Subramanian M, Francis P, Bilke S, Li X L, Hara T, Lu X, Jones M F, Walker R L, Zhu Y, Pineda M, Lee C, Varanasi L, Yang Y, Martinez L A, Luo J, Ambs S, Sharma S, Wakefield L M, Meltzer P S, Lal A
Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, Washington, DC, USA.
Oncogene. 2015 Feb 26;34(9):1094-104. doi: 10.1038/onc.2014.46. Epub 2014 Mar 24.
Most p53 mutations in human cancers are missense mutations resulting in a full-length mutant p53 protein. Besides losing tumor suppressor activity, some hotspot p53 mutants gain oncogenic functions. This effect is mediated in part, through gene expression changes due to inhibition of p63 and p73 by mutant p53 at their target gene promoters. Here, we report that the tumor suppressor microRNA let-7i is downregulated by mutant p53 in multiple cell lines expressing endogenous mutant p53. In breast cancer patients, significantly decreased let-7i levels were associated with missense mutations in p53. Chromatin immunoprecipitation and promoter luciferase assays established let-7i as a transcriptional target of mutant p53 through p63. Introduction of let-7i to mutant p53 cells significantly inhibited migration, invasion and metastasis by repressing a network of oncogenes including E2F5, LIN28B, MYC and NRAS. Our findings demonstrate that repression of let-7i expression by mutant p53 has a key role in enhancing migration, invasion and metastasis.
人类癌症中大多数p53突变是错义突变，会产生全长突变型p53蛋白。除了失去肿瘤抑制活性外，一些热点p53突变体还获得了致癌功能。这种效应部分是通过突变型p53在其靶基因启动子处抑制p63和p73导致基因表达变化来介导的。在此，我们报告在多种表达内源性突变型p53的细胞系中，肿瘤抑制性微小RNA let-7i被突变型p53下调。在乳腺癌患者中，let-7i水平显著降低与p53错义突变有关。染色质免疫沉淀和启动子荧光素酶测定确定let-7i是突变型p53通过p63的转录靶点。将let-7i导入突变型p53细胞通过抑制包括E2F5、LIN28B、MYC和NRAS在内的致癌基因网络，显著抑制了迁移、侵袭和转移。我们的研究结果表明，突变型p53对let-7i表达的抑制在增强迁移、侵袭和转移中起关键作用。
