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LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7

The RNA-binding proteins LIN28A and LIN28B have diverse functions in embryonic stem cells, cellular reprogramming, growth, and oncogenesis. Many of these effects occur via direct inhibition of Let-7 microRNAs (miRNAs), although Let-7-independent effects have been surmised. We report that intestine t...

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Autores principales: Madison, Blair B., Liu, Qi, Zhong, Xue, Hahn, Christopher M., Lin, Nan, Emmett, Matthew J., Stanger, Ben Z., Lee, Ju-Seog, Rustgi, Anil K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814644/
https://www.ncbi.nlm.nih.gov/pubmed/24142874
http://dx.doi.org/10.1101/gad.224659.113
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author Madison, Blair B.
Liu, Qi
Zhong, Xue
Hahn, Christopher M.
Lin, Nan
Emmett, Matthew J.
Stanger, Ben Z.
Lee, Ju-Seog
Rustgi, Anil K.
author_facet Madison, Blair B.
Liu, Qi
Zhong, Xue
Hahn, Christopher M.
Lin, Nan
Emmett, Matthew J.
Stanger, Ben Z.
Lee, Ju-Seog
Rustgi, Anil K.
author_sort Madison, Blair B.
collection PubMed
description The RNA-binding proteins LIN28A and LIN28B have diverse functions in embryonic stem cells, cellular reprogramming, growth, and oncogenesis. Many of these effects occur via direct inhibition of Let-7 microRNAs (miRNAs), although Let-7-independent effects have been surmised. We report that intestine targeted expression of LIN28B causes intestinal hypertrophy, crypt expansion, and Paneth cell loss. Furthermore, LIN28B fosters intestinal polyp and adenocarcinoma formation. To examine potential Let-7-independent functions of LIN28B, we pursued ribonucleoprotein cross-linking, immunoprecipitation, and high-throughput sequencing (CLIP-seq) to identify direct RNA targets. This revealed that LIN28B bound a substantial number of mRNAs and modestly augmented protein levels of these target mRNAs in vivo. Conversely, Let-7 had a profound effect; modulation of Let-7 levels via deletion of the mirLet7c2/mirLet7b genes recapitulated effects of Lin28b overexpression. Furthermore, intestine-specific Let-7 expression could reverse hypertrophy and Paneth cell depletion caused by Lin28b. This was independent of effects on insulin–PI3K–mTOR signaling. Our study reveals that Let-7 miRNAs are critical for repressing intestinal tissue growth and promoting Paneth cell differentiation. Let-7-dependent effects of LIN28B may supersede Let-7-independent effects on intestinal tissue growth. In summary, LIN28B can definitively act as an oncogene in the absence of canonical genetic alterations.
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spelling pubmed-38146442014-04-15 LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7 Madison, Blair B. Liu, Qi Zhong, Xue Hahn, Christopher M. Lin, Nan Emmett, Matthew J. Stanger, Ben Z. Lee, Ju-Seog Rustgi, Anil K. Genes Dev Research Paper The RNA-binding proteins LIN28A and LIN28B have diverse functions in embryonic stem cells, cellular reprogramming, growth, and oncogenesis. Many of these effects occur via direct inhibition of Let-7 microRNAs (miRNAs), although Let-7-independent effects have been surmised. We report that intestine targeted expression of LIN28B causes intestinal hypertrophy, crypt expansion, and Paneth cell loss. Furthermore, LIN28B fosters intestinal polyp and adenocarcinoma formation. To examine potential Let-7-independent functions of LIN28B, we pursued ribonucleoprotein cross-linking, immunoprecipitation, and high-throughput sequencing (CLIP-seq) to identify direct RNA targets. This revealed that LIN28B bound a substantial number of mRNAs and modestly augmented protein levels of these target mRNAs in vivo. Conversely, Let-7 had a profound effect; modulation of Let-7 levels via deletion of the mirLet7c2/mirLet7b genes recapitulated effects of Lin28b overexpression. Furthermore, intestine-specific Let-7 expression could reverse hypertrophy and Paneth cell depletion caused by Lin28b. This was independent of effects on insulin–PI3K–mTOR signaling. Our study reveals that Let-7 miRNAs are critical for repressing intestinal tissue growth and promoting Paneth cell differentiation. Let-7-dependent effects of LIN28B may supersede Let-7-independent effects on intestinal tissue growth. In summary, LIN28B can definitively act as an oncogene in the absence of canonical genetic alterations. Cold Spring Harbor Laboratory Press 2013-10-15 /pmc/articles/PMC3814644/ /pubmed/24142874 http://dx.doi.org/10.1101/gad.224659.113 Text en © 2013 Madison et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
spellingShingle Research Paper
Madison, Blair B.
Liu, Qi
Zhong, Xue
Hahn, Christopher M.
Lin, Nan
Emmett, Matthew J.
Stanger, Ben Z.
Lee, Ju-Seog
Rustgi, Anil K.
LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7
title LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7
title_full LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7
title_fullStr LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7
title_full_unstemmed LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7
title_short LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7
title_sort lin28b promotes growth and tumorigenesis of the intestinal epithelium via let-7
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814644/
https://www.ncbi.nlm.nih.gov/pubmed/24142874
http://dx.doi.org/10.1101/gad.224659.113
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