TY - JOUR
T1 - C-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-β signaling in diffuse-type gastric carcinoma
AU - Kiyono, Kunihiko
AU - Suzuki, Hiroshi I.
AU - Morishita, Yasuyuki
AU - Komuro, Akiyoshi
AU - Iwata, Caname
AU - Yashiro, Masakazu
AU - Hirakawa, Kosei
AU - Kano, Mitsunobu R.
AU - Miyazono, Kohei
PY - 2009/10/1
Y1 - 2009/10/1
N2 - c-Ski, originally identified as a proto-oncogene product, is an important negative regulator of transforming growth factor (TGF)-β family signaling through interaction with Smad2, Smad3, and Smad4. High expression of c-Ski has been found in some cancers, including gastric cancer. We previously showed that disruption of TGF-β signaling by dominant-negative TGF-β type II receptor in a diffuse-type gastric carcinoma model accelerated tumor growth through induction of tumor angiogenesis by decreased expression of the anti-angiogenic factor thrombospondin (TSP)-1. Here, we examined the function of c-Ski in human diffuse-type gastric carcinoma OCUM-2MLN cells. Overexpression of c-Ski inhibited TGF-β signaling in OCUM-2MLN cells. Interestingly, c-Ski overexpression resulted in extensive acceleration of the growth of subcutaneous xenografts in BALB/c nu/nu female mice (6 weeks of age). Similar to tumors expressing dominant-negative TGF-β type II receptor, histochemical studies revealed less fibrosis and increased angiogenesis in xenografted tumors expressing c-Ski compared to control tumors. Induction of TSP-1 mRNA by TGF-β was attenuated by c-Ski in vitro, and expression of TSP-1 mRNA was decreased in tumors expressing c-Ski in vivo. These findings suggest that c-Ski overexpression promotes the growth of diffuse-type gastric carcinoma through induction of angiogenesis. (Cancer Sci 2009; 100: 1809-1816).
AB - c-Ski, originally identified as a proto-oncogene product, is an important negative regulator of transforming growth factor (TGF)-β family signaling through interaction with Smad2, Smad3, and Smad4. High expression of c-Ski has been found in some cancers, including gastric cancer. We previously showed that disruption of TGF-β signaling by dominant-negative TGF-β type II receptor in a diffuse-type gastric carcinoma model accelerated tumor growth through induction of tumor angiogenesis by decreased expression of the anti-angiogenic factor thrombospondin (TSP)-1. Here, we examined the function of c-Ski in human diffuse-type gastric carcinoma OCUM-2MLN cells. Overexpression of c-Ski inhibited TGF-β signaling in OCUM-2MLN cells. Interestingly, c-Ski overexpression resulted in extensive acceleration of the growth of subcutaneous xenografts in BALB/c nu/nu female mice (6 weeks of age). Similar to tumors expressing dominant-negative TGF-β type II receptor, histochemical studies revealed less fibrosis and increased angiogenesis in xenografted tumors expressing c-Ski compared to control tumors. Induction of TSP-1 mRNA by TGF-β was attenuated by c-Ski in vitro, and expression of TSP-1 mRNA was decreased in tumors expressing c-Ski in vivo. These findings suggest that c-Ski overexpression promotes the growth of diffuse-type gastric carcinoma through induction of angiogenesis. (Cancer Sci 2009; 100: 1809-1816).
UR - http://www.scopus.com/inward/record.url?scp=70349599607&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70349599607&partnerID=8YFLogxK
U2 - 10.1111/j.1349-7006.2009.01248.x
DO - 10.1111/j.1349-7006.2009.01248.x
M3 - Article
C2 - 19594546
AN - SCOPUS:70349599607
VL - 100
SP - 1809
EP - 1816
JO - Cancer Science
JF - Cancer Science
SN - 1347-9032
IS - 10
ER -