Wang Xiaohong, Wang Hsu-Kun, McCoy J Philip, Banerjee Nilam S, Rader Janet S, Broker Thomas R, Meyers Craig, Chow Louise T, Zheng Zhi-Ming
HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
RNA. 2009 Apr;15(4):637-47. doi: 10.1261/rna.1442309. Epub 2009 Mar 3.
MicroRNAs (miRNA) play pivotal roles in controlling cell proliferation and differentiation. Aberrant miRNA expression in human is becoming recognized as a new molecular mechanism of carcinogenesis. However, the causes for alterations in miRNA expression remain largely unknown. Infection with oncogenic human papillomavirus types 16 (HPV16) and 18 (HPV18) can lead to cervical and other ano-genital cancers. Here, we have demonstrated that cervical cancer tissues and cervical cancer-derived cell lines containing oncogenic HPVs display reduced expression of tumor-suppressive miR-34a. The reduction of miR-34a expression in organotypic tissues derived from HPV-containing primary human keratinocytes correlates with the early productive phase and is attributed to the expression of viral E6, which destabilizes the tumor suppressor p53, a known miR-34a transactivator. Knockdown of viral E6 expression in HPV16(+) and HPV18(+) cervical cancer cell lines by siRNAs leads to an increased expression of p53 and miR-34a and accumulation of miR-34a in G(0)/G(1) phase cells. Ectopic expression of miR-34a in HPV18(+) HeLa cells and HPV(-) HCT116 cells results in a substantial induction of cell growth retardation and a moderate cell apoptosis. Together, this is the first time a viral oncoprotein has been shown to regulate cellular miRNA expression. Our data have provided new insights into mechanisms by which high-risk HPVs contribute to the development of cervical cancer.
微小RNA（miRNA）在控制细胞增殖和分化中起关键作用。人类中miRNA表达异常正被认为是一种新的致癌分子机制。然而，miRNA表达改变的原因在很大程度上仍不清楚。感染致癌性人乳头瘤病毒16型（HPV16）和18型（HPV18）可导致宫颈癌和其他肛门生殖器癌。在此，我们已证明含有致癌性HPV的宫颈癌组织和宫颈癌衍生细胞系显示出肿瘤抑制性miR-34a表达降低。来自含HPV的原代人角质形成细胞的器官样组织中miR-34a表达的降低与早期生产阶段相关，并且归因于病毒E6的表达，其使肿瘤抑制因子p53不稳定，p53是一种已知的miR-34a反式激活因子。通过小干扰RNA（siRNA）敲低HPV16（+）和HPV18（+）宫颈癌细胞系中的病毒E6表达导致p53和miR-34a表达增加以及miR-34a在G（0）/G（1）期细胞中积累。在HPV18（+）HeLa细胞和HPV（-）HCT116细胞中异位表达miR-34a导致细胞生长明显迟缓并适度诱导细胞凋亡。总之，这是首次证明病毒癌蛋白可调节细胞miRNA表达。我们的数据为高危HPV促进宫颈癌发生发展的机制提供了新的见解。
