Downregulation of 5-hydroxymethylcytosine is associated with the progression of cervical intraepithelial neoplasia
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- Kato, Masaya
- 九州大学大学院医学研究院生殖病態生理学 順天堂大学大学院医学研究科産婦人科学
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- 小野山, 一郎
- 九州大学大学院医学研究院生殖病態生理学
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- 川上, 穣
- 九州大学大学院医学研究院生殖病態生理学
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- Yoshida, Sachiko
- 九州大学大学院医学研究院生殖病態生理学
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- Kawamura, Keiko
- 九州大学大学院医学研究院生殖病態生理学
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- Kodama, Keisuke
- 九州大学大学院医学研究院生殖病態生理学
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- Hori, Emiko
- 九州大学大学院医学研究院生殖病態生理学
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- Cui, Lin
- 九州大学大学院医学研究院生殖病態生理学
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- 松村, 友美子
- 九州大学大学院医学研究院生殖病態生理学
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- 八木, 裕史
- 九州大学大学院医学研究院生殖病態生理学
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- 淺野間, 和夫
- 九州大学大学院医学研究院生殖病態生理学
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- 矢幡, 秀昭
- 九州大学大学院医学研究院生殖病態生理学
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- 板倉, 敦夫
- 順天堂大学大学院医学研究科産婦人科学
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- 竹田, 省
- 順天堂大学大学院医学研究科産婦人科学
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- 加藤, 聖子
- 九州大学大学院医学研究院生殖病態生理学
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- Qian Tao
- editor
抄録
Around the world, cervical cancer is one of the most common neoplastic diseases among women, and the prognosis of patients in an advanced stage remains poor. To reduce the mortality rate of cervical cancer, early diagnosis and treatment are essential. DNA methylation is an important aspect of gene regulation, and aberrant DNA methylation contributes to carcinogenesis and cancer progression in various cancers. Although 5-methylcytosine (5mC) has been analyzed intensively, the function of 5-hydroxymethylcytosine (5hmC) has not been clarified. The purpose of our study was to identify the molecular biomarkers for early diagnosis of cervical tumors due to epigenetic alterations. To assess the clinical relevance of DNA methylation, we used immunohistochemistry (IHC) to characterize the level of 5hmC in 102 archived human cervical intraepithelial neoplasia (CIN) samples and cervical cancer specimens. The level of 5hmC was significantly decreased between CIN2 and CIN3. The progression of cervical tumors is caused by a reduction of TP53 and RB1 because of HPV infection. We observed that Tp53 and Rb1 were knocked down in mouse embryonic fibroblasts (MEF), a model of normal cells. The level of 5hmC was reduced in Tp53-knockdown cells, and the expression levels of DNA methyltransferase 1 (DNMT1) and ten-eleven translocation methylcytosine dioxygenase 1 (TET1) were induced. In contrast, there was no significant change in Rb1-knockdown cells. Mechanistically, we focused on apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) 3B (A3B) as a cause of 5hmC reduction after TP53 knockdown. In the human cell line HHUA with a wild-type TP53 gene, A3B was induced in TP53-knockdown cells, and A3B knockdown recovered 5hmC levels in TP53-knockdown cells. These data indicate that TP53 suppression leads to 5hmC reduction in part through A3B induction. Moreover, IHC showed that expression levels of A3B in CIN3 were significantly higher than those in both normal epithelium and in CIN2. In conclusion, 5hmC levels are decreased between CIN2 and CIN3 through the TP53-A3B pathway. Since A3B could impair genome stability, 5hmC loss might increase the chances of accumulating mutations and of progressing from CIN3 to cervical cancer. Thus, these epigenetic changes could predict whether CINs are progressing to cancer or disappearing.
収録刊行物
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- PLoS ONE
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PLoS ONE 15 (11), e0241482-, 2020-11-03
Public Library of Science
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キーワード
詳細情報 詳細情報について
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- CRID
- 1050580007680812544
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- NII論文ID
- 120007044541
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- ISSN
- 19326203
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- HANDLE
- 2324/4479070
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- 本文言語コード
- en
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- 資料種別
- journal article
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- データソース種別
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- IRDB
- Crossref
- CiNii Articles
- KAKEN