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B7-H3 silencing by RNAi inhibits tumor progression and enhances chemosensitivity in U937 cells

Authors Zhang W, Wang J, Wang Y, Dong F, Zhu M, Wan W, Li H, Wu F, Yan X, Ke X

Received 23 March 2015

Accepted for publication 30 April 2015

Published 14 July 2015 Volume 2015:8 Pages 1721—1733

DOI https://doi.org/10.2147/OTT.S85272

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Faris Farassati

Wei Zhang, Jing Wang, Yanfang Wang, Fei Dong, Mingxia Zhu, Wenli Wan, Haishen Li, Feifei Wu, Xinxing Yan, Xiaoyan Ke

Department of Hematology and Lymphoma Research Center, Peking University Third Hospital, Beijing, People’s Republic of China

Background: The role of B7-H3 in acute monocytic leukemia U937 cells has not been thoroughly investigated.
Materials and methods: B7-H3 knockdown in the U937 cell line was performed using small hairpin (sh)RNA lentivirus transduction. The effects on cell proliferation, cycle, migration, and invasion were investigated by Cell Counting Kit-8 assay, methyl cellulose colony-forming assay, propidium iodide staining, and Transwell assays in vitro. Changes in cell growth inhibition and apoptosis, when combined with chemotherapy drugs, were determined using the Cell Counting Kit-8 and Annexin V-FITC/PI assays. U937 xenograft models were used to assess the effects of B7-H3 on tumorigenicity and the therapeutic effect of B7-H3 knockdown in combination with chemotherapy drugs in vivo.
Results: Downregulation of B7-H3 significantly decreased U937 cell growth and colony-forming ability. The mean inhibition rate of tumor growth with B7-H3 knockdown was 59.4%, and the expression of both Ki-67 and PCNA in xenografts was significantly reduced. After B7-H3 silencing, the U937 cell cycle was arrested at the G0/G1 phase. The cell migration rate of B7-H3 knockdown cells was reduced more than fivefold, and invasion capacity decreased by 86.7%. B7-H3 RNAi profoundly increased the antitumor effect of chemotherapy in vitro and in vivo. On day 19, inhibition rates of tumor growth in B7-H3 shRNA combined with idarubicin, cytarabine, and idarubicin plus cytarabine were 70.5%, 80.0%, and 90.0%, respectively (P=0.006, P=0.004, and P=0.016, respectively).
Conclusion: B7-H3 may promote U937 cell progression, and shRNA targeting B7-H3 significantly enhances sensitivity to chemotherapeutic drugs. These results may provide new insight into the function of B7-H3 and a promising therapeutic approach targeting B7-H3 in acute monocytic leukemia.

Keywords: B7-H3, acute monocytic leukemia, cancer gene therapy, chemosensitivity

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