Calcium-activated potassium channels as potential early markers of human cervical cancer

Ramírez,Ana; Vera,Eunice; Gamboa‑Domínguez,Armando; Lambert,Paul; Gariglio,Patricio; Camacho,Javier

doi:10.3892/ol.2018.8187

Calcium-activated potassium channels as potential early markers of human cervical cancer

Authors:
- Ana Ramírez
- Eunice Vera
- Armando Gamboa‑Domínguez
- Paul Lambert
- Patricio Gariglio
- Javier Camacho
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Affiliations: Department of Pharmacology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City 07360, Mexico, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición ‘Salvador Zubirán’, Mexico City 14000, Mexico, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA, Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City 07360, Mexico
Published online on: March 7, 2018 https://doi.org/10.3892/ol.2018.8187
Pages: 7249-7254

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Abstract

Cervical cancer is a major cause of cancer-associated mortality in women in developing countries. Thus, novel early markers are required. Ion channels have gained great interest as tumor markers, including cervical cancer. The calcium‑activated potassium channel KCNMA1 (subunit α‑1 from subfamily M) has been associated with different malignancies, including tumors such as breast and ovarian cancer that are influenced by hormones. The KCNMA1 channel blocker iberiotoxin decreases the proliferation of HeLa cervical cancer cells. Nevertheless, KCNMA1 channel expression during cervical carcinogenesis remains elusive. Therefore, KCNMA1 expression was studied in cervical cancer development. FVB transgenic mice expressing the E7‑oncogene of high‑risk human papilloma virus, and non‑transgenic mice were treated with estradiol‑releasing pellets during 3 or 6 months to induce cervical lesions. Twenty‑four human cervical biopsies from non‑cancerous, low‑ or high‑grade intraepithelial lesions, or cervical cancer were also studied. mRNA and protein expression was assessed by reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry, respectively. Cervical dysplasia and carcinoma were observed only in the transgenic mice treated with estradiol for 3 and 6 months, respectively. Estradiol treatment increased KCNMA1 mRNA and protein expression in all groups; however, the highest levels were observed in the transgenic mice with carcinoma. KCNMA1 protein expression in the squamous cells of the transformation zone was observed only in the transgenic mice with cervical dysplasia or cancer. Human biopsies from non‑cancerous cervix did not display KCNMA1 protein expression; in contrast, the majority of the tissues with cervical lesions (16/18) displayed KCNMA1 protein expression. The lowest channel immunostaining intensity was observed in biopsies from low‑grade dysplasia and the strongest in the carcinoma tissues. These results suggest KCNMA1 channels as potential early cervical cancer markers.

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1	Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain J, Garcia FA, Moriarty AT, Waxman AG, Wilbur DC, et al: American Cancer Society, American society for colposcopy and cervical pathology and american society for clinical pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 137:516–542. 2012. View Article : Google Scholar : PubMed/NCBI
2	Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: GLOBOCAN 2012 v1.0. Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]IARC. Lyon: 2013, http://globocan.iarc.frAugust 2–2017
3	Au WW, Abdou-Salama S, Sierra-Torres CH and Al-Hendy A: Environmental risk factors for prevention and molecular intervention of cervical cancer. Int J Hyg Environ Healt. 210:671–678. 2007. View Article : Google Scholar
4	Chung SH, Franceschi S and Lambert PF: Estrogen and ERalpha: Culprits in cervical cancer? Trends Endocrinol Metab. 21:504–511. 2010. View Article : Google Scholar : PubMed/NCBI
5	Veerapaneni P, Kirma N, Nair HB, Hammes LS, Hall KL and Tekmal RR: Elevated aromatase expression correlates with cervical carcinoma progression. Gynecol Oncol. 114:496–500. 2009. View Article : Google Scholar : PubMed/NCBI
6	Brake T and Lambert PF: Estrogen contributes to the onset, persistence and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model. Proc Natl Acad Sci USA. 102:2490–2455. 2005. View Article : Google Scholar : PubMed/NCBI
7	Lastraioli E, Iorio J and Arcangeli A: Ion channel expression as promising cancer biomarker. Biochim Biophys Acta. 1848:2685–2702. 2015. View Article : Google Scholar : PubMed/NCBI
8	Pardo LA and Stühmer W: The roles of K (+) channels in cancer. Nat Rev Cancer. 14:39–48. 2014. View Article : Google Scholar : PubMed/NCBI
9	Salkoff L, Butler A, Ferreira G, Santi C and Wei A: High-conductance potassium channels of the SLO family. Nat Rev Neurosci. 7:921–931. 2006. View Article : Google Scholar : PubMed/NCBI
10	Contet C, Goulding SP, Kuljis DA and Barth AL: BK channels in the central nervous system. Int Rev Neurobiol. 128:281–342. 2016. View Article : Google Scholar : PubMed/NCBI
11	Ge L, Hoa NT, Wilson Z, Arismendi-Morillo G, Kong XT, Tajhya RB, Beeton C and Jadus MR: Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy. Int immunopharmacol. 22:427–443. 2014. View Article : Google Scholar : PubMed/NCBI
12	Liu X and Chang Y, Reinhart PH, Sontheimer H and Chang Y: Cloning and characterization of glioma BK, a novel BK channel isoform highly expressed in human glioma cells. J Neurosci. 22:1840–1849. 2002. View Article : Google Scholar : PubMed/NCBI
13	Oeggerli M, Tian Y, Ruiz C, Wijker B, Sauter G, Obermann E, Güth U, Zlobec I, Sausbier M, Kunzelmann K and Bubendorf L: Role of KCNMA1 in breast cancer. PLoS One. 7:e416642012. View Article : Google Scholar : PubMed/NCBI
14	Bloch M, Ousingsawat J, Simon R, Schraml P, Gasser TC, Mihatsch MJ, Kunzelmann K and Bubendorf L: KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer. Oncogene. 26:2525–2534. 2007. View Article : Google Scholar : PubMed/NCBI
15	Han X, Wang F, Yao W, Xing H, Weng D, Song X, Chen G, Xi L, Zhu T, Zhou J, et al: Heat shock proteins and p53 play a critical role in K⁺ channel-mediated tumor cell proliferation and apoptosis. Apoptosis. 12:1837–1846. 2007. View Article : Google Scholar : PubMed/NCBI
16	Herber R, Liem A, Pitot H and Lambert PF: Squamous epithelial hyperplasia and carcinoma in mice transgenic for the human papillomavirus type 16 E7 oncogene. J Virol. 70:1873–1881. 1996.PubMed/NCBI
17	Riley RR, Duensing S, Brake T, Münger K, Lambert PF and Arbeit JM: Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis. Cancer Res. 63:4862–4871. 2003.PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Sierra Ibarra E, Díaz Chávez J, Cortés-Malagón EM, Uribe-Figueroa L, Hidalgo-Miranda A, Lambert PF and Gariglio P: Differential gene expression between skin and cervix induced by the E7 oncoprotein in a transgenic mouse model. Virology. 433:337–345. 2012. View Article : Google Scholar : PubMed/NCBI
20	Cortés-Malagón EM, Bonilla-Delgado J, Díaz-Chávez J, Hidalgo-Miranda A, Romero-Cordoba S, Uren A, Celik H, McCormick M, Munguía-Moreno JA, Ibarra-Sierra E, et al: Gene expression profile regulated by the HPV16 E7 oncoprotein and estradiol in cervical tissue. Virology. 447:155–165. 2013. View Article : Google Scholar : PubMed/NCBI
21	Díaz L, Ceja-Ochoa I, Restrepo-Angulo I, Larrea F, Ávila-Chávez E, García-Becerra R, Borja-Cacho E, Barrera D, Ahumada E, Gariglio P, et al: Estrogens and human papilloma virus oncogenes regulate human ether-à-go-go-1 potassium channel expression. Cancer Res. 69:3300–3307. 2009. View Article : Google Scholar : PubMed/NCBI
22	Ortiz CS, Montante-Montes D, Saqui-Salces M, Hinojosa LM, Gamboa-Domínguez A, Hernández-Gallegos E, Martínez-Benítez B, Del Rosario Solís-Pancoatl M, Garcia-Villa E, Ramírez A, et al: Eag1 potassium channels as markers of cervical dysplasia. Oncol Rep. 26:1377–1383. 2011.PubMed/NCBI
23	Bentzen BH, Olesen SP, Rønn LC and Grunnet M: BK channel activators and their therapeutic perspectives. Front Physiol. 5:3892014. View Article : Google Scholar : PubMed/NCBI
24	McCobb DP, Fowler NL, Featherstone T, Lingle CJ, Saito M, Krause JE and Salkoff L: A human calcium-activated potassium channel gene expressed in vascular smooth muscle. Am J Physiol. 269:H767–H777. 1995.PubMed/NCBI
25	Kundu P, Alioua A, Stefani E and Toro L: Regulation of mouse Slo gene expression: Multiple promoters, transcription start sites and genomic action of estrogen. J Biol Chem. 282:27478–27492. 2007. View Article : Google Scholar : PubMed/NCBI
26	Valverde MA, Rojas P, Amigo J, Cosmelli D, Orio P, Bahamonde MI, Mann GE, Vergara C and Latorre R: Acute activation of maxi-K channels (hSlo) by estradiol binding to the β subunit. Science. 285:1929–1931. 1999. View Article : Google Scholar : PubMed/NCBI
27	Benkusky NA, Fergus DJ, Zucchero TM and England SK: Regulation of the Ca₂+-sensitive domains of the maxi-K channel in the mouse myometrium during gestation. J Biol Chem. 275:27712–27719. 2000.PubMed/NCBI
28	Mazar J, DeYoung K, Khaitan D, Meister E, Almodovar A, Goydos J, Ray A and Perera RJ: The regulation of miRNA-211 expression and its role in melanoma cell invasiveness. PLoS One. 5:e137792010. View Article : Google Scholar : PubMed/NCBI
29	Tang T, Wong HK, Gu W, Yu MY, To KF, Wang CC, Wong YF, Cheung TH, Chung TK and Choy KW: MicroRNA-182 plays an onco-miRNA role in cervical cancer. Gynecol Oncol. 129:199–208. 2013. View Article : Google Scholar : PubMed/NCBI