B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

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

doi:10.3892/ijo.2015.2962

B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

Authors:
- Wei Zhang
- Yanfang Wang
- Jing Wang
- Fei Dong
- Mingxia Zhu
- Wenli Wan
- Haishen Li
- Feifei Wu
- Xinxing Yan
- Xiaoyan Ke
View Affiliations

Affiliations: Department of Hematology and Lymphoma Research Center, Peking University Third Hospital, Beijing 100191, P.R. China
Published online on: April 9, 2015 https://doi.org/10.3892/ijo.2015.2962
Pages: 2562-2572

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Abstract

B7-H3 (CD276), known as a member of B7 immunoregulatory family, is a type I transmembrane glycoprotein aberrantly expressed in numerous types of cancer and associated with poor prognosis. However, the role of B7-H3 in oncogenesis and chemosensitivity of mantle cell lymphoma (MCL) remains unknown. We determined the effects of downregulating B7-H3 expression on tumor progression and the sensitivity of chemotherapeutic drug in mantle cell lymphoma. B7-H3 knockdown was performed using lentivirus transduction in the Maver and Z138 mantle cell lymphoma cell lines, respectively. The effects of B7-H3 on cell proliferation, cycle, migration and invasion were investigated by CCK-8 assay, methyl cellulose colony forming assay, PI staining, and Transwell assays in vitro. By establishing Maver and Z138 xenograft models, the effects of B7-H3 on tumorigenicity were observed, and Ki-67 and PCNA was detected by immunohistochemistry. The downregulation of B7-H3 significantly decreased tumor proliferation in MCL in vitro and in vivo. In the B7-H3 knockdown groups of Maver and Z138 xenograft models, the mean inhibition rate of tumor growth was 59.1 and 65.0% (p=0.010 and 0.003), and the expression of both Ki-67 and PCNA were significantly lower, respectively. After B7-H3 silencing, the cell cycles of Maver and Z138 were both arrested at G0/G1 phase, and the cell migration rates and invasion capacity were decreased as well. Moreover, the impacts of B7-H3 RNAi on the antitumor effect of chemotherapy drugs were determined with CCK-8 and Annexin V-FITC/PI assays in vitro and with xenograft models in vivo. The silencing of B7-H3 increased the sensitivity of Maver and Z138 cells to rituximab and bendamustine and enhanced the drug-induced apoptosis, respectively. Our study demonstrates for the first time that B7-H3 promotes mantle cell lymphoma progression and B7-H3 knockdown significantly enhances the chemosensitivity. This may provide a new therapeutic approach to mantle cell lymphoma.

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1	Campo E and Rule S: Mantle cell lymphoma: Evolving management strategies. Blood. 125:48–55. 2015. View Article : Google Scholar
2	Chen Y, Wang M and Romaguera J: Current regimens and novel agents for mantle cell lymphoma. Br J Haematol. 167:3–18. 2014. View Article : Google Scholar : PubMed/NCBI
3	Ghielmini M and Zucca E: How I treat mantle cell lymphoma. Blood. 114:1469–1476. 2009. View Article : Google Scholar : PubMed/NCBI
4	Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, Dong H, Sica GL, Zhu G, Tamada K, et al: B7-H3: A costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol. 2:269–274. 2001. View Article : Google Scholar : PubMed/NCBI
5	Steinberger P, Majdic O, Derdak SV, Pfistershammer K, Kirchberger S, Klauser C, Zlabinger G, Pickl WF, Stöckl J and Knapp W: Molecular characterization of human 4Ig-B7-H3, a member of the B7 family with four Ig-like domains. J Immunol. 172:2352–2359. 2004. View Article : Google Scholar : PubMed/NCBI
6	Xu H, Cheung IY, Guo HF and Cheung NK: MicroRNA miR-29 modulates expression of immunoinhibitory molecule B7-H3: Potential implications for immune based therapy of human solid tumors. Cancer Res. 69:6275–6281. 2009. View Article : Google Scholar : PubMed/NCBI
7	Chen C, Shen Y, Qu QX, Chen XQ, Zhang XG and Huang JA: Induced expression of B7-H3 on the lung cancer cells and macrophages suppresses T-cell mediating anti-tumor immune response. Exp Cell Res. 319:96–102. 2013. View Article : Google Scholar
8	Yamato I, Sho M, Nomi T, Akahori T, Shimada K, Hotta K, Kanehiro H, Konishi N, Yagita H and Nakajima Y: Clinical importance of B7-H3 expression in human pancreatic cancer. Br J Cancer. 101:1709–1716. 2009. View Article : Google Scholar : PubMed/NCBI
9	Ingebrigtsen VA, Boye K, Tekle C, Nesland JM, Flatmark K and Fodstad O: B7-H3 expression in colorectal cancer: Nuclear localization strongly predicts poor outcome in colon cancer. Int J Cancer. 131:2528–2536. 2012. View Article : Google Scholar : PubMed/NCBI
10	Sun TW, Gao Q, Qiu SJ, Zhou J, Wang XY, Yi Y, Shi JY, Xu YF, Shi YH, Song K, et al: B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence. Cancer Immunol Immunother. 61:2171–2182. 2012. View Article : Google Scholar : PubMed/NCBI
11	Arigami T, Narita N, Mizuno R, Nguyen L, Ye X, Chung A, Giuliano AE and Hoon DS: B7-h3 ligand expression by primary breast cancer and associated with regional nodal metastasis. Ann Surg. 252:1044–1051. 2010. View Article : Google Scholar : PubMed/NCBI
12	Hu Y, Lv X, Wu Y, Xu J, Wang L, Chen W, Zhang W, Li J, Zhang S and Qiu H: Expression of costimulatory molecule B7-H3 and its prognostic implications in human acute leukemia. Hematology. Aug 16–2014.(Epub ahead of print). PubMed/NCBI
13	Zhao D, Lin L, Ge Q, et al: Relation of B7-H3 molecule expression in multiple myeloma with poor prognosis and bone destruction. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 21:637–642. 2013.(In Chinese). PubMed/NCBI
14	Wilcox RA, Ansell SM, Lim MS, Zou W and Chen L: The B7 homologues and their receptors in hematologic malignancies. Eur J Haematol. 88:465–475. 2012. View Article : Google Scholar : PubMed/NCBI
15	Luo L, Chapoval AI, Flies DB, Zhu G, Hirano F, Wang S, Lau JS, Dong H, Tamada K, Flies AS, et al: B7-H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8⁺ cytolytic T cells. J Immunol. 173:5445–5450. 2004. View Article : Google Scholar : PubMed/NCBI
16	Sun X, Vale M, Leung E, Kanwar JR, Gupta R and Krissansen GW: Mouse B7-H3 induces antitumor immunity. Gene Ther. 10:1728–1734. 2003. View Article : Google Scholar : PubMed/NCBI
17	Brunner A, Hinterholzer S, Riss P, Heinze G and Brustmann H: Immunoexpression of B7-H3 in endometrial cancer: Relation to tumor T-cell infiltration and prognosis. Gynecol Oncol. 124:105–111. 2012. View Article : Google Scholar
18	Leitner J, Klauser C, Pickl WF, Stöckl J, Majdic O, Bardet AF, Kreil DP, Dong C, Yamazaki T, Zlabinger G, et al: B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction. Eur J Immunol. 39:1754–1764. 2009. View Article : Google Scholar : PubMed/NCBI
19	Suh WK, Gajewska BU, Okada H, Gronski MA, Bertram EM, Dawicki W, Duncan GS, Bukczynski J, Plyte S, Elia A, et al: The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol. 4:899–906. 2003. View Article : Google Scholar : PubMed/NCBI
20	Tekle C, Nygren MK, Chen YW, Dybsjord I, Nesland JM, Maelandsmo GM and Fodstad O: B7-H3 contributes to the metastatic capacity of melanoma cells by modulation of known metastasis-associated genes. Int J Cancer. 130:2282–2290. 2012. View Article : Google Scholar
21	Chen YW, Tekle C and Fodstad O: The immunoregulatory protein human B7H3 is a tumor-associated antigen that regulates tumor cell migration and invasion. Curr Cancer Drug Targets. 8:404–413. 2008. View Article : Google Scholar : PubMed/NCBI
22	Lemke D, Pfenning PN, Sahm F, Klein AC, Kempf T, Warnken U, Schnölzer M, Tudoran R, Weller M, Platten M, et al: Costimulatory protein 4IgB7H3 drives the malignant phenotype of glioblastoma by mediating immune escape and invasiveness. Clin Cancer Res. 18:105–117. 2012. View Article : Google Scholar
23	Zhao X, Li DC, Zhu XG, Gan WJ, Li Z, Xiong F, Zhang ZX, Zhang GB, Zhang XG and Zhao H: B7-H3 overexpression in pancreatic cancer promotes tumor progression. Int J Mol Med. 31:283–291. 2013.
24	Yuan H, Wei X, Zhang G, Li C, Zhang X and Hou J: B7-H3 over expression in prostate cancer promotes tumor cell progression. J Urol. 186:1093–1099. 2011. View Article : Google Scholar : PubMed/NCBI
25	Wang L, Zhang Q, Chen W, Shan B, Ding Y, Zhang G, Cao N, Liu L and Zhang Y: B7-H3 is overexpressed in patients suffering osteosarcoma and associated with tumor aggressiveness and metastasis. PLoS One. 8:e706892013. View Article : Google Scholar : PubMed/NCBI
26	Liu H, Tekle C, Chen YW, Kristian A, Zhao Y, Zhou M, Liu Z, Ding Y, Wang B, Mælandsmo GM, et al: B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation. Mol Cancer Ther. 10:960–971. 2011. View Article : Google Scholar : PubMed/NCBI
27	Zhao X, Zhang GB, Gan WJ, Xiong F, Li Z, Zhao H, Zhu DM, Zhang B, Zhang XG and Li DC: Silencing of B7-H3 increases gemcitabine sensitivity by promoting apoptosis in pancreatic carcinoma. Oncol Lett. 5:805–812. 2013.PubMed/NCBI
28	Li Y, Wang J, Li C and Ke XY: Contribution of PD-L1 to oncogenesis of lymphoma and its RNAi-based targeting therapy. Leuk Lymphoma. 53:2015–2023. 2012. View Article : Google Scholar : PubMed/NCBI
29	Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, et al; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: An open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 381:1203–1210. 2013. View Article : Google Scholar : PubMed/NCBI
30	Wang J, Chong KK, Nakamura Y, Nguyen L, Huang SK, Kuo C, Zhang W, Yu H, Morton DL and Hoon DS: B7-H3 associated with tumor progression and epigenetic regulatory activity in cutaneous melanoma. J Invest Dermatol. 133:2050–2058. 2013. View Article : Google Scholar : PubMed/NCBI
31	Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK and Wang X: B7-H3 and B7-H4 expression in non-small-cell lung cancer. Lung Cancer. 53:143–151. 2006. View Article : Google Scholar : PubMed/NCBI
32	Shapiro SD: Matrix metalloproteinase degradation of extracellular matrix: Biological consequences. Curr Opin Cell Biol. 10:602–608. 1998. View Article : Google Scholar : PubMed/NCBI
33	Mussetti A, Kumar A, Dahi PB, Perales MA and Sauter CS: Lifting the mantle: Unveiling new treatment approaches in relapsed or refractory mantle cell lymphoma. Blood. Nov 1–2014.(Epub ahead of print). pii: S0268-960X(14)00083-6. View Article : Google Scholar
34	Gil L, Kazmierczak M, Kroll-Balcerzak R and Komarnicki M: Bendamustine-based therapy as first-line treatment for non-Hodgkin lymphoma. Med Oncol. 31:9442014. View Article : Google Scholar : PubMed/NCBI
35	Loo D, Alderson RF, Chen FZ, Huang L, Zhang W, Gorlatov S, Burke S, Ciccarone V, Li H, Yang Y, et al: Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity. Clin Cancer Res. 18:3834–3845. 2012. View Article : Google Scholar : PubMed/NCBI