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Activation of the Ig Iα1 promoter by the transcription factor Ets-1 triggers Ig Iα1–Cα1 germline transcription in epithelial cancer cells

Cellular & Molecular Immunology volume 11, pages 197–205 (2014)Cite this article

Abstract

Immunoglobulins (Igs) are known to be synthesized and secreted only by B lymphocytes. Class switch recombination (CSR) is a key event that enables B cells to express Igs, and one of the crucial steps for CSR initiation is the germline transcription of Ig genes. Surprisingly, recent studies have demonstrated that the Ig genes are also expressed in some epithelial cancer cells; however, the mechanisms underlying how cancer cells initiate CSR and express Igs are still unknown. In this study, we confirmed that the Ig Iα1 promoter in cancer cell lines was activated by the Ets-1 transcription factor, and the activity of the Ig Iα1 promoter and Ig Iα1–Cα1 germline transcription were attenuated after knockdown of Ets-1 by specific small interfering RNAs (siRNA). Furthermore, the expression of Ets-1 and Igα heavy chain in cancer cells was dose dependently upregulated by TGF-β1. These results indicate that activation of the Ig Iα1 promoter by the transcription factor Ets-1 is a critical pathway and provides a novel mechanism for Ig expression in non-B cell cancers.

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References

  1. Hu D, Zheng H, Liu H, Li M, Ren W, Liao W et al. Immunoglobulin expression and its biological significance in cancer cells. Cell Mol Immunol 2008; 5: 319–324.

    Article  CAS  Google Scholar 

  2. Chen Z, Qiu X, Gu J . Immunoglobulin expression in non-lymphoid lineage and neoplastic cells. Am J Pathol 2009; 174: 1139–1148.

    Article  CAS  Google Scholar 

  3. Cao Y, Sun Y, Poirier S, Winterstein D, Hegamyer G, Seed J et al. Isolation and partial characterization of a transformation-associated sequence from human nasopharyngeal carcinoma. Mol Carcinog 1991; 4: 297–307.

    Article  CAS  Google Scholar 

  4. Li M, Ren W, Weng XX, Liao W, Xia LQ, Deng X et al. Nucleotide sequence analysis of a transforming gene isolated from nasopharyngeal carcinoma cell line CNE2: an aberrant human immunoglobulin kappa light chain which lacks variable region. DNA Seq 2001; 12: 331–335.

    Article  CAS  Google Scholar 

  5. Kimoto Y . Expression of heavy-chain constant region of immunoglobulin and T-cell receptor gene transcripts in human non-hematopoietic tumor cell lines. Genes Chromosomes Cancer 1998; 22: 83–86.

    Article  CAS  Google Scholar 

  6. Qiu X, Zhu X, Zhang L, Mao Y, Zhang J, Hao P et al. Human epithelial cancers secrete immunoglobulin g with unidentified specificity to promote growth and survival of tumor cells. Cancer Res 2003; 63: 6488–6495.

    CAS  Google Scholar 

  7. Babbage G, Ottensmeier CH, Blaydes J, Stevenson FK, Sahota SS . Immunoglobulin heavy chain locus events and expression of activation-induced cytidine deaminase in epithelial breast cancer cell lines. Cancer Res 2006; 66: 3996–4000.

    Article  CAS  Google Scholar 

  8. Chen Z, Gu J . Immunoglobulin G expression in carcinomas and cancer cell lines. FASEB J 2007; 21: 2931–2938.

    Article  Google Scholar 

  9. Geng LY, Shi ZZ, Dong Q, Cai XH, Zhang YM, Cao W et al. Expression of SNC73, a transcript of the immunoglobulin alpha-1 gene, in human epithelial carcinomas. World J Gastroenterol 2007; 13: 2305–2311.

    Article  CAS  Google Scholar 

  10. Huang J, Sun X, Mao Y, Zhu X, Zhang P, Zhang L et al. Expression of immunoglobulin gene with classical V–(D)–J rearrangement in mouse brain neurons. Int J Biochem Cell Biol 2008; 40: 1604–1615.

    Article  CAS  Google Scholar 

  11. Zhu X, Li C, Sun X, Mao Y, Li G, Liu X et al. Immunoglobulin mRNA and protein expression in human oral epithelial tumor cells. Appl Immunohistochem Mol Morphol 2008; 16: 232–238.

    Article  CAS  Google Scholar 

  12. Huang J, Zhang L, Ma T, Zhang P, Qiu X . Expression of immunoglobulin gene with classical V–(D)–J rearrangement in mouse testis and epididymis. J Histochem Cytochem 2009; 57: 339–349.

    Article  CAS  Google Scholar 

  13. Zhang S, Mao Y, Huang J, Ma T, Zhang L, Zhu X et al. Immunoglobulin gene locus events in epithelial cells of lactating mouse mammary glands. Cell Mol Life Sci 2010; 67: 985–994.

    Article  CAS  Google Scholar 

  14. Zheng H, Li M, Liu H, Ren W, Hu DS, Shi Y et al. Immunoglobulin alpha heavy chain derived from human epithelial cancer cells promotes the access of S phase and growth of cancer cells. Cell Biol Int 2007; 31: 82–87.

    Article  CAS  Google Scholar 

  15. Li M, Zheng H, Duan Z, Liu H, Hu D, Bode A et al. Promotion of cell proliferation and inhibition of ADCC by cancerous immunoglobulin expressed in cancer cell lines. Cell Mol Immunol 2012; 9: 54–61.

    Article  Google Scholar 

  16. Jung D, Giallourakis C, Mostoslavsky R, Alt FW . Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol 2006; 24: 541–570.

    Article  CAS  Google Scholar 

  17. Stavnezer J, Guikema JE, Schrader CE . Mechanism and regulation of class switch recombination. Annu Rev Immunol 2008; 26: 261–292.

    Article  CAS  Google Scholar 

  18. Zheng H, Li M, Ren W, Zeng L, Liu HD, Hu D et al. Expression and secretion of immunoglobulin alpha heavy chain with diverse VDJ recombinations by human epithelial cancer cells. Mol Immunol 2007; 44: 2221–2227.

    Article  CAS  Google Scholar 

  19. Zheng J, Huang J, Mao Y, Liu S, Sun X, Zhu X et al. Immunoglobulin gene transcripts have distinct VHDJH recombination characteristics in human epithelial cancer cells. J Biol Chem 2009; 284: 13610–13619.

    Article  CAS  Google Scholar 

  20. Chen Z, Xiao Y, Zhang J, Li J, Liu Y, Zhao Y et al. Transcription factors E2A, FOXO1 and FOXP1 regulate recombination activating gene expression in cancer cells. PLoS ONE 2011; 6: e20475.

    Article  CAS  Google Scholar 

  21. Ramiro AR, Stavropoulos P, Jankovic M, Nussenzweig MC . Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nat Immunol 2003; 4: 452–456.

    Article  CAS  Google Scholar 

  22. Shen HM, Storb U . Activation-induced cytidine deaminase (AID) can target both DNA strands when the DNA is supercoiled. Proc Natl Acad Sci USA 2004; 101: 12997–13002.

    Article  CAS  Google Scholar 

  23. Wang L, Whang N, Wuerffel R, Kenter AL . AID-dependent histone acetylation is detected in immunoglobulin S regions. J Exp Med 2006; 203: 215–226.

    Article  CAS  Google Scholar 

  24. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T . Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 2000; 102: 553–563.

    Article  CAS  Google Scholar 

  25. Stavnezer J, Schrader CE . Mismatch repair converts AID-instigated nicks to double-strand breaks for antibody class-switch recombination. Trends Genet 2006; 22: 23–28.

    Article  CAS  Google Scholar 

  26. Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M et al. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 2007; 449: 478–482.

    Article  CAS  Google Scholar 

  27. Cerutti A . The regulation of IgA class switching. Nat Rev Immunol 2008; 8: 421–434.

    Article  CAS  Google Scholar 

  28. Hu D, Duan Z, Li M, Jiang Y, Liu H, Zheng H et al. Heterogeneity of aberrant immunoglobulin expression in cancer cells. Cell Mol Immunol 2011; 8: 479–485.

    Article  CAS  Google Scholar 

  29. Liu H, Duan Z, Zheng H, Hu D, Li M, Tao Y et al. EBV-encoded LMP1 upregulates Igkappa 3′enhancer activity and Igkappa expression in nasopharyngeal cancer cells by activating the Ets-1 through ERKs signaling. PLoS ONE 2012; 7: e32624.

    Article  CAS  Google Scholar 

  30. Cerutti A, Zan H, Schaffer A, Bergsagel L, Harindranath N, Max EE et al. CD40 ligand and appropriate cytokines induce switching to IgG, IgA, and IgE and coordinated germinal center and plasmacytoid phenotypic differentiation in a human monoclonal IgM+IgD+ B cell line. J Immunol 1998; 160: 2145–2157.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Oikawa T, Yamada T, Kihara-Negishi F, Yamamoto H, Kondoh N, Hitomi Y et al. The role of Ets family transcription factor PU.1 in hematopoietic cell differentiation, proliferation and apoptosis. Cell Death Differ 1999; 6: 599–608.

    Article  CAS  Google Scholar 

  32. Hahne JC, Okuducu AF, Sahin A, Fafeur V, Kiriakidis S, Wernert N . The transcription factor ETS-1: its role in tumour development and strategies for its inhibition. Mini Rev Med Chem 2008; 8: 1095–1105.

    Article  CAS  Google Scholar 

  33. Schwarzenbach H, Newell JW, Matthias P . Involvement of the Ets family factor PU.1 in the activation of immunoglobulin promoters. J Biol Chem 1995; 270: 898–907.

    Article  CAS  Google Scholar 

  34. Zhu X, Wu L, Zhang L, Hao P, Zhang S, Huang J et al. Distinct regulatory mechanism of immunoglobulin gene transcription in epithelial cancer cells. Cell Mol Immunol 2010; 7: 279–286.

    Article  CAS  Google Scholar 

  35. Ikushima H, Miyazono K . TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 2010; 10: 415–424.

    Article  CAS  Google Scholar 

  36. Sundqvist A, Zieba A, Vasilaki E, Herrera Hidalgo C, Soderberg O, Koinuma D et al. Specific interactions between Smad proteins and AP-1 components determine TGFbeta-induced breast cancer cell invasion. Oncogene 2013; 32: 3606–3615.

    Article  CAS  Google Scholar 

  37. Liu HD, Zheng H, Li M, Hu DS, Tang M, Cao Y . Upregulated expression of kappa light chain by Epstein-Barr virus encoded latent membrane protein 1 in nasopharyngeal carcinoma cells via NF-kappaB and AP-1 pathways. Cell Signal 2007; 19: 419–427.

    Article  CAS  Google Scholar 

  38. Liu H, Zheng H, Duan Z, Hu D, Li M, Liu S et al. LMP1-augmented kappa intron enhancer activity contributes to upregulation expression of Ig kappa light chain via NF-kappaB and AP-1 pathways in nasopharyngeal carcinoma cells. Mol Cancer 2009; 8: 92.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National High Technology Research and Development Program (863) of China (No. 2006AA02A404) and the National Nature Science Foundation of China (Nos. 30772465 and 30973399).

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Author notes

  1. Dr Y Cao, Laboratory of Tumor Molecular Biology, Cancer Research Institute, Central South University, Changsha 410078, China. E-mail: ycao98@vip.sina.com

Authors and Affiliations

  1. Laboratory of Tumor Molecular Biology, Cancer Research Institute, Central South University, Changsha, China

    Zhi Duan, Hui Zheng, San Xu, Yiqun Jiang, Duosha Hu, Wei Li & Ya Cao

  2. Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China

    Zhi Duan, Hui Zheng, San Xu, Yiqun Jiang, Duosha Hu, Wei Li & Ya Cao

  3. Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China

    Zhi Duan, Hui Zheng, San Xu, Yiqun Jiang, Duosha Hu, Wei Li & Ya Cao

  4. Department of Cardiothoracic Surgery, Center of Clinical Gene Diagnosis and Therapy, The Second Xiangya Hospital, Central South University, Changsha, China

    Haidan Liu

  5. Department of Immunology, Xiangya Medical College, Central South University, Changsha, China

    Ming Li

  6. The Hormel Institute, University of Minnesota, Austin, MN, USA

    Wei Li, Ann M. Bode & Zigang Dong

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Duan, Z., Zheng, H., Xu, S. et al. Activation of the Ig Iα1 promoter by the transcription factor Ets-1 triggers Ig Iα1–Cα1 germline transcription in epithelial cancer cells. Cell Mol Immunol 11, 197–205 (2014). https://doi.org/10.1038/cmi.2013.52

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