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Current Cancer Drug Targets

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

Hypermethylation of Single CpG Dinucleotides at the Promoter of CXCL13 Gene Promoting Cell Migration in Cervical Cancer

Author(s): Dong Ma , Shao-Bei Fan , Na Hua, Guo-Hua Li, Quan Chang and Xiao Liu *

Volume 20, Issue 5, 2020

Page: [355 - 363] Pages: 9

DOI: 10.2174/1568009620666200102123635

Price: $65

Abstract

Background: Chemokine 13 (CXCL13) and its chemokine receptor 5 (CXCR5) are involved in the onset of various types of cancer. However, their role in cervical cancer (CC) remains unknown.

Objective: To investigate the role of chemokine 13 (CXCL13) and its receptor in CC.

Methods: The expression of CXCL13/CXCR5 and the infiltration of CXCR5+CD8+ T cells in CC, cervical intraepithelial neoplasia (CIN), normal cervical epithelial (NCE) tissues, and in CC cell lines were analysed and the associated clinical significance was determined. In vitro, CXCL13 overexpression and DNA methyltransferase inhibition (through S110) were used to investigate the biological function and the underlying mechanism that regulates CXCL13 expression. Tumor growth and liver metastasis were also evaluated in the xenogenous subcutaneously implant model.

Results: CXCL13/CXCR5 expression levels and the infiltration of CXCR5+CD8+ T cells were significantly decreased in CC tissues compared with CIN and NCE tissues. CXCL13 downregulation was significantly correlated with the FIGO stages, lymph node metastasis, interstitial infiltration depth, and pathological grade. The overexpression of CXCL13 suppressed CC cell migration. CXCL13 downregulation was associated with hypermethylation in CC cell lines, and primary tumor biopsies. Furthermore, a CpG dinucleotide at the HIF-1a transcription factor motifs in the promoter element of CXCL13 was consistently methylated in CC cells and associated with HIF-1a. CXCL13 overexpression and S110 treatment dramatically repressed tumor growth and liver metastasis in the xenograft model; whereas it’s low expression increased the risk of death in CC patients.

Conclusion: DNA methylation-dependent CXCL13 downregulation may promote cervical carcinogenesis and progression.

Keywords: Cervical cancer, HIF-1a, methylation, CXCL13, proliferation, liver metastasis.

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[1]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[2]
Wu, Z.; Qin, Y.; Yu, L.; Lin, C.; Wang, H.; Cui, J.; Liu, B.; Liao, Y.; Warren, D.; Zhang, X.; Chen, W. Association between human papillomavirus (HPV) 16, HPV18, and other HR-HPV viral load and the histological classification of cervical lesions: Results from a large-scale cross-sectional study. J. Med. Virol., 2017, 89(3), 535-541.
[http://dx.doi.org/10.1002/jmv.24645] [PMID: 27464021]
[3]
Ellingsen, C.; Walenta, S.; Hompland, T.; Mueller-Klieser, W.; Rofstad, E.K. The microenvironment of cervical carcinoma xenografts: Associations with lymph node metastasis and its assessment by DCE-MRI. Transl. Oncol., 2013, 6(5), 607-617.
[http://dx.doi.org/10.1593/tlo.13313] [PMID: 24151541]
[4]
Karhausen, J.; Furuta, G.T.; Tomaszewski, J.E.; Johnson, R.S.; Colgan, S.P.; Haase, V.H. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J. Clin. Invest., 2004, 114(8), 1098-1106.
[http://dx.doi.org/10.1172/JCI200421086] [PMID: 15489957]
[5]
Zlotnik, A.; Burkhardt, A.M.; Homey, B. Homeostatic chemokine receptors and organ-specific metastasis. Nat. Rev. Immunol., 2011, 11(9), 597-606.
[http://dx.doi.org/10.1038/nri3049] [PMID: 21866172]
[6]
Aust, G.; Sittig, D.; Becherer, L.; Anderegg, U.; Schütz, A.; Lamesch, P.; Schmücking, E. The role of CXCR5 and its ligand CXCL13 in the compartmentalization of lymphocytes in thyroids affected by autoimmune thyroid diseases. Eur. J. Endocrinol., 2004, 150(2), 225-234.
[http://dx.doi.org/10.1530/eje.0.1500225] [PMID: 14763921]
[7]
Ammirante, M.; Shalapour, S.; Kang, Y.; Jamieson, C.A.; Karin, M. Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc. Natl. Acad. Sci. USA, 2014, 111(41), 14776-14781.
[http://dx.doi.org/10.1073/pnas.1416498111] [PMID: 25267627]
[8]
Sambandam, Y.; Sundaram, K.; Liu, A.; Kirkwood, K.L.; Ries, W.L.; Reddy, S.V. CXCL13 activation of c-Myc induces RANK ligand expression in stromal/preosteoblast cells in the oral squamous cell carcinoma tumor-bone microenvironment. Oncogene, 2013, 32(1), 97-105.
[http://dx.doi.org/10.1038/onc.2012.24] [PMID: 22330139]
[9]
Qi, X.W.; Xia, S.H.; Yin, Y.; Jin, L.F.; Pu, Y.; Hua, D.; Wu, H.R. Expression features of CXCR5 and its ligand, CXCL13 associated with poor prognosis of advanced colorectal cancer. Eur. Rev. Med. Pharmacol. Sci., 2014, 18(13), 1916-1924.
[PMID: 25010623]
[10]
Singh, R.; Gupta, P.; Kloecker, G.H.; Singh, S.; Lillard, J.W., Jr Expression and clinical significance of CXCR5/CXCL13 in human non‑small cell lung carcinoma. Int. J. Oncol., 2014, 45(6), 2232-2240.
[http://dx.doi.org/10.3892/ijo.2014.2688] [PMID: 25271023]
[11]
Razis, E.; Kalogeras, K.T.; Kotoula, V.; Eleftheraki, A.G.; Nikitas, N.; Kronenwett, R.; Timotheadou, E.; Christodoulou, C.; Pectasides, D.; Gogas, H.; Wirtz, R.M.; Makatsoris, T.; Bafaloukos, D.; Aravantinos, G.; Televantou, D.; Pavlidis, N.; Fountzilas, G. Improved outcome of high-risk early HER2 positive breast cancer with high CXCL13-CXCR5 messenger RNA expression. Clin. Breast Cancer, 2012, 12(3), 183-193.
[http://dx.doi.org/10.1016/j.clbc.2012.03.006] [PMID: 22607768]
[12]
Majmundar, A.J.; Wong, W.J.; Simon, M.C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell, 2010, 40(2), 294-309.
[http://dx.doi.org/10.1016/j.molcel.2010.09.022] [PMID: 20965423]
[13]
Nanduri, J.; Semenza, G.L.; Prabhakar, N.R. Epigenetic changes by DNA methylation in chronic and intermittent hypoxia. Am. J. Physiol. Lung Cell. Mol. Physiol., 2017, 313(6), L1096-L1100.
[http://dx.doi.org/10.1152/ajplung.00325.2017] [PMID: 28839104]
[14]
Karouzakis, E.; Rengel, Y.; Jüngel, A.; Kolling, C.; Gay, R.E.; Michel, B.A.; Tak, P.P.; Gay, S.; Neidhart, M.; Ospelt, C. DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts. Genes Immun., 2011, 12(8), 643-652.
[http://dx.doi.org/10.1038/gene.2011.45] [PMID: 21753787]
[15]
Ma, D.; Chang, L.Y.; Zhao, S.; Zhao, J.J.; Xiong, Y.J.; Cao, F.Y.; Yuan, L.; Zhang, Q.; Wang, X.Y.; Geng, M.L.; Zheng, H.Y.; Li, O. KLF5 promotes cervical cancer proliferation, migration and invasion in a manner partly dependent on TNFRSF11a expression. Sci. Rep., 2017, 7(1), 15683.
[http://dx.doi.org/10.1038/s41598-017-15979-1] [PMID: 29146991]
[16]
Wang, W.; Zhang, L.; Zhang, X.; Xue, R.; Li, L.; Zhao, W.; Fu, Q.; Mi, W.; Li, Y. Lentiviral-mediated overexpression of the 18 kDa translocator protein (TSPO) in the hippocampal dentate gyrus ameliorates LPS-induced cognitive impairment in mice. Front. Pharmacol., 2016, 7, 384.
[http://dx.doi.org/10.3389/fphar.2016.00384] [PMID: 27803668]
[17]
Coral, S.; Parisi, G.; Nicolay, H.J.; Colizzi, F.; Danielli, R.; Fratta, E.; Covre, A.; Taverna, P.; Sigalotti, L.; Maio, M. Immunomodulatory activity of SGI-110, a 5-aza-2′-deoxycytidine-containing demethylating dinucleotide. Cancer Immunol. Immunother., 2013, 62(3), 605-614.
[http://dx.doi.org/10.1007/s00262-012-1365-7] [PMID: 23138873]
[18]
Chuang, J.C.; Warner, S.L.; Vollmer, D.; Vankayalapati, H.; Redkar, S.; Bearss, D.J.; Qiu, X.; Yoo, C.B.; Jones, P.A. S110, a 5-Aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol. Cancer Ther., 2010, 9(5), 1443-1450.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-1048] [PMID: 20442312]
[19]
He, R.; Hou, S.; Liu, C.; Zhang, A.; Bai, Q.; Han, M.; Yang, Y.; Wei, G.; Shen, T.; Yang, X.; Xu, L.; Chen, X.; Hao, Y.; Wang, P.; Zhu, C.; Ou, J.; Liang, H.; Ni, T.; Zhang, X.; Zhou, X.; Deng, K.; Chen, Y.; Luo, Y.; Xu, J.; Qi, H.; Wu, Y.; Ye, L. Erratum: Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection. Nature, 2016, 540(7633), 7663, 470.
[20]
He, Q.F.; Xu, Y.; Li, J.; Huang, Z.M.; Li, X.H.; Wang, X. CD8+ T-cell exhaustion in cancer: mechanisms and new area for cancer immunotherapy. Brief. Funct. Genomics, 2019, 18(2), 99-106.
[http://dx.doi.org/10.1093/bfgp/ely006] [PMID: 29554204]
[21]
Chen, D.S.; Irving, B.A.; Hodi, F.S. Molecular pathways: Next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clin. Cancer Res., 2012, 18(24), 6580-6587.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-1362] [PMID: 23087408]
[22]
Jones, G.W.; Hill, D.G.; Jones, S.A. Understanding immune cells in tertiary lymphoid organ development: It is all starting to come together. Front. Immunol., 2016, 7, 401.
[http://dx.doi.org/10.3389/fimmu.2016.00401] [PMID: 27752256]
[23]
Jones, P.A.; Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet., 2002, 3(6), 415-428.
[http://dx.doi.org/10.1038/nrg816] [PMID: 12042769]

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