PMID- 24142874
OWN - NLM
STAT- MEDLINE
DCOM- 20131213
LR  - 20211021
IS  - 1549-5477 (Electronic)
IS  - 0890-9369 (Print)
IS  - 0890-9369 (Linking)
VI  - 27
IP  - 20
DP  - 2013 Oct 15
TI  - LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7.
PG  - 2233-45
LID - 10.1101/gad.224659.113 [doi]
AB  - 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.
FAU - Madison, Blair B
AU  - Madison BB
AD  - Division of Gastroenterology, University of Pennsylvania Perelman School of 
      Medicine, Philadelphia, Pennsylvania 19104, USA;
FAU - Liu, Qi
AU  - Liu Q
FAU - Zhong, Xue
AU  - Zhong X
FAU - Hahn, Christopher M
AU  - Hahn CM
FAU - Lin, Nan
AU  - Lin N
FAU - Emmett, Matthew J
AU  - Emmett MJ
FAU - Stanger, Ben Z
AU  - Stanger BZ
FAU - Lee, Ju-Seog
AU  - Lee JS
FAU - Rustgi, Anil K
AU  - Rustgi AK
LA  - eng
GR  - P50 CA095103/CA/NCI NIH HHS/United States
GR  - P30 DK050306/DK/NIDDK NIH HHS/United States
GR  - DK083111/DK/NIDDK NIH HHS/United States
GR  - R01 DK056645/DK/NIDDK NIH HHS/United States
GR  - K01DK093885/DK/NIDDK NIH HHS/United States
GR  - K01 DK093885/DK/NIDDK NIH HHS/United States
GR  - DP2 DK083111/DK/NIDDK NIH HHS/United States
GR  - P30 CA068485/CA/NCI NIH HHS/United States
GR  - P30 CA016520/CA/NCI NIH HHS/United States
GR  - DK083355/DK/NIDDK NIH HHS/United States
GR  - P30-DK050306/DK/NIDDK NIH HHS/United States
GR  - R01 DK083355/DK/NIDDK NIH HHS/United States
GR  - R01-DK056645/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Genes Dev
JT  - Genes & development
JID - 8711660
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Lin28b protein, mouse)
RN  - 0 (MicroRNAs)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (mirnlet7 microRNA, mouse)
SB  - IM
MH  - Animals
MH  - Carcinogenesis/*genetics
MH  - Cell Differentiation
MH  - DNA-Binding Proteins/*genetics/metabolism
MH  - *Gene Expression Regulation
MH  - Intestinal Mucosa/cytology/growth & 
      development/metabolism/pathology/*physiopathology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - MicroRNAs/*genetics/metabolism
MH  - Paneth Cells/cytology
MH  - Protein Binding
MH  - Protein Biosynthesis
MH  - RNA, Messenger/metabolism
MH  - RNA-Binding Proteins
MH  - Signal Transduction
PMC - PMC3814644
OTO - NOTNLM
OT  - CLIP-seq
OT  - LIN28B
OT  - Let-7
OT  - Paneth cells
OT  - colon cancer
OT  - intestinal epithelium
EDAT- 2013/10/22 06:00
MHDA- 2013/12/18 06:00
PMCR- 2014/04/15
CRDT- 2013/10/22 06:00
PHST- 2013/10/22 06:00 [entrez]
PHST- 2013/10/22 06:00 [pubmed]
PHST- 2013/12/18 06:00 [medline]
PHST- 2014/04/15 00:00 [pmc-release]
AID - 27/20/2233 [pii]
AID - 10.1101/gad.224659.113 [doi]
PST - ppublish
SO  - Genes Dev. 2013 Oct 15;27(20):2233-45. doi: 10.1101/gad.224659.113.