Upregulation of polycistronic microRNA-143 and microRNA-145 in colonocytes suppresses colitis and inflammation-associated colon cancer

Urszula Dougherty, Reba Mustafi, Hongyan Zhu, Xiaorong Zhu, Dilip Deb, Stephen C. Meredith, Fatma Ayaloglu-Butun, Michelle Fletcher, Arantxa Sanchez, Joel Pekow, Zifeng Deng, Nader Amini, Vani J. Konda, Vijaya L. Rao, Atsushi Sakuraba, Akushika Kwesi, Sonia S. Kupfer, Alessandro Fichera, Loren Joseph, John HartFang He, Tong Chuan He, Diana West-Szymanski, Yan Chun Li, Marc Bissonnette*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Because ADAM17 promotes colonic tumorigenesis, we investigated potential miRNAs regulating ADAM17; and examined effects of diet and tumorigenesis on these miRNAs. We also examined pre-miRNA processing and tumour suppressor roles of several of these miRNAs in experimental colon cancer. Using TargetScan, miR-145, miR-148a, and miR-152 were predicted to regulate ADAM17. miR-143 was also investigated as miR-143 and miR-145 are co-transcribed and associated with decreased tumour growth. HCT116 colon cancer cells (CCC) were co-transfected with predicted ADAM17-regulating miRNAs and luciferase reporters controlled by ADAM17-3’UTR. Separately, pre-miR-143 processing by colonic cells was measured. miRNAs were quantified by RT-PCR. Tumours were induced with AOM/DSS in WT and transgenic mice (Tg) expressing pre-miR-143/miR-145 under villin promoter. HCT116 transfection with miR-145, −148a or −152, but not scrambled miRNA inhibited ADAM17 expression and luciferase activity. The latter was suppressed by mutations in ADAM17-3’UTR. Lysates from colonocytes, but not CCC, processed pre-miR-143 and mixing experiments suggested CCC lacked a competency factor. Colonic miR-143, miR-145, miR-148a, and miR-152 were downregulated in tumours and more moderately by feeding mice a Western diet. Tg mice were resistant to DSS colitis and had significantly lower cancer incidence and tumour multiplicity. Tg expression blocked up-regulation of putative targets of miR-143 and miR-145, including ADAM17, K-Ras, XPO5, and SET. miR-145, miR-148a, and miR-152 directly suppress colonocyte ADAM17 and are down-regulated in colon cancer. This is the first direct demonstration of tumour suppressor roles for miR-143 and miR-145 in an in vivo model of colonic tumorigenesis.

Original languageEnglish (US)
JournalEpigenetics
DOIs
StateAccepted/In press - 2020

Keywords

  • DSS colitis
  • azoxymethane
  • colon cancer
  • miR-143/miR-145

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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