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Diagnostic Availability of Estrogen Receptor Alpha mRNA on Cervical Cancer Tissue

자궁경부암 조직에서 에스트로겐 수용체 알파 mRNA의 진단적 유용성

  • Kim, Geehyuk (Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University) ;
  • Yu, Kwangmin (Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University) ;
  • Kim, Jungho (Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University) ;
  • Kim, Seoyong (Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University) ;
  • Park, Sunyoung (Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University) ;
  • Ahn, Sungwoo (Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University) ;
  • Lee, Ji-Young (Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University) ;
  • Kim, Sunghyun (Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan) ;
  • Park, Ho-Hyun (Department of Biomedical Laboratory Science, Mokpo Science University) ;
  • Lee, Dongsup (Department of Clinical Laboratory Science, Hyejeon College)
  • 김지혁 (연세대학교 임상병리학과) ;
  • 유광민 (연세대학교 임상병리학과) ;
  • 김정호 (연세대학교 임상병리학과) ;
  • 김서용 (연세대학교 임상병리학과) ;
  • 박선영 (연세대학교 임상병리학과) ;
  • 안성우 (연세대학교 임상병리학과) ;
  • 이지영 (연세대학교 임상병리학과) ;
  • 김성현 (부산가톨릭대학교 임상병리학과) ;
  • 박호현 (목포과학대학교 임상병리과) ;
  • 이동섭 (혜전대학교 임상병리과)
  • Received : 2018.10.11
  • Accepted : 2018.11.14
  • Published : 2018.12.31

Abstract

Cervical cancer is the fourth most frequently diagnosed cancer in women worldwide. In lower Human Development Index countries, it has the second highest incidence and mortality among cancer in women. Therefore, better diagnosis and treatment systems are needed. Among them, estrogen receptor alpha ($ER-{\alpha}$) mRNA expression has been analyzed with RT-qPCR since several studies reported that $ER-{\alpha}$ is necessary in the maturation of the uterus and is related to cervical cancer. In this study, $ER-{\alpha}$ quantitative analysis was performed on various lesions and normal tissue samples. Based on the receiver operating characteristic (ROC) curve, its sensitivity and specificity were 85% and 75%, respectively, showing higher or similar results to those of conventional HPV tests. In addition, its expression level was analyzed with clinical information. With regression analysis, the R square value between the $ER-{\alpha}$ mRNA expression level and menopause status was 0.5041, indicating a strong correlation. This study was performed as part of a pilot study and suggests that $ER-{\alpha}$ is related to carcinogenesis. Future studies will examine other hormones and menopausal factors with a larger sample size.

자궁경부암은 세계적으로 여성에서 네번째로 많이 진단되는 암이다. 개발 지수가 낮은 개발도상국이나 후진국에서는 자궁경부암의 발생률과 사망률이 훨씬 심각하다. 따라서 더 나은 진단법과 치료법이 시급하다. 인유두종바이러스가 자궁경부암 발생의 주요 원인으로 알려진 이후로 바이러스에 대한 검사가 세포검사 조직검사와 함께 자궁경부암을 진단하는데 일상적으로 쓰이고 있다. 하지만, HPV 검사에서 음성을 보이는 환자가 자궁경부암으로 발전하는 사례가 계속해서 발견되고 있다. 본 연구에서는 HPV 외에 자궁경부암의 원인으로 생각되는 인자들에 대해 분석하였다. 그 중에서도 에스트로겐 수용체 알파의 mRNA 발현양을 실시간 역전사 중합효소 연쇄반응을 통해 분석하였다. 에스트로겐 수용체 알파에 대해서는 예전부터 자궁내막을 성숙시키면서 동시에 자궁경부암의 발암 기전에 연관이 있을 것이라는 추측이 있었는데, 본 연구에서는 이에 대해 임상검체를 통해 양적 분석을 진행하였다. ROC 곡선을 바탕으로, 85%의 민감도와 75%의 특이도를 확인할 수 있었는데, 이 값은 기존의 HPV 검사법보다 유사하거나 더 높은 값이었다. 나이, 병변의 심한 정도 등을 포함한 임상 정보를 바탕으로 회귀 분석한 결과 폐경 여부와 에스트로겐 수용체 알파의 발현양이 높은 연관성을 확인하였다. 본 연구는 예비 연구의 일종으로, 추후 연구에서 가능성이 확인된 호르몬과 폐경에 관련된 유전자를 대상으로 더 많은 검체로 분석해야 할 것이다.

Keywords

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;0:1-31.
  2. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12-19. https://doi.org/10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F
  3. Franco EL, Duarte-Franco E, Ferenczy A. Cervical cancer: epidemiology, prevention and the role of human papillomavirus infection. CMAJ. 2001;164:1017-1025.
  4. Park SY, Wang HY, Kim SH, Kim GH, Bong SY, Jang HS, et al. Performance of HPV E6/E7 mRNA genotyping test on paired cervical. Biomedical Science Letters. 2016;22:98-106. https://doi.org/10.15616/BSL.2016.22.3.98
  5. Goodman A. HPV testing as a screen for cervical cancer. BMJ. 2015;350:h2372. https://doi.org/10.1136/bmj.h2372
  6. Riley RR, Duensing S, Brake T, Munger K, Lambert PF, Arbeit JM. Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis. Cancer Res. 2003;63:4862-4871.
  7. Shai A, Brake T, Somoza C, Lambert PF. The human papillomavirus E6 oncogene dysregulates the cell cycle and contributes to cervical carcinogenesis through two independent activities. Cancer Res. 2007;67:1626-1635. https://doi.org/10.1158/0008-5472.CAN-06-3344
  8. Arbeit JM1, Howley PM, Hanahan D. Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice. Proc Natl Acad Sci U S A. 1996;93:2930-2935. https://doi.org/10.1073/pnas.93.7.2930
  9. Elson DA, Riley RR, Lacey A, Thordarson G, Talamantes FJ, Arbeit JM. Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis. Cancer Res. 2000;60:1267-1275.
  10. Chung SH, Franceschi S, Lambert PF. Estrogen and ER-${\alpha}$: culprits in cervical cancer?. Trends Endocrinol Metab. 2010;21:504-511. https://doi.org/10.1016/j.tem.2010.03.005
  11. Spurgeon ME, Chung SH, Lambert PF. Recurrence of cervical cancer in mice after selective estrogen receptor modulator therapy. Am J Pathol. 2014;184:530-540. https://doi.org/10.1016/j.ajpath.2013.10.013
  12. Hellberg D. Sex steroids and cervical cancer. Anticancer Res. 2012;32:3045-3054.
  13. Giron RA, Montano LF, Escobar ML, Lopez-Marure R. Dehydroepiandrosterone inhibits the proliferation and induces the death of HPV-positive and HPV-negative cervical cancer cells through an androgen- and estrogen-receptor independent mechanism. FEBS J. 2009;276:5598-5609. https://doi.org/10.1111/j.1742-4658.2009.07253.x
  14. den Boon JA, Pyeon D, Wang SS, Horswill M, Schiffman M, Sherman M, et al. Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling. Proc Natl Acad Sci U S A. 2015;112:E3255-264. https://doi.org/10.1073/pnas.1509322112
  15. Moodley J. Combined oral contraceptives and cervical cancer. Curr Opin Obstet Gynecol. 2004;16:27-29. https://doi.org/10.1097/00001703-200402000-00006
  16. Gierisch JM, Coeytaux RR, Urrutia RP, Havrilesky LJ, Moorman PG, Lowery WJ, et al.. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. 2013;22:1931-1943. https://doi.org/10.1158/1055-9965.EPI-13-0298
  17. Gheit T, Landi S, Gemignani F, Snijders PJ, Vaccarella S, Franceschi S, et al. Development of a sensitive and specific assay combining multiplex PCR and DNA microarray primer extension to detect high-risk mucosal human papillomavirus types. J Clin Microbiol. 2006;44:2025-2031. https://doi.org/10.1128/JCM.02305-05
  18. Kitchener HC, Almonte M, Gilham C, Dowie R, Stoykova B, Sargent A, et al. ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening. Health Technol Assess. 2009;13:1-150, iii-iv.
  19. de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. The Lancet Oncology. 2010;11, 1048-1056. https://doi.org/10.1016/S1470-2045(10)70230-8
  20. Hellman K, Lindquist D, Ranhem C, Wilander E, Andersson S. Human papillomavirus, p16(INK4A), and Ki-67 in relation to clinicopathological variables and survival in primary carcinoma of the vagina. Br J Cancer. 2014;110:1561-1570. https://doi.org/10.1038/bjc.2014.32
  21. Paterni I, Granchi C, Katzenellenbogen JA, Minutolo F. Estrogen receptors alpha ($ER{\alpha}$) and beta ($ER{\beta}$): subtype-selective ligands and clinical potential. Steroids. 2014;90:13-29. https://doi.org/10.1016/j.steroids.2014.06.012
  22. Lee HR, Kim TH, Choi KC. Functions and physiological roles of two types of estrogen receptors, $ER{\alpha}$ and $ER{\beta}$, identified by estrogen receptor knockout mouse. Lab Anim Res. 2012;28:71-76. https://doi.org/10.5625/lar.2012.28.2.71
  23. Hess RA. Estrogen in the adult male reproductive tract: a review. Reprod Biol Endocrinol. 2003;9:1-52.
  24. Hong D, Lu W, Ye F, Hu Y, Xie X. Gene silencing of HPV16 E6/E7 induced by promoter-targeting siRNA in SiHa cells. Br j Cancer. 2009;101:1798-1804. https://doi.org/10.1038/sj.bjc.6605344
  25. Benard VB, Watson M, Castle PE, Saraiya M. Cervical carcinoma rates among young females in the United States. Obstet Gynecol. 2012;120:1117-1123.
  26. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008. IJC. 2010;127:2893-2917. https://doi.org/10.1002/ijc.25516.
  27. World Health Organization (WHO). Comprehensive cervical cancer control: a guide to essential practice. 2nd ed. 2014;9-40. [Internet]. Geneva: World Health Organization; 2018 [cited 2018 Nov 1]. Available from: http://www.who.int/reproductivehealth/publications/cancers/cervical-cancer-guide/en/.
  28. LaCour DE, Trimble C. Human papillomavirus in infants: transmission, prevalence, and persistence. J Pediatr Adolesc Gynecol. 2012;25: 93-97. https://doi.org/10.1016/j.jpag.2011.03.001
  29. Koshiol J, Lindsay L, Pimenta JM, Poole C, Jenkins D, Smith JS. Persistent human papillomavirus infection and cervical neoplasia: a systematic review and meta-analysis. Am J Epidemiol. 2008;168:123-137. https://doi.org/10.1093/aje/kwn036
  30. Rao X, Huang X, Zhou Z, Lin X. An improvement of the 2^(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostat Bioinforma Biomath. 2013;3:71-85.
  31. Shen K, Yueng W, Ngan H. Estrogen and progesterone receptors in normal cervix and primary cervical carcinoma. Chin Med J (Engl). 1994;107:648-652.
  32. Kumar MM, Davuluri S, Poojar S, Mukherjee G, Bajpai AK, Bafna UD, et al. Role of estrogen receptor alpha in human cervical cancer-associated fibroblasts: a transcriptomic study. Tumour Biol. 2016;37:4409-4420. https://doi.org/10.1007/s13277-015-4257-6.
  33. Kim G, Cho H, Lee D, Park S, Lee J, Wang HY, et al. Comparison of FFPE historical versus LBP cytological samples for HPV detection and typing in cervical cancer. Exp Mol Pathol. 2017;102:321-326. https://doi.org/ 10.1016/j.yexmp.2017.02.015.
  34. Barut MU, Kale A, Kuyumcuoglu U, Bozkurt M, Agacayak E, Ozekinci S, et al. Analysis of sensitivity, specificity, and positive and negative predictive values of smear and colposcopy in diagnosis of premalignant and malignant cervical lesions. Med Sci Monit. 2015;21:3860-3867. https://doi.org/10.12659/MSM.895227.
  35. Benevolo M, Vocaturo A, Caraceni D, French D, Rosini S, Zappacosta R, et al. Sensitivity, specificity, and clinical value of human papillomavirus (HPV) E6/E7 mRNA assay as a triage test for cervical cytology and HPV DNA test. J Clin Microbiol. 2011;49:2643-2650. . https://doi.org/10.1128/JCM.02570-10.
  36. Radley D, Saah A, Stanley M. Persistent infection with human papillomavirus 16 or 18 is strongly linked with high-grade cervical disease. Hum Vaccin Immunother. 2016;12:768-772. https://doi.org/ 10.1080/21645515.2015.1088616.
  37. Ferenczy A, Franco E. Persistent human papillomavirus infection and cervical neoplasia. Lancet Oncol. 2002;3:11-16. https://doi.org/10.1016/S1470-2045(01)00617-9.
  38. Park SY, Yoon HS, Bang HE, Kim Y, Choi SK, Ahn SW, et al. Analytical performance of sensitivity and specificity for rapid multiplex high risk human papillomavirus detection kit: HPV ViroCheck. Korean J Clin Lab Sci. 2017;49:446-454. https://doi.org/10.15324/kjcls.2017.49.4.446.
  39. Kim IK, Choi HM, Kim MH. Menopausal knowledge and management in peri-menopausal women. J Korean Soc Menopause. 2012;18:124-131. https://doi.org/10.6118/jksm.2012.18.2.124.
  40. Lee KH, Che SC. Introduction to partial least square: common criteria and practical considerations. Adv Mater Res. 2013;779-780:1766-1769. https://doi.org/10.4028/www.scientific.net/AMR.779-780.1766.
  41. Moore DS, Notz WI, Flinger MA. The basic practice of statistics. 6th ed. New York: W. H. Freeman and company; 2013. p138.
  42. Schneider A, Hommel G, Blettner M. Linear regression analysis:part 14 of a series on evaluation of scientific publications. Dtsch Arztebl Int. 2010;107:776-782. https://doi.org/10.3238/arztebl.2010.0776.
  43. Zhai Y, Bommer GT, Feng Y, Wiese AB, Fearon ER, Cho KR. Loss of estrogen receptor 1 enhances cervical cancer invasion. Am J Pathol. 2010;177: 884-895. https://doi.org/10.2353/ajpath.2010.091166.
  44. Roura E, Travier N, Waterboer T, de Sanjose S, Bosch FX, Pawlita M, et al. The influence of hormonal factors on the risk of developing cervical cancer and pre-cancer: results from the EPIC cohort. PLoS One. 2016;11:e0147029. https://doi.org/10.1371/journal.pone.0147029.
  45. Lau SK, Chu PG, Weiss LM. Immunohistochemical expression of estrogen receptor in pulmonary adenocarcinoma. Appl Immunohistochem Mol Morphol. 2006;14:83-87. https://doi.org/ 10.1097/01.pai.0000168593.35850.9c.
  46. Liu S, Semenciw R, Mao Y. Cervical cancer: the increasing incidence of adenocarcinoma and adenosquamous carcinoma in younger women. CMAJ. 2001;164:1151-1152.
  47. van der Horst J, Siebers AG, Bulten J, Massuger LF, de Kok IM. Increasing incidence of invasive and in situ cervical adenocarcinoma in the Netherlands during 2004-2013. Cancer Med. 2017;6:416-423. https://doi.org/10.1002/cam4.971.