c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma.

Abstract

c-Ski, originally identified as a proto-oncogene product, is an important negative regulator of transforming growth factor (TGF)-beta 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-beta signaling by dominant-negative TGF-beta 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-beta 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-beta 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-beta 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.

• Authors: Kunihiko Kiyono, Hiroshi I Suzuki, Yasuyuki Morishita, Akiyoshi Komuro, Caname Iwata, Masakazu Yashiro, Kosei Hirakawa, Mitsunobu R Kano, Kohei Miyazono
• Journal: Cancer science (Cancer Sci) Vol. 100 Issue 10 Pg. 1809-16 (Oct 2009) ISSN: 1349-7006 [Electronic] England
• PMID: 19594546 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• MAS1 protein, human
• Proto-Oncogene Mas
• Proto-Oncogene Proteins
• Thrombospondin 1
• Transforming Growth Factor beta
• SKI protein, human

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Animals
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation
• DNA-Binding Proteins (biosynthesis, genetics)
• Female
• Humans
• Immunohistochemistry
• Mice
• Mice, Nude
• Neovascularization, Pathologic (genetics, metabolism, pathology)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins (biosynthesis, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (physiology)
• Stomach Neoplasms (genetics, metabolism, pathology)
• Thrombospondin 1 (metabolism)
• Transforming Growth Factor beta (metabolism)
• Up-Regulation
• Xenograft Model Antitumor Assays