小RNA
生物
利基
病理
干细胞
签名(拓扑)
细胞
癌症研究
细胞生物学
医学
基因
遗传学
生物化学
几何学
数学
作者
Vignesh Viswanathan,Shirish Damle,Tao Zhang,Lynn Opdenaker,Shirin Modarai,Monica Accerbi,Skye Schmidt,Pamela Green,Deni S. Galileo,Juan Palazzo,Jeremy Z. Fields,Sepehr Sedigh Haghighat,Isidore Rigoutsos,Greg Gonye,Bruce M. Boman
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2017-05-10
卷期号:77 (14): 3778-3790
被引量:18
标识
DOI:10.1158/0008-5472.can-16-2388
摘要
Abstract Malignant transformation of tissue stem cells (SC) may be the root of most cancer. Accordingly, we identified miRNA expression patterns in the normal human colonic SC niche to understand how cancer stem cells (CSC) may arise. In profiling miRNA expression in SC-enriched crypt subsections isolated from fresh, normal surgical specimens, we identified 16 miRNAs that were differentially expressed in the crypt bottom, creating an SC signature for normal colonic epithelia (NCE). A parallel analysis of colorectal cancer tissues showed differential expression of 83 miRNAs relative to NCE. Within the 16 miRNA signature for the normal SC niche, we found that miR-206, miR-007-3, and miR-23b individually could distinguish colorectal cancer from NCE. Notably, miR-23b, which was increased in colorectal cancer, was predicted to target the SC-expressed G protein-coupled receptor LGR5. Cell biology investigations showed that miR-23b regulated CSC phenotypes globally at the level of proliferation, cell cycle, self-renewal, epithelial–mesenchymal transition, invasion, and resistance to the colorectal cancer chemotherapeutic agent 5-fluorouracil. In mechanistic experiments, we found that miR-23b decreased LGR5 expression and increased ALDH+ CSCs. CSC analyses confirmed that levels of LGR5 and miR-23b are inversely correlated in ALDH+ CSCs and that distinct subpopulations of LGR5+ and ALDH+ CSCs exist. Overall, our results define a critical function for miR-23b, which, by targeting LGR5, contributes to overpopulation of ALDH+ CSCs and colorectal cancer. Cancer Res; 77(14); 3778–90. ©2017 AACR.
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