kuk

AU - Kim, Hyun Koo

AU - Kim, Jun Suk

AU - Oh, Sang Cheul

PY - 2011/11/15

Y1 - 2011/11/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=81155126047&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81155126047&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-11-1338

DO - 10.1158/0008-5472.CAN-11-1338

M3 - Article

VL - 71

SP - 7061

EP - 7070

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 22

ER -