title: LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7.
abstract: 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.
authors.affiliation: Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Blair B
authors.initials: BB
authors.lastname: Madison
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Xue
authors.initials: X
authors.lastname: Zhong
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hahn
authors.forename: Nan
authors.initials: N
authors.lastname: Lin
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Emmett
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D007413:Intestinal Mucosa / Q000166:cytology / Q000254:growth & development / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D019879:Paneth Cells / Q000166:cytology; D011485:Protein Binding; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; C570876:Lin28b protein, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse
keywords: CLIP-seq; LIN28B; Let-7; Paneth cells; colon cancer; intestinal epithelium