Reversibility of Aberrant Global DNA and Estrogen Receptor-α Gene Methylation Distinguishes Colorectal Precancer from Cancer

International Journal of Clinical and Experimental Pathology

Rulong Shen¹  Jian-Xin Gao¹  Yiqing Xu¹  Shi Chang¹  Lianhui Tao¹  James Van Brocklyn¹ 

关键词: Precancer;    DNA methylation;    colorectal cancer;    estrogen receptor-α;    nonsteroidal anti-inflammatory drugs;    cancer progression;    epigenetic;    tumor initiation;   

DOI  :  

学科分类：生理学与病理学

来源: e-Century Publishing Corporation

【 摘 要 】

Alterations in the global methylation of DNA and in specific regulatory genes are two epigenetic alterations found in cancer. However, the significance of epigenetic changes for diagnosis and/or prognosis of colorectal cancer have not been established, although it has been extensively investigated. Recently we have identified a new type of cancer cell called precancerous stem cells (pCSCs) and proposed that cancer may arise from a lengthy development process of tumor initiating cells (TICs) → pCSCs → cancer stem cells (CSCs) → cancer, which is in parallel to histological changes of hyperplasia (TICs) → precancer (pCSCs) → carcinoma (CSCs/cancer cells), accompanied by clonal evolutionary epigenetic and genetic alterations. In this study, we investigated whether aberrant DNA methylation can be used as a biomarker for the differentiation between premalignant and malignant lesions in the colorectum. The profile of global DNA and estrogen receptor (ER)-α gene methylation during cancer development was determined by analysis of 5-methylcytosine (5-MeC) using immunohistochemical (IHC) staining, dot blot analysis or a quantitative gene methylation assay (QGMA). Herein we show that global DNA hypomethylation and ER-α gene hypermethylation are progressively enhanced from hyperplastic polyps (HPs) → adenomatous polyps (APs) → adenomatous carcinoma (AdCa). The aberrant methylation can be completely reversed in APs, but not in AdCa by a nonsteroidal anti-inflammatory drug (NSAID) celecoxib, which is a selective inhibitor of cyclooxygenase-2 (Cox-2), suggesting that the epigenetic alterations between colorectal precancer (AP) and cancer (AdCa) are fundamentally different in response to anti-cancer therapy. In normal colorectal mucosa, while global DNA methylation was not affected by aging, ER-α gene methylation was significantly increased with aging. However, this increase did not reach the level observed in colorectal APs. Taken together, reversibility of aberrant global DNA and ER-α gene methylation distinguishes colorectal precancer from cancer.

【 授权许可】

Unknown