Upregulation of BMI1-suppressor miRNAs (miR-200c, miR-203) during terminal differentiation of colon epithelial cells

Shigeo Hisamori, Junko Mukohyama, Sanjay Koul, Takanori Hayashi, Michael Evan Rothenberg, Masao Maeda, Taichi Isobe, Luis Enrique Valencia Salazar, Xin Qian, Darius Michael Johnston, Dalong Qian, Kaiqin Lao, Naoya Asai, Yoshihiro Kakeji, Vincenzo Alessandro Gennarino, Debashis Sahoo, Piero Dalerba, Yohei Shimono

Research output: Contribution to journalArticlepeer-review

Abstract

Background: MicroRNAs (miRNAs) are key regulators of stem cell functions, including self-renewal and differentiation. In this study, we aimed to identify miRNAs that are upregulated during terminal differentiation in the human colon epithelium, and elucidate their role in the mechanistic control of stem cell properties. Methods: “Bottom-of-the-crypt” (EPCAM+/CD44+/CD66alow) and “top-of-the-crypt” (EPCAM+/CD44neg/CD66ahigh) epithelial cells from 8 primary colon specimens (6 human, 2 murine) were purified by flow cytometry and analyzed for differential expression of 335 miRNAs. The miRNAs displaying the highest upregulation in “top-of-the-crypt” (terminally differentiated) epithelial cells were tested for positive correlation and association with survival outcomes in a colon cancer RNA-seq database (n = 439 patients). The two miRNAs with the strongest “top-of-the-crypt” expression profile were evaluated for capacity to downregulate self-renewal effectors and inhibit in vitro proliferation of colon cancer cells, in vitro organoid formation by normal colon epithelial cells and in vivo tumorigenicity by patient-derivedxenografts (PDX). Results: Six miRNAs (miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-345) were upregulated in “top-of-the-crypt” cells and positively correlated in expression among colon carcinomas. Overexpression of the three miRNAs with the highest inter-correlation coefficients (miR-200a, miR-200b, miR-200c) associated with improved survival. The top two over-expressed miRNAs (miR-200c, miR-203) cooperated synergistically in suppressing expression of BMI1, a key regulator of self-renewal in stem cell populations, and in inhibiting proliferation, organoid-formation and tumorigenicity of colon epithelial cells. Conclusion: In the colon epithelium, terminal differentiation associates with the coordinated upregulation of miR-200c and miR-203, which cooperate to suppress BMI1 and disable the expansion capacity of epithelial cells.

Original languageEnglish
Pages (from-to)407-422
Number of pages16
JournalJournal of Gastroenterology
Volume57
Issue number6
DOIs
Publication statusPublished - 06-2022

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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