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Genes Dev. 2015 May 15;29(10):1074-86. doi: 10.1101/gad.256693.114. Epub 2015 May 8.

LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans.

Author information

1
Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA; Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA; Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA;
2
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
3
Thermo Fisher Scientific, Incorporated, South San Francisco, California 94080, USA;
4
Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas 75390, USA;
5
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA; Harvard Medical School, Boston, Massachusetts 02115, USA; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA;
6
Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA; Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA; Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA; Howard Hughes Medical Institute, Boston, Massachusetts 02138, USA george.daley@childrens.harvard.edu.

Abstract

Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in Apc(Min/+) mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38% of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target.

KEYWORDS:

LIN28; WNT; colorectal cancer; invasive adenocarcinoma; let-7 miRNA; oncogene cooperation

PMID:
25956904
PMCID:
PMC4441054
DOI:
10.1101/gad.256693.114
[Indexed for MEDLINE]
Free PMC Article

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