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The role of semaphorin 4D in tumor development and angiogenesis in human breast cancer

Authors Jiang H, Chen C, Sun Q, Wu J, Qiu L, Gao C, Liu W, Yang J, Jun N, Dong J

Received 9 June 2016

Accepted for publication 22 August 2016

Published 26 September 2016 Volume 2016:9 Pages 5737—5750

DOI https://doi.org/10.2147/OTT.S114708

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 4

Editor who approved publication: Dr Jianmin Xu


Hongchao Jiang,1,2 Ceshi Chen,3 Qiangming Sun,4 Jing Wu,3 Lijuan Qiu,4 Change Gao,5 Weiqing Liu,5 Jun Yang,5 Nie Jun,2 Jian Dong2

1Department of Oncology, The Affiliated Children’s Hospital of Kunming Medical University, 2Department of Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Provincial Tumor Hospital, 3Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, 4Molecular Epidemiology Joint Laboratory, Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, 5Department of Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China

Background: Semaphorin 4D (Sema4D) is highly expressed in certain types of tumors and functions in the regulation of tumor angiogenesis and growth. However, it is still not clear regarding the roles of Sema4D in breast cancer. This study was designed to explore the effects of Sema4D on proliferation, cell cycle progression, apoptosis, invasion, migration, tumor growth, and angiogenesis in breast cancer.
Materials and methods: The expression level of Sema4D was investigated in MCF10A, 184A1, HCC1937, MDA-MB-468, MDA-MB-231, Hs578T, BT474, MCF-7, and T47D breast cancer cell lines by Western blotting analysis. Sema4D downregulation or overexpression was established by infection with lentiviruses-encoding Sema4D short hairpin RNA (shRNA) or Sema4D. To evaluate the effects of Sema4D on cell proliferation, cell cycle progression, apoptosis, invasion, and migration of MDA-MB-231 and MDA-MB-468 cells, methods including MTT assay, flow cytometry, wound healing assay, and transwell experiments were applied. BALB/c nude mice were injected with MDA-MB-231 cells, which were respectively infected with lentiviruses-encoding Sema4D, Sema4D shRNA, and GFP, followed by tumor angiogenesis assay.
Results: Sema4D was expressed at higher levels in breast cancer cell lines compared with the normal human breast epithelial cell lines, especially in MDA-MB-231 and MDA-MB-468 cells. Cell proliferation ability was remarkably inhibited in Sema4D downregulated condition, whereas the proportions of cells in the G0/G1 phase and apoptosis increased in MDA-MB-231 and MDA-MB-468 cells. In addition, the invasion and migration abilities of these cells were obviously reduced. Xenograft growth as well as angiogenesis was inhibited when infected with lentiviruses-encoding Sema4D shRNA in vivo.
Conclusion: Downregulation of Sema4D had notable influence on cell proliferation ability, invasion, migration, and apoptosis of both MDA-MB-231 and MDA-MB-468 cells. Furthermore, infection with lentiviruses-encoding Sema4D shRNA obviously inhibited tumor growth and angiogenesis in BALB/c nude mice. Our results showed that Sema4D may represent a novel therapeutic target for human breast cancer.

Keywords: semaphorin 4D, breast cancer, apoptosis, angiogenesis, proliferation

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