Knockdown of B7-H6 inhibits tumor progression and enhances chemosensitivity in B-cell non-Hodgkin lymphoma

  • Authors:
    • Feifei Wu
    • Jing Wang
    • Xiaoyan Ke
  • View Affiliations

  • Published online on: February 17, 2016     https://doi.org/10.3892/ijo.2016.3393
  • Pages: 1561-1570
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

B7 homologue 6 (B7-H6) is a new member of the B7 family molecules and is selectively expressed on tumor cells, especially in hematologic malignancies. However, the role of B7-H6 in lymphoma progression and chemosensitivity remains unclear. We determined the effects of downregulating B7-H6 expression on tumorigenesis and chemosensitivity in B-cell lymphoma. Stable B7-H6 knockdown in CA46 cells was established with a lentiviral system. The expression of mRNA was measured by PCR while protein expression was detected by western blotting and flow cytometry. Cell viability, apoptosis and cell cycle distribution were analyzed using CCK-8, colony formation and flow cytometry assays, respectively. Cell migration and invasion were determined using the Transwell chamber assay. B7-H6 was widely expressed in B-cell lymphomas. Knockdown of B7-H6 inhibited cell proliferation, colony formation and migration and invasion of lymphoma cells. After B7-H6 silencing, CA46 cells were arrested in G0/G1 phase. Moreover, the silencing of B7-H6 increased cell apoptosis and sensitivity to vincristine and dexamethasone. Investigation of expression of downstream targets of STAT3 supported a theory in which B7-H6 knockdown may confer an antitumor effect via abrogation of the STAT3 pathway. This study demonstrates that B7-H6 plays an important role in the pathogenesis and chemosensitivity of lymphoma. B7-H6 is therefore a potential clinical biomarker and therapeutic target in B-cell lymphomas.

References

1 

Forman D, Bray F and Brewster D: Cancer Incidence in Five Continents Vol X (eletronic version). IARC; Lyon: 2013, http://ci5.iarc.fr/Default.aspxurisimplehttp://ci5.iarc.fr/Default.aspx. Accessed January 2, 2014

2 

Zappasodi R, de Braud F and Di Nicola M: Lymphoma immunotherapy: Current status. Front Immunol. 6:4482015. View Article : Google Scholar : PubMed/NCBI

3 

Brandt CS, Baratin M, Yi EC, Kennedy J, Gao Z, Fox B, Haldeman B, Ostrander CD, Kaifu T, Chabannon C, et al: The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J Exp Med. 206:1495–1503. 2009. View Article : Google Scholar : PubMed/NCBI

4 

Zhou Y, Xu Y, Chen L, Xu B, Wu C and Jiang J: B7-H6 expression correlates with cancer progression and patient's survival in human ovarian cancer. Int J Clin Exp Pathol. 8:9428–9433. 2015.PubMed/NCBI

5 

Wu MR, Zhang T, DeMars LR and Sentman CL: B7H6-specific chimeric antigen receptors lead to tumor elimination and host antitumor immunity. Gene Ther. 22:675–684. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Semeraro M, Rusakiewicz S, Minard-Colin V, Delahaye NF, Enot D, Vély F, Marabelle A, Papoular B, Piperoglou C, Ponzoni M, et al: Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients. Sci Transl Med. 7:283ra552015. View Article : Google Scholar : PubMed/NCBI

7 

Kellner C, Maurer T, Hallack D, Repp R, van de Winkel JG, Parren PW, Valerius T, Humpe A, Gramatzki M and Peipp M: Mimicking an induced self phenotype by coating lymphomas with the NKp30 ligand B7-H6 promotes NK cell cytotoxicity. J Immunol. 189:5037–5046. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Wu MR, Zhang T, Gacerez AT, Coupet TA, DeMars LR and Sentman CL: B7H6-specific bispecific T cell engagers lead to tumor elimination and host antitumor immunity. J Immunol. 194:5305–5311. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Mir MA and Agrewala JN: Signaling through CD80: An approach for treating lymphomas. Expert Opin Ther Targets. 12:969–979. 2008. View Article : Google Scholar : PubMed/NCBI

10 

Philips GK and Atkins M: Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies. Int Immunol. 27:39–46. 2015. View Article : Google Scholar

11 

Leung J and Suh WK: The CD28-B7 family in anti-tumor immunity: Emerging concepts in cancer immunotherapy. Immune Netw. 14:265–276. 2014. View Article : Google Scholar :

12 

Seliger B and Quandt D: The expression, function, and clinical relevance of B7 family members in cancer. Cancer Immunol Immunother. 61:1327–1341. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Zhang W, Wang Y, Wang J, Dong F, Zhu M, Wan W, Li H, Wu F, Yan X and Ke X: B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity. Int J Oncol. 46:2562–2572. 2015.PubMed/NCBI

14 

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

15 

Kaifu T, Escalière B, Gastinel LN, Vivier E and Baratin M: B7-H6/NKp30 interaction: A mechanism of alerting NK cells against tumors. Cell Mol Life Sci. 68:3531–3539. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Zhang T, Wu MR and Sentman CL: An NKp30-based chimeric antigen receptor promotes T cell effector functions and antitumor efficacy in vivo. J Immunol. 189:2290–2299. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Schlecker E, Fiegler N, Arnold A, Altevogt P, Rose-John S, Moldenhauer G, Sucker A, Paschen A, von Strandmann EP, Textor S, et al: Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30. Cancer Res. 74:3429–3440. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Fiegler N, Textor S, Arnold A, Rölle A, Oehme I, Breuhahn K, Moldenhauer G, Witzens-Harig M and Cerwenka A: Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. Blood. 122:684–693. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Chen XJ, Shen J, Zhang GB and Chen WC: B7-H6 protein expression has no prognostic significance in human gastric carcinoma. Pathol Oncol Res. 20:203–207. 2014. View Article : Google Scholar

20 

Zhang X, Zhang G, Qin Y, Bai R and Huang J: B7-H6 expression in non-small cell lung cancers. Int J Clin Exp Pathol. 7:6936–6942. 2014.PubMed/NCBI

21 

Baran-Marszak F, Boukhiar M, Harel S, Laguillier C, Roger C, Gressin R, Martin A, Fagard R, Varin-Blank N, Ajchenbaum-Cymbalista F, et al: Constitutive and B-cell receptor-induced activation of STAT3 are important signaling pathways targeted by bortezomib in leukemic mantle cell lymphoma. Haematologica. 95:1865–1872. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Munoz J, Dhillon N, Janku F, Watowich SS and Hong DS: STAT3 inhibitors: Finding a home in lymphoma and leukemia. Oncologist. 19:536–544. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Soldini D, Montagna C, Schüffler P, Martin V, Georgis A, Thiesler T, Curioni-Fontecedro A, Went P, Bosshard G, Dehler S, et al: A new diagnostic algorithm for Burkitt and diffuse large B-cell lymphomas based on the expression of CSE1L and STAT3 and on MYC rearrangement predicts outcome. Ann Oncol. 24:193–201. 2013. View Article : Google Scholar

24 

Lu S, Gao Y, Huang X and Wang X: GYY4137, a hydrogen sulfide (H2S) donor, shows potent anti-hepatocellular carcinoma activity through blocking the STAT3 pathway. Int J Oncol. 44:1259–1267. 2014.PubMed/NCBI

25 

Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

26 

He C, Liu Z, Ji J and Zhu H: Prognostic value of survivin in patients with non-Hodgkin's lymphoma: A meta-analysis. Int J Clin Exp Med. 8:5847–5854. 2015.PubMed/NCBI

27 

Wang SC: PCNA: A silent housekeeper or a potential therapeutic target? Trends Pharmacol Sci. 35:178–186. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Said J, Lones M and Yea S: Burkitt lymphoma and MYC: What else is new? Adv Anat Pathol. 21:160–165. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Brinkmann K and Kashkar H: Targeting the mitochondrial apoptotic pathway: A preferred approach in hematologic malignancies? Cell Death Dis. 5:e10982014. View Article : Google Scholar : PubMed/NCBI

30 

Hardwick JM and Soane L: Multiple functions of BCL-2 family proteins. Cold Spring Harb Perspect Biol. 5:a87222013. View Article : Google Scholar

31 

Shalini S, Dorstyn L, Dawar S and Kumar S: Old, new and emerging functions of caspases. Cell Death Differ. 22:526–539. 2015. View Article : Google Scholar

32 

Yang WJ, Yu Z and Qiu LG: Research advances of signal pathway in the pathogenesis of mantle cell lymphoma. Zhonghua Xue Ye Xue Za Zhi. 34:1073–1075. 2013.(In Chinese). PubMed/NCBI

33 

Bonn BR, Krieger D and Burkhardt B: Cell cycle regulatory molecular profiles of pediatric T-cell lymphoblastic leukemia and lymphoma. Leuk Lymphoma. 53:557–568. 2012. View Article : Google Scholar

34 

Tamura K: Development of cell-cycle checkpoint therapy for solid tumors. Jpn J Clin Oncol. 45:1097–1102. 2015.PubMed/NCBI

35 

Besson A, Dowdy SF and Roberts JM: CDK inhibitors: Cell cycle regulators and beyond. Dev Cell. 14:159–169. 2008. View Article : Google Scholar : PubMed/NCBI

36 

Migliaccio I, Di Leo A and Malorni L: Cyclin-dependent kinase 4/6 inhibitors in breast cancer therapy. Curr Opin Oncol. 26:568–575. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Dutto I, Tillhon M, Cazzalini O, Stivala LA and Prosperi E: Biology of the cell cycle inhibitor p21(CDKN1A): Molecular mechanisms and relevance in chemical toxicology. Arch Toxicol. 89:155–178. 2015. View Article : Google Scholar

38 

Hazar B, Polat G, Seyrek E, Bağdatoğlğlu O, Kanik A and Tiftik N: Prognostic value of matrix metalloproteinases (MMP-2 and MMP-9) in Hodgkin's and non-Hodgkin's lymphoma. Int J Clin Pract. 58:139–143. 2004. View Article : Google Scholar : PubMed/NCBI

39 

Suminoe A, Matsuzaki A, Hattori H, Koga Y, Ishii E and Hara T: Expression of matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) genes in blasts of infant acute lymphoblastic leukemia with organ involvement. Leuk Res. 31:1437–1440. 2007. View Article : Google Scholar : PubMed/NCBI

40 

Xiong A, Yang Z, Shen Y, Zhou J and Shen Q: Transcription factor STAT3 as a novel molecular target for cancer prevention. Cancers (Basel). 6:926–957. 2014. View Article : Google Scholar

Related Articles

Journal Cover

April 2016
Volume 48 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Wu, F., Wang, J., & Ke, X. (2016). Knockdown of B7-H6 inhibits tumor progression and enhances chemosensitivity in B-cell non-Hodgkin lymphoma. International Journal of Oncology, 48, 1561-1570. https://doi.org/10.3892/ijo.2016.3393
MLA
Wu, F., Wang, J., Ke, X."Knockdown of B7-H6 inhibits tumor progression and enhances chemosensitivity in B-cell non-Hodgkin lymphoma". International Journal of Oncology 48.4 (2016): 1561-1570.
Chicago
Wu, F., Wang, J., Ke, X."Knockdown of B7-H6 inhibits tumor progression and enhances chemosensitivity in B-cell non-Hodgkin lymphoma". International Journal of Oncology 48, no. 4 (2016): 1561-1570. https://doi.org/10.3892/ijo.2016.3393