TY - JOUR
T1 - Upregulation of polycistronic microRNA-143 and microRNA-145 in colonocytes suppresses colitis and inflammation-associated colon cancer
AU - Dougherty, Urszula
AU - Mustafi, Reba
AU - Zhu, Hongyan
AU - Zhu, Xiaorong
AU - Deb, Dilip
AU - Meredith, Stephen C.
AU - Ayaloglu-Butun, Fatma
AU - Fletcher, Michelle
AU - Sanchez, Arantxa
AU - Pekow, Joel
AU - Deng, Zifeng
AU - Amini, Nader
AU - Konda, Vani J.
AU - Rao, Vijaya L.
AU - Sakuraba, Atsushi
AU - Kwesi, Akushika
AU - Kupfer, Sonia S.
AU - Fichera, Alessandro
AU - Joseph, Loren
AU - Hart, John
AU - He, Fang
AU - He, Tong Chuan
AU - West-Szymanski, Diana
AU - Li, Yan Chun
AU - Bissonnette, Marc
N1 - Funding Information:
Grant Support : This work was supported by the National Institutes of Health Grants [R01 CA164124-01 and R01 CA180087-01 (YCL), R01 CA226303 (TCH)] and the Samuel Freedman GI Cancer Laboratory Fund at the University of Chicago and the University of Chicago Cancer Research Foundation (UCCRF) Women’s Board. The transgenic mouse was created by The Transgenic Mouse Core at the University of Chicago that receives financial support from NIH NCI Cancer Center Support Grant P30CA014599.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - DSS colitis
KW - azoxymethane
KW - colon cancer
KW - miR-143/miR-145
UR - http://www.scopus.com/inward/record.url?scp=85098486094&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098486094&partnerID=8YFLogxK
U2 - 10.1080/15592294.2020.1863117
DO - 10.1080/15592294.2020.1863117
M3 - Article
C2 - 33356812
AN - SCOPUS:85098486094
JO - Epigenetics
JF - Epigenetics
SN - 1559-2294
ER -