Epigenetic alterations in cervical carcinogenesis : Prediction of carcinogenesis and application for cancer treatment.

2010 Fiscal Year Final Research Report

• Project/Area Number: 19591937
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Saga University
• Principal Investigator: IWASAKA Tsuyoshi Saga University, 医学部, 教授 (60117067)
• Co-Investigator(Kenkyū-buntansha): JOH Keiichiro 佐賀大学, 医学部, 准教授 (90124809) ; NAKAO Yoshihumi 佐賀大学, 医学部, 講師 (30336119)
• Project Period (FY): 2007 – 2010
• Keywords: 婦人科腫瘍学 / 子宮頸癌 / エピジェネティクス / メチル化 / ヒストン修飾 / HPV

Research Abstract

To elucidate the silencing mechanism of retinoic acid receptor β2 (RARβ2) in cervical carcinogenesis, we investigated RARβ2 expression and the status of both DNA methylation and histone modifications at the promoter in cervical cancer celllines. RARβ2 was frequently repressed in cancer cell lines and in primary cancers ofthe cervix. Although the majority of RARβ2-negative cancers had methylated promoter, RARβ2 was repressed with hypomethylated promoter in a substantial fraction of the cancers. The RARβ2-negative cells with hypomethylated promoters showed a repressive histone modification pattern at the promoter. RARβ2 was reactivated by a histone deacetylase inhibitor, accompanied by formation of active histone modifications. The repressive modification was also observed in cells repressed with hypermethylated promoter, but RARβ2 was reactivated only by DNA demethylating agent and not by histone deacetylase inhibitor. Our results suggest that RARβ2 is silenced by either of the two key epigenetic pathways, DNA methylation or repressive histone modifications, depending on the individual cancer cells. Furthermore, DNA demethylating agent and histone deacetylase inhibitor might be useful for the treatment of cervical cancers.

Research Products

• [Journal Article] Predicting the progression of cervical precursor lesions by human papillomavirus genotyping : a prospective cohort study. (2010)
  • Author(s): Matsumoto K, Oki A, Furuta R, Maeda H, Yasugi T, Takatsuka N, Mitsuhashi A, Fujii T, Hirai Y, Iwasaka T, Yaegashi N, Watanabe Y, Nagai Y, Kitagawa T, Yoshikawa H.
  • Journal Title: International Journal of Cancer in press
  • Peer Reviewed
• [Journal Article] Gene expression profiles and microsatellite instability in uterine corpus Endometrioid adenocarcinoma. (2010)
  • Author(s): Koyamatsu Y, Sakamoto M, Miyake K, Muroya T, Sugano K, Nakao Y, Yokoyama M, Iwasaka T.
  • Journal Title: J Obstet Gynecol Res 36 Pages: 336-343
  • Peer Reviewed
• [Journal Article] Antisense transcription occurs at the promoter of a mouse imprinted gene, Commdl, on the repressed paternal allele. (2009)
  • Author(s): Keiichiro J, Yatsuki H, Higashimoto K, Mukai T, Soejima H.
  • Journal Title: Journal of Biochemistry 146 Pages: 771-774
  • Peer Reviewed
• [Journal Article] Anti-proliferative effects of the major polyphenol, (-)-epigallocatechin gallate and retinoic acid in cervical adenocarcinoma. (2008)
  • Author(s): Yokoyama M, Noguchi M, Nakao Y, Yasunaga M, Yamasaki F, Iwasaka T.
  • Journal Title: Gynecologic Oncology 108 Pages: 326-331
  • Peer Reviewed
• [Journal Article] Retinoic acid receptor β2 is epigenetically silenced either by DNA methylation or repressive histone modifications at the promoter in cervical cancer cells. (2007)
  • Author(s): Zhang Z, Joh K, Yatsuki H, Zhao W, Soejima H, Higashimoto K, Noguchi M, Yokoyama M, Iwasaka T, Mukai T.
  • Journal Title: CANCER Letters 247 Pages: 318-327
  • Peer Reviewed
• [Presentation] Morphological Analysis of Nucleoli with Endocervical Glandular Cell Lines. (2007)
  • Author(s): Watanabe S, Kaku T, Tamiya S, Sugishima S, Noguchi M, Uchiyama M, Yasunaga M, Nakao Y, Yokoyama M, Iwasaka T.
  • Organizer: 16th International Congress of Cytology, Vancouver, British Colombia
  • Place of Presentation: Canada
  • Year and Date: 20070513-20070517
• [Remarks] ホームページ等