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British Journal of Cancer (2011) 105, 1210 1217 & 2011 Cancer Research UK All rights reserved 0007 0920/11
http://www.bjcancer.com
Web End =www.bjcancer.com
Activin A inhibits vascular endothelial cell growth and suppresses tumour angiogenesis in gastric cancer
H Kaneda1,2, T Arao1, K Matsumoto1, MA De Velasco1, D Tamura1, K Aomatsu1, K Kudo1, K Sakai1, T Nagai1, Y Fujita1, K Tanaka2, K Yanagihara3, Y Yamada4, I Okamoto2, K Nakagawa2 and K Nishio*,11Department of Genome Biology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; 2Departmentof Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; 3Laboratory of Health Sciences, Department of Life Sciences, Yasuda Womens University Faculty of Pharmacy, 6-13-1 Yasuhigashi, Asaminami-ku, Hiroshima 731-0153, Japan;
4Department of Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan
BACKGROUND: Activin A is a multi-functional cytokine belonging to the transforming growth factor-b (TGF-b) superfamily; however, the effect of activin A on angiogenesis remains largely unclear. We found that inhibin b A subunit (INHBA) mRNA is overexpressed in gastric cancer (GC) specimens and investigated the effect of activin A, a homodimer of INHBA, on angiogenesis in GC.
METHODS: Anti-angiogenic effects of activin A via p21 induction were evaluated using human umbilical vein endothelial cells (HUVECs) in vitro and a stable INHBA-introduced GC cell line in vivo.
RESULTS: Compared with TGF-b, activin A potently inhibited the cellular proliferation and tube formation of HUVECs with induction of p21. A promoter assay and a chromatin immunoprecipitation assay revealed that activin A directly regulates p21 transcriptional activity through Smads. Stable p21-knockdown significantly enhanced the cellular proliferation of HUVECs. Notably, stable p21-knockdown exhibited a resistance to activin-mediated growth inhibition in HUVECs, indicating that p21 induction has a key role on activin A-mediated growth inhibition in vascular endothelial cells. Finally, a stable INHBA-introduced GC cell line exhibited a decrease in tumour growth and angiogenesis in vivo.
CONCLUSION: Our findings highlight the suppressive role of activin A, unlike TGF-b, on tumour growth and angiogenesis in GC. British Journal of Cancer (2011) 105, 12101217. doi:http://dx.doi.org/10.1038/bjc.2011.348
Web End =10.1038/bjc.2011.348 http://www.bjcancer.com
Web End =www.bjcancer.com Published online 6 September 2011& 2011 Cancer Research UK
Keywords: activin A; p21CIP1/WAF1; angiogenesis; gastric cancer
MolecularDiagnostics
Activins are homodimers formed by the assembly of two closely related inhibin...