TY - JOUR
T1 - Activin A inhibits vascular endothelial cell growth and suppresses tumour angiogenesis in gastric cancer
AU - Kaneda, H.
AU - Arao, T.
AU - Matsumoto, K.
AU - De Velasco, M. A.
AU - Tamura, D.
AU - Aomatsu, K.
AU - Kudo, K.
AU - Sakai, K.
AU - Nagai, T.
AU - Fujita, Y.
AU - Tanaka, K.
AU - Yanagihara, K.
AU - Yamada, Y.
AU - Okamoto, I.
AU - Nakagawa, K.
AU - Nishio, K.
N1 - Funding Information:
We thank Mrs Eiko Honda, Mr Shinji Kurashimo, and Miss Tomoko Kitayama for their technical assistance. This work was supported by funds for the Comprehensive 3rd Term of the 10-year Strategy for Cancer Control, a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (19209018), and a fund from the Health and Labor Scientific Research Grants (20-9). HK is the recipient of a Research Resident Fellowship from the Foundation of Promotion of Cancer Research in Japan.
PY - 2011/10/11
Y1 - 2011/10/11
N2 - Background: Activin A is a multi-functional cytokine belonging to the transforming growth factor-Β (TGF-Β) superfamily; however, the effect of activin A on angiogenesis remains largely unclear. We found that inhibin Β 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-Β, 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-Β, on tumour growth and angiogenesis in GC.
AB - Background: Activin A is a multi-functional cytokine belonging to the transforming growth factor-Β (TGF-Β) superfamily; however, the effect of activin A on angiogenesis remains largely unclear. We found that inhibin Β 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-Β, 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-Β, on tumour growth and angiogenesis in GC.
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U2 - 10.1038/bjc.2011.348
DO - 10.1038/bjc.2011.348
M3 - Article
C2 - 21897392
AN - SCOPUS:80053977129
VL - 105
SP - 1210
EP - 1217
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 8
ER -
