Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, Columbus, OH 43210, USA.
Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4908-13. doi: 10.1073/pnas.1101795108. Epub 2011 Mar 7.
Infection-driven inflammation has been implicated in the pathogenesis of ~15-20% of human tumors. Expression of microRNA-155 (miR-155) is elevated during innate immune response and autoimmune disorders as well as in various malignancies. However, the molecular mechanisms providing miR-155 with its oncogenic properties remain unclear. We examined the effects of miR-155 overexpression and proinflammatory environment on the frequency of spontaneous hypoxanthine phosphoribosyltransferase (HPRT) mutations that can be detected based on the resistance to 6-thioguanine. Both miR-155 overexpression and inflammatory environment increased the frequency of HPRT mutations and down-regulated WEE1 (WEE1 homolog-S. pombe), a kinase that blocks cell-cycle progression. The increased frequency of HPRT mutation was only modestly attributable to defects in mismatch repair machinery. This result suggests that miR-155 enhances the mutation rate by simultaneously targeting different genes that suppress mutations and decreasing the efficiency of DNA safeguard mechanisms by targeting of cell-cycle regulators such as WEE1. By simultaneously targeting tumor suppressor genes and inducing a mutator phenotype, miR-155 may allow the selection of gene alterations required for tumor development and progression. Hence, we anticipate that the development of drugs reducing endogenous miR-155 levels might be key in the treatment of inflammation-related cancers.
在大约 15%-20%的人类肿瘤的发病机制中，感染驱动的炎症被认为起了作用。微 RNA-155 (miR-155) 的表达在先天免疫反应和自身免疫性疾病以及各种恶性肿瘤中升高。然而，提供 miR-155 致癌特性的分子机制尚不清楚。我们研究了 miR-155 过表达和促炎环境对自发次黄嘌呤磷酸核糖基转移酶 (HPRT) 突变频率的影响，这种突变可以基于对 6-硫鸟嘌呤的抗性来检测。miR-155 过表达和炎症环境均增加了 HPRT 突变的频率，并下调了 WEE1（裂殖酵母 WEE1 同源物），一种阻止细胞周期进程的激酶。HPRT 突变频率的增加仅部分归因于错配修复机制的缺陷。这一结果表明，miR-155 通过同时靶向抑制突变的不同基因，并通过靶向细胞周期调节剂（如 WEE1）来降低 DNA 保护机制的效率，从而提高突变率。通过同时靶向肿瘤抑制基因并诱导突变体表型，miR-155 可能允许选择肿瘤发展和进展所需的基因改变。因此，我们预计降低内源性 miR-155 水平的药物的开发可能是治疗与炎症相关的癌症的关键。
