title: LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans.
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.
authors.affiliation: 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;
authors.forename: Ho-Chou
authors.initials: HC
authors.lastname: Tu
authors.affiliation: 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;
authors.forename: Sarah
authors.initials: S
authors.lastname: Schwitalla
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Qian
authors.affiliation: 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;
authors.forename: Grace S
authors.initials: GS
authors.lastname: LaPier
authors.affiliation: 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;
authors.forename: Alena
authors.initials: A
authors.lastname: Yermalovich
authors.affiliation: Thermo Fisher Scientific, Incorporated, South San Francisco, California 94080, USA;
authors.forename: Yuan-Chieh
authors.initials: YC
authors.lastname: Ku
authors.affiliation: Thermo Fisher Scientific, Incorporated, South San Francisco, California 94080, USA;
authors.forename: Shann-Ching
authors.initials: SC
authors.lastname: Chen
authors.affiliation: 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;
authors.forename: Srinivas R
authors.initials: SR
authors.lastname: Viswanathan
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas 75390, USA;
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inamura
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
authors.forename: Sun A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mima
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Sukawa
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
authors.forename: Juhong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Thermo Fisher Scientific, Incorporated, South San Francisco, California 94080, USA;
authors.forename: Gavin
authors.initials: G
authors.lastname: Meredith
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: 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;
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.affiliation: 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.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000230:Adenocarcinoma / Q000503:physiopathology*; D000818:Animals; D015179:Colorectal Neoplasms / Q000503:physiopathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: C488352:Lin-28 protein, mouse; C000715187:Lin28A protein, human; D016601:RNA-Binding Proteins; D051153:Wnt Proteins
keywords: LIN28; WNT; colorectal cancer; invasive adenocarcinoma; let-7 miRNA; oncogene cooperation