An miRNA expression signature for the human colonic stem cell niche distinguishes malignant from normal epithelia

Malignant transformation of tissue stem cells may be the root of most cancer. Accordingly, we identified miRNA expression patterns in the normal human colonic stem cell (SC) niche to understand how cancer stem cells (CSCs) 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 a SC signature for normal colonic epithelia (NCE). A parallel analysis of colorectal cancer (CRC) tissues showed differential expression of 83 miRNAs relative to NCE. Within the 16 miRNA signature for the normal SC niche, we found that miRNA-206, miRNA-007-3 and miRNA-23b individually could distinguish CRC from NCE. Notably, miRNA-23b, which was increased in CRC, was predicted to target the SC-expressed G protein-coupled receptor LGR5. Cell biology investigations showed that miRNA-23b regulated CSC phenotypes globally at the level of proliferation, cell-cycle, self-renewal, EMT, invasion, and resistance to the CRC chemotherapeutic agent 5-FU. In mechanistic experiments we found that miRNA-23b decreased LGR5 expression and increased ALDH+ CSCs. CSC analyses confirmed that levels of LGR5 and miRNA-23b are inversely correlated in ALDH+ CSCs and that distinct sub-populations of LGR5+ and ALDH+ CSCs exist. Overall, our results define a critical function for miRNA-23b, which, by targeting LGR5, contributes to overpopulation of ALDH+ CSCs and CRC.

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