Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Oncogene. 2013 Jan 3;32(1):15-26. doi: 10.1038/onc.2012.29. Epub 2012 Feb 13.
Epigenetic modifications are a driving force in carcinogenesis. However, their role in cancer metastasis remains poorly understood. The present study investigated the role of DNA methylation in the cervical cancer metastasis. Here, we report evidence of the overexpression of DNA methyltransferases 3B (DNMT3B) in invasive cervical cancer and of the inhibition of metastasis by DNMT3B interference. Using methyl-DNA immunoprecipitation coupled with microarray analysis, we found that the protein tyrosine phosphatase receptor type R (PTPRR) was silenced through DNMT3B-mediated methylation in the cervical cancer. PTPRR inhibited p44/42 MAPK signaling, the expression of the transcription factor AP1, human papillomavirus (HPV) oncogenes E6/E7 and DNMTs. The methylation status of PTPRR increased in cervical scrapings (n=358) in accordance with disease severity, especially in invasive cancer. Methylation of the PTPRR promoter has an important role in the metastasis and may be a biomarker of invasive cervical cancer.
表观遗传修饰是癌症发生的驱动力。然而，它们在癌症转移中的作用仍知之甚少。本研究探讨了 DNA 甲基化在宫颈癌转移中的作用。在这里，我们报告了 DNA 甲基转移酶 3B（DNMT3B）在浸润性宫颈癌中过度表达的证据，以及 DNMT3B 干扰抑制转移的证据。通过甲基化 DNA 免疫沉淀结合微阵列分析，我们发现蛋白酪氨酸磷酸酶受体 R（PTPRR）在宫颈癌中被 DNMT3B 介导的甲基化沉默。PTPRR 抑制了 p44/42 MAPK 信号通路、转录因子 AP1、人乳头瘤病毒（HPV）致癌基因 E6/E7 和 DNMTs 的表达。PTPRR 的甲基化状态在宫颈刮片（n=358）中与疾病严重程度一致增加，尤其是在浸润性癌中。PTPRR 启动子的甲基化在转移中起着重要作用，可能是侵袭性宫颈癌的生物标志物。
