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LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms

Abstract

Lin28b is an RNA-binding protein that inhibits biogenesis of let-7 microRNAs. LIN28B is overexpressed in diverse cancers, yet a specific role in the molecular pathogenesis of colon cancer has to be elucidated. We have determined that human colon tumors exhibit decreased levels of mature let-7 isoforms and increased expression of LIN28B. To determine LIN28B's mechanistic role in colon cancer, we expressed LIN28B in immortalized colonic epithelial cells and human colon cancer cell lines. We found that LIN28B promotes cell migration, invasion and transforms immortalized colonic epithelial cells. In addition, constitutive LIN28B expression increases expression of intestinal stem cell markers LGR5 and PROM1 in the presence of let-7 restoration. This may occur as a result of Lin28b protein binding LGR5 and PROM1 mRNA, suggesting that a subset of LIN28B functions is independent of its ability to repress let-7. Our findings establish a new role for LIN28B in human colon cancer pathogenesis, and suggest LIN28B post-transcriptionally regulates LGR5 and PROM1 through a let-7-independent mechanism.

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Acknowledgements

This work was supported by R01-DK056645 (AR, CK and PM). Hauser Foundation, National Colon Cancer Research Alliance (EIF) and American Cancer Society Research Professorship (AR). Catrina King is a Pfizer Animal Health scholarship recipient, a doctoral candidate in Biomedical Graduate Studies, and a student of the School of Veterinary Medicine at the University of Pennsylvania. We thank Dr Joshua Mendell for gifts of LIN28B expression vectors, as well as Ben Rhoades and Mark Bowser for technical assistance. We also acknowledge help from the NIH/NIDDK P30-DK050306 Center for Molecular Studies in Digestive and Liver Diseases and its Molecular Biology and Cell Culture Core Facilities and NIH U01-DK085551. Louise Wang was supported by an NIH ARRA student fellowship through the NIH P30 DK050306.

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Correspondence to A K Rustgi.

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King, C., Wang, L., Winograd, R. et al. LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms. Oncogene 30, 4185–4193 (2011). https://doi.org/10.1038/onc.2011.131

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