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Published in: Journal of Translational Medicine 1/2016

Open Access 01-12-2016 | Research

Human epithelial-type ovarian tumour marker beta-2-microglobulin is regulated by the TGF-β signaling pathway

Authors: Wenwen Sun, Lu Gui, Xulei Zuo, Lingyun Zhang, Daibing Zhou, Xiaoling Duan, Weimin Ren, Guoxiong Xu

Published in: Journal of Translational Medicine | Issue 1/2016

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Abstract

Background

Beta-2-microglobulin (B2M), a light chain subunit of the major histocompatibility complex (MHC) class I complex, has been implicated in tumorigenesis. However, whether it is expressed in different epithelial-type ovarian tumours remains unknown. This study was performed to examine the expression of B2M in different histopathological types of ovarian tumours, to explore the function of B2M in ovarian cancer (OC) cells and to investigate the mechanisms underlying the regulation of B2M by the TGF-β signaling pathway.

Methods

B2M expression in normal ovarian tissues and epithelia-type ovarian tumours was detected by immunohistochemistry and Western blot, followed by the analysis of association with clinical features. OC cells were transfected with B2M-siRNA and cell proliferation, migration and invasion were determined by WST-1 assay, wound healing assay and Transwell invasion assay, respectively. The regulation of B2M by the TGF-β signaling pathway in OC cells was examined by Western blot, ELISA and qRT-PCR.

Results

We found that B2M was overexpressed in ovarian borderline and malignant tumours compared with benign tumours and normal controls, but was not associated with age, tumour size, lymph node metastasis and clinical stage. Knocking down of B2M led to a decrease in OC cell proliferation, migration and invasion. The expression of B2M was downregulated by TGF-β1 in OC cells, which was abolished in the presence of the inhibitor of TGF-β type I receptor.

Conclusion

Our findings suggest that B2M is a potential tissue biomarker and therapeutic target of borderline and malignant ovarian tumours and the dysregulation of B2M in these tumours may be mediated by the TGF-β signaling pathway.
Literature
1.
go back to reference Melillo L, Musto P, Tomasi P, Cascavilla N, Bodenizza C, Ladogana S, et al. Serum beta 2-microglobulin in malignant lymphoproliferative disorders. Tumori. 1988;74(2):129–35.PubMed Melillo L, Musto P, Tomasi P, Cascavilla N, Bodenizza C, Ladogana S, et al. Serum beta 2-microglobulin in malignant lymphoproliferative disorders. Tumori. 1988;74(2):129–35.PubMed
2.
go back to reference Gussow D, Rein R, Ginjaar I, Hochstenbach F, Seemann G, Kottman A, et al. The human beta 2-microglobulin gene. Primary structure and definition of the transcriptional unit. J Immunol. 1987;139(9):3132–8.PubMed Gussow D, Rein R, Ginjaar I, Hochstenbach F, Seemann G, Kottman A, et al. The human beta 2-microglobulin gene. Primary structure and definition of the transcriptional unit. J Immunol. 1987;139(9):3132–8.PubMed
3.
go back to reference Liabeuf A, le de Kaouel Borgne C, Kourilsky FM, Malissen B, Manuel Y, Sanderson AR. An antigenic determinant of human beta 2-microglobulin masked by the association with HLA heavy chains at the cell surface: analysis using monoclonal antibodies. J Immunol. 1981;127(4):1542–8.PubMed Liabeuf A, le de Kaouel Borgne C, Kourilsky FM, Malissen B, Manuel Y, Sanderson AR. An antigenic determinant of human beta 2-microglobulin masked by the association with HLA heavy chains at the cell surface: analysis using monoclonal antibodies. J Immunol. 1981;127(4):1542–8.PubMed
4.
go back to reference Klein B, Levin I, Lurie H, Nyska A, Shapira J, Kravits M, et al. Elevated pretreatment levels of soluble CD8 and Beta-2-microglobulin as indicators of relapse in breast-cancer patients. Int J Oncol. 1994;4(2):471–4.PubMed Klein B, Levin I, Lurie H, Nyska A, Shapira J, Kravits M, et al. Elevated pretreatment levels of soluble CD8 and Beta-2-microglobulin as indicators of relapse in breast-cancer patients. Int J Oncol. 1994;4(2):471–4.PubMed
6.
go back to reference Sasaki T, Ravindranath MH, Terasaki PI, Freitas MC, Kawakita S, Jucaud V. Gastric cancer progression may involve a shift in HLA-E profile from an intact heterodimer to beta2-microglobulin-free monomer. Int J Cancer. 2014;134(7):1558–70. doi:10.1002/ijc.28484.CrossRefPubMed Sasaki T, Ravindranath MH, Terasaki PI, Freitas MC, Kawakita S, Jucaud V. Gastric cancer progression may involve a shift in HLA-E profile from an intact heterodimer to beta2-microglobulin-free monomer. Int J Cancer. 2014;134(7):1558–70. doi:10.​1002/​ijc.​28484.CrossRefPubMed
7.
go back to reference Charalabopoulos K, Papalimneou V, Charalabopoulos A, Zoganas L, Andronadi V, Stefanou D, et al. Serum estimation of carcinoembryonic antigen, beta(2)-microglobulin and calcitonin as tumor markers in primary lung cancer. J BUON. 2003;8(1):35–7.PubMed Charalabopoulos K, Papalimneou V, Charalabopoulos A, Zoganas L, Andronadi V, Stefanou D, et al. Serum estimation of carcinoembryonic antigen, beta(2)-microglobulin and calcitonin as tumor markers in primary lung cancer. J BUON. 2003;8(1):35–7.PubMed
8.
go back to reference Manzar W, Raghavan MR, Aroor AR, Keshavamurthy KR. Evaluation of serum beta 2-microglobulin in oral cancer. Aust Dent J. 1992;37(1):39–42.CrossRefPubMed Manzar W, Raghavan MR, Aroor AR, Keshavamurthy KR. Evaluation of serum beta 2-microglobulin in oral cancer. Aust Dent J. 1992;37(1):39–42.CrossRefPubMed
9.
go back to reference Khoo SK, Daunter B, Mackay E. Carcinoembryonic antigen and beta 2-microglobulin as serum tumor markers in women with genital cancer. Int J Gynaecol Obstet. 1979;16(5):388–93.PubMed Khoo SK, Daunter B, Mackay E. Carcinoembryonic antigen and beta 2-microglobulin as serum tumor markers in women with genital cancer. Int J Gynaecol Obstet. 1979;16(5):388–93.PubMed
10.
11.
go back to reference Johnson H Jr, Flye MW, Javadpour N. Serum beta 2 microglobulin levels in patients with testicular cancer. Urology. 1980;16(5):522–4.CrossRefPubMed Johnson H Jr, Flye MW, Javadpour N. Serum beta 2 microglobulin levels in patients with testicular cancer. Urology. 1980;16(5):522–4.CrossRefPubMed
13.
go back to reference Nomura T, Huang WC, Zhau HE, Josson S, Mimata H, Chung LW. Beta2-Microglobulin-mediated signaling as a target for cancer therapy. Anticancer Agents Med Chem. 2014;14(3):343–52.CrossRefPubMedPubMedCentral Nomura T, Huang WC, Zhau HE, Josson S, Mimata H, Chung LW. Beta2-Microglobulin-mediated signaling as a target for cancer therapy. Anticancer Agents Med Chem. 2014;14(3):343–52.CrossRefPubMedPubMedCentral
14.
go back to reference del Campo AB, Kyte JA, Carretero J, Zinchencko S, Mendez R, Gonzalez-Aseguinolaza G, et al. Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma. Int J Cancer. 2014;134(1):102–13. doi:10.1002/ijc.28338.CrossRefPubMed del Campo AB, Kyte JA, Carretero J, Zinchencko S, Mendez R, Gonzalez-Aseguinolaza G, et al. Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma. Int J Cancer. 2014;134(1):102–13. doi:10.​1002/​ijc.​28338.CrossRefPubMed
15.
go back to reference Bossard C, Bezieau S, Matysiak-Budnik T, Volteau C, Laboisse CL, Jotereau F, et al. HLA-E/beta2 microglobulin overexpression in colorectal cancer is associated with recruitment of inhibitory immune cells and tumor progression. Int J Cancer. 2012;131(4):855–63. doi:10.1002/ijc.26453.CrossRefPubMed Bossard C, Bezieau S, Matysiak-Budnik T, Volteau C, Laboisse CL, Jotereau F, et al. HLA-E/beta2 microglobulin overexpression in colorectal cancer is associated with recruitment of inhibitory immune cells and tumor progression. Int J Cancer. 2012;131(4):855–63. doi:10.​1002/​ijc.​26453.CrossRefPubMed
16.
go back to reference Nomura T, Huang WC, Zhau HE, Wu D, Xie Z, Mimata H, et al. Beta2-microglobulin promotes the growth of human renal cell carcinoma through the activation of the protein kinase A, cyclic AMP-responsive element-binding protein, and vascular endothelial growth factor axis. Clin Cancer Res. 2006;12(24):7294–305. doi:10.1158/1078-0432.CCR-06-2060.CrossRefPubMed Nomura T, Huang WC, Zhau HE, Wu D, Xie Z, Mimata H, et al. Beta2-microglobulin promotes the growth of human renal cell carcinoma through the activation of the protein kinase A, cyclic AMP-responsive element-binding protein, and vascular endothelial growth factor axis. Clin Cancer Res. 2006;12(24):7294–305. doi:10.​1158/​1078-0432.​CCR-06-2060.CrossRefPubMed
17.
go back to reference Rowley DR, Dang TD, McBride L, Gerdes MJ, Lu B, Larsen M. Beta-2 microglobulin is mitogenic to PC-3 prostatic carcinoma cells and antagonistic to transforming growth factor beta 1 action. Cancer Res. 1995;55(4):781–6.PubMed Rowley DR, Dang TD, McBride L, Gerdes MJ, Lu B, Larsen M. Beta-2 microglobulin is mitogenic to PC-3 prostatic carcinoma cells and antagonistic to transforming growth factor beta 1 action. Cancer Res. 1995;55(4):781–6.PubMed
19.
go back to reference Miyazawa K, Shinozaki M, Hara T, Furuya T, Miyazono K. Two major Smad pathways in TGF-beta superfamily signalling. Genes Cells. 2002;7(12):1191–204.CrossRefPubMed Miyazawa K, Shinozaki M, Hara T, Furuya T, Miyazono K. Two major Smad pathways in TGF-beta superfamily signalling. Genes Cells. 2002;7(12):1191–204.CrossRefPubMed
21.
go back to reference Prat J, Franceschi S. Cancers of the female reproductive organs. In: Stewart BW, Wild CP, editors. World Cancer Report 2014. Lyon: International Agency for Research on Cancer; 2014. p. 660–83. Prat J, Franceschi S. Cancers of the female reproductive organs. In: Stewart BW, Wild CP, editors. World Cancer Report 2014. Lyon: International Agency for Research on Cancer; 2014. p. 660–83.
24.
go back to reference Ween MP, Lokman NA, Hoffmann P, Rodgers RJ, Ricciardelli C, Oehler MK. Transforming growth factor-beta-induced protein secreted by peritoneal cells increases the metastatic potential of ovarian cancer cells. Int J Cancer. 2011;128(7):1570–84. doi:10.1002/ijc.25494.CrossRefPubMed Ween MP, Lokman NA, Hoffmann P, Rodgers RJ, Ricciardelli C, Oehler MK. Transforming growth factor-beta-induced protein secreted by peritoneal cells increases the metastatic potential of ovarian cancer cells. Int J Cancer. 2011;128(7):1570–84. doi:10.​1002/​ijc.​25494.CrossRefPubMed
27.
go back to reference Kucukgoz Gulec U, Paydas S, Guzel AB, Buyukkurt S, Seydaoglu G, Vardar MA, et al. Comparative analysis of CA 125, ferritin, beta-2 microglobulin, lactic dehydrogenase levels in serum and peritoneal fluid in patients with ovarian neoplasia. Med Oncol. 2012;29(4):2937–43. doi:10.1007/s12032-012-0165-4.CrossRefPubMed Kucukgoz Gulec U, Paydas S, Guzel AB, Buyukkurt S, Seydaoglu G, Vardar MA, et al. Comparative analysis of CA 125, ferritin, beta-2 microglobulin, lactic dehydrogenase levels in serum and peritoneal fluid in patients with ovarian neoplasia. Med Oncol. 2012;29(4):2937–43. doi:10.​1007/​s12032-012-0165-4.CrossRefPubMed
28.
go back to reference Bowen NJ, Walker LD, Matyunina LV, Logani S, Totten KA, Benigno BB, et al. Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells. BMC Med Genomics. 2009;2:71. doi:10.1186/1755-8794-2-71.CrossRefPubMedPubMedCentral Bowen NJ, Walker LD, Matyunina LV, Logani S, Totten KA, Benigno BB, et al. Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells. BMC Med Genomics. 2009;2:71. doi:10.​1186/​1755-8794-2-71.CrossRefPubMedPubMedCentral
30.
31.
go back to reference Yang HS, Li Y, Deng HX, Peng F. Identification of beta2-microglobulin as a potential target for ovarian cancer. Cancer Biol Ther. 2009;8(24):2323–8.CrossRefPubMed Yang HS, Li Y, Deng HX, Peng F. Identification of beta2-microglobulin as a potential target for ovarian cancer. Cancer Biol Ther. 2009;8(24):2323–8.CrossRefPubMed
34.
go back to reference Berchuck A, Rodriguez G, Olt G, Whitaker R, Boente MP, Arrick BA, et al. Regulation of growth of normal ovarian epithelial cells and ovarian cancer cell lines by transforming growth factor-beta. Am J Obstet Gynecol. 1992;166(2):676–84.CrossRefPubMed Berchuck A, Rodriguez G, Olt G, Whitaker R, Boente MP, Arrick BA, et al. Regulation of growth of normal ovarian epithelial cells and ovarian cancer cell lines by transforming growth factor-beta. Am J Obstet Gynecol. 1992;166(2):676–84.CrossRefPubMed
35.
go back to reference Wong AS, Leung PC. Role of endocrine and growth factors on the ovarian surface epithelium. J Obstet Gynaecol Res. 2007;33(1):3–16.CrossRefPubMed Wong AS, Leung PC. Role of endocrine and growth factors on the ovarian surface epithelium. J Obstet Gynaecol Res. 2007;33(1):3–16.CrossRefPubMed
36.
go back to reference Cardillo MR, Yap E, Castagna G. Molecular genetic analysis of TGF-beta1 in ovarian neoplasia. J Exp Clin Cancer Res. 1997;16(1):49–56.PubMed Cardillo MR, Yap E, Castagna G. Molecular genetic analysis of TGF-beta1 in ovarian neoplasia. J Exp Clin Cancer Res. 1997;16(1):49–56.PubMed
37.
go back to reference Wang D, Kanuma T, Mizunuma H, Takama F, Ibuki Y, Wake N, et al. Analysis of specific gene mutations in the transforming growth factor-beta signal transduction pathway in human ovarian cancer. Cancer Res. 2000;60(16):4507–12.PubMed Wang D, Kanuma T, Mizunuma H, Takama F, Ibuki Y, Wake N, et al. Analysis of specific gene mutations in the transforming growth factor-beta signal transduction pathway in human ovarian cancer. Cancer Res. 2000;60(16):4507–12.PubMed
38.
go back to reference Chen T, Triplett J, Dehner B, Hurst B, Colligan B, Pemberton J, et al. Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas. Cancer Res. 2001;61(12):4679–82.PubMed Chen T, Triplett J, Dehner B, Hurst B, Colligan B, Pemberton J, et al. Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas. Cancer Res. 2001;61(12):4679–82.PubMed
39.
go back to reference Lynch MA, Nakashima R, Song H, DeGroff VL, Wang D, Enomoto T, et al. Mutational analysis of the transforming growth factor beta receptor type II gene in human ovarian carcinoma. Cancer Res. 1998;58(19):4227–32.PubMed Lynch MA, Nakashima R, Song H, DeGroff VL, Wang D, Enomoto T, et al. Mutational analysis of the transforming growth factor beta receptor type II gene in human ovarian carcinoma. Cancer Res. 1998;58(19):4227–32.PubMed
40.
go back to reference Toutirais O, Chartier P, Dubois D, Bouet F, Leveque J, Catros-Quemener V, et al. Constitutive expression of TGF-beta1, interleukin-6 and interleukin-8 by tumor cells as a major component of immune escape in human ovarian carcinoma. Eur Cytokine Netw. 2003;14(4):246–55.PubMed Toutirais O, Chartier P, Dubois D, Bouet F, Leveque J, Catros-Quemener V, et al. Constitutive expression of TGF-beta1, interleukin-6 and interleukin-8 by tumor cells as a major component of immune escape in human ovarian carcinoma. Eur Cytokine Netw. 2003;14(4):246–55.PubMed
Metadata
Title
Human epithelial-type ovarian tumour marker beta-2-microglobulin is regulated by the TGF-β signaling pathway
Authors
Wenwen Sun
Lu Gui
Xulei Zuo
Lingyun Zhang
Daibing Zhou
Xiaoling Duan
Weimin Ren
Guoxiong Xu
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2016
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-016-0832-x

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