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01-05-2015 | Original Paper

Tight junction protein claudin-6 inhibits growth and induces the apoptosis of cervical carcinoma cells in vitro and in vivo

Authors: Xiaowei Zhang, Yang Ruan, Yanru Li, Dongjing Lin, Chengshi Quan

Published in: Medical Oncology | Issue 5/2015

Abstract

Claudin-6, a member of claudin family integral membrane proteins, has recently been reported to be a tumor suppressor for breast cancer. However, whether it plays a role in other types of cancer remains unclear. In the present study, we showed that the expression of claudin-6 is down-regulated in cervical carcinoma tissues as revealed by immunohistochemistry. Through over-expressing claudin-6 in HeLa and C33A cervical carcinoma cells, we found that claudin-6 is localized at plasma membrane and it increases transepithelial electrical resistance of the cells. Gain of claudin-6 expression suppresses cell proliferation, colony formation in vitro, and tumor growth in vivo. The effects are accompanied and potentially caused by promotion of tumor cell apoptosis. Taken together, these results suggest that claudin-6 may function as a tumor suppressor and loss of claudin-6 contributes to enhanced tumorigenic properties of cervical carcinoma cells.

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Dejana E. Endothelial cell–cell junctions: happy together. Nat Rev Mol Cell Biol. 2004;5(4):261–70.CrossRefPubMed

Gumbiner BM. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell. 1996;84(3):345–57.CrossRefPubMed

Gonzalez-Mariscal L, Betanzos A, Nava P, Jaramillo B. Tight junction proteins. Prog Biophys Mol Biol. 2003;81(1):1–44.CrossRefPubMed

Gonzalez-Mariscal L, Bautista P. Tight junctions. Berlin: Springer; 2006.CrossRef

Fanning AS, Mitic LL, Anderson JM. Transmembrane proteins in the tight junction barrier. J Am Soc Nephrol. 1999;10(6):1337–45.PubMed

Bojarski C, Weiske J, Schöneberg T, Schröder W, Mankertz J, Schulzke J-D, et al. The specific fates of tight junction proteins in apoptotic epithelial cells. J Cell Sci. 2004;117(10):2097–107.CrossRefPubMed

Hewitt KJ, Agarwal R, Morin PJ. The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer. 2006;6(1):186.CrossRefPubMedCentralPubMed

Shang X, Lin X, Alvarez E, Manorek G, Howell SB. Tight junction proteins claudin-3 and claudin-4 control tumor growth and metastases. Neoplasia. 2012;14(10):974-IN22.CrossRef

Krause G, Winkler L, Mueller SL, Haseloff RF, Piontek J, Blasig IE. Structure and function of claudins. Biochimica et Biophysica Acta (BBA)-Biomembranes. 2008;1778(3):631–45.CrossRef

10.

Lal-Nag M, Morin PJ. The claudins. Genome Biol. 2009;10(8):235.CrossRefPubMedCentralPubMed

11.

Morin PJ. Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res. 2005;65(21):9603–6.CrossRefPubMed

12.

Oliveira S, Morgado-Diaz J. Claudins: multifunctional players in epithelial tight junctions and their role in cancer. Cell Mol Life Sci. 2007;64(1):17–28.CrossRefPubMed

13.

Kinugasa T, Huo Q, Higashi D, Shibaguchi H, Kuroki M, Tanaka T, et al. Selective up-regulation of claudin-1 and claudin-2 in colorectal cancer. Anticancer Res. 2007;27(6A):3729–34.PubMed

14.

Lanigan F, McKiernan E, Brennan DJ, Hegarty S, Millikan RC, McBryan J, et al. Increased claudin-4 expression is associated with poor prognosis and high tumour grade in breast cancer. Int J Cancer. 2009;124(9):2088–97.CrossRefPubMed

15.

Katoh M, Katoh M. CLDN23 gene, frequently down-regulated in intestinal-type gastric cancer, is a novel member of CLAUDIN gene family. Int J Mol Med. 2003;11(6):683–9.PubMed

16.

Turksen K, Troy TC. Claudin-6: a novel tight junction molecule is developmentally regulated in mouse embryonic epithelium. Dev Dyn. 2001;222(2):292–300.CrossRefPubMed

17.

Itoh M, Furuse M, Morita K, Kubota K, Saitou M, Tsukita S. Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. J Cell Biol. 1999;147(6):1351–63.CrossRefPubMedCentralPubMed

18.

Quan C, Lu S-J. Identification of genes preferentially expressed in mammary epithelial cells of Copenhagen rat using subtractive hybridization and microarrays. Carcinogenesis. 2003;24(10):1593–9.CrossRefPubMed

19.

Wu Q, Liu Y, Ren Y, Xu X, Yu L, Li Y, et al. Tight junction protein, claudin-6, downregulates the malignant phenotype of breast carcinoma. Eur J Cancer Prev. 2010;19(3):186–94.CrossRefPubMed

20.

Rendón-Huerta E, Teresa F, Teresa GM, Xochitl G-S, Georgina A-F, Veronica Z-Z, et al. Distribution and expression pattern of claudins 6, 7, and 9 in diffuse-and intestinal-type gastric adenocarcinomas. J Gastrointest Cancer. 2010;41(1):52–9.CrossRefPubMed

21.

Sullivan LM, Yankovich T, Le P, Martinez D, Santi M, Biegel JA, et al. Claudin-6 is a non-specific marker for malignant rhabdoid and other pediatric tumors. Am J Surg Pathol. 2012;36(1):73.CrossRefPubMedCentralPubMed

22.

Birks DK, Kleinschmidt-DeMasters BK, Donson AM, Barton VN, McNatt SA, Foreman NK, et al. Claudin 6 is a positive marker for atypical teratoid/rhabdoid tumors. Brain Pathol. 2010;20(1):140–50.CrossRefPubMed

23.

Lin Z, Zhang X, Liu Z, Liu Q, Wang L, Lu Y, et al. The distinct expression patterns of claudin-2,-6, and -11 between human gastric neoplasms and adjacent non-neoplastic tissues. Diagn Pathol. 2013;8(1):133–9.CrossRefPubMedCentralPubMed

24.

Pozarowski P, Darzynkiewicz Z. Analysis of cell cycle by flow cytometry. In: Schönthal AH, editor. Checkpoint controls and cancer. Methods in molecular biology, vol 281. Springer; 2004. p 301–311.

25.

Butcher DT, Alliston T, Weaver VM. A tense situation: forcing tumour progression. Nat Rev Cancer. 2009;9(2):108–22.CrossRefPubMedCentralPubMed

26.

Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003;3(5):362–74.CrossRefPubMed

27.

Kojima T, Sawada N. Regulation of tight junctions in human normal pancreatic duct epithelial cells and cancer cells. Ann N Y Acad Sci. 2012;1257(1):85–92.CrossRefPubMed

28.

Steed E, Balda MS, Matter K. Dynamics and functions of tight junctions. Trends Cell Biol. 2010;20(3):142–9.CrossRefPubMed

29.

Agarwal R, Mori Y, Cheng Y, Jin Z, Olaru AV, Hamilton JP, et al. Silencing of claudin-11 is associated with increased invasiveness of gastric cancer cells. PLoS One. 2009;4(11):e8002.CrossRefPubMedCentralPubMed

30.

Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, et al. Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene. 2003;22(13):2021–33.CrossRefPubMed

31.

Osanai M, Murata M, Chiba H, Kojima T, Sawada N. Epigenetic silencing of claudin-6 promotes anchorage-independent growth of breast carcinoma cells. Cancer Sci. 2007;98(10):1557–62.CrossRefPubMed

32.

Matter K, Balda MS. Signalling to and from tight junctions. Nat Rev Mol Cell Biol. 2003;4(3):225–37.CrossRefPubMed

33.

Anderson JM, Van Itallie CM, Fanning AS. Setting up a selective barrier at the apical junction complex. Curr Opin Cell Biol. 2004;16(2):140–5.CrossRefPubMed

34.

Dhawan P, Singh AB, Deane NG, No Y, Shiou S-R, Schmidt C, et al. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J Clin Investig. 2005;115(7):1765–76.CrossRefPubMedCentralPubMed

35.

Lu Z, Ding L, Hong H, Hoggard J, Lu Q, Chen Y-H. Claudin-7 inhibits human lung cancer cell migration and invasion through ERK/MAPK signaling pathway. Exp Cell Res. 2011;317(13):1935–46.CrossRefPubMedCentralPubMed

36.

Hoevel T, Macek R, Swisshelm K, Kubbies M. Reexpression of the TJ protein CLDN1 induces apoptosis in breast tumor spheroids. Int J Cancer. 2004;108(3):374–83.CrossRefPubMed

Title: Tight junction protein claudin-6 inhibits growth and induces the apoptosis of cervical carcinoma cells in vitro and in vivo
Authors: Xiaowei Zhang
Yang Ruan
Yanru Li
Dongjing Lin
Chengshi Quan
Publication date: 01-05-2015
Publisher: Springer US
Published in: Medical Oncology / Issue 5/2015
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI: https://doi.org/10.1007/s12032-015-0600-4

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