title: Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells.
abstract: Expression of the Wnt target gene phospholipase D1 (PLD1) is up-regulated in various carcinomas, including colorectal cancer (CRC). However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological targeting of PLD1 disrupts spontaneous and colitis-associated intestinal tumorigenesis in Apc(Min/+) and azoxymethane/dextran sodium sulfate mice models. Intestinal epithelial cell-specific PLD1 overexpression in Apc(Min/+) mice accelerated tumorigenesis with increased proliferation and nuclear β-catenin levels compared with Apc(Min/+) mice. Moreover, PLD1 inactivation suppressed the self-renewal capacity of colon cancer-initiating cells (CC-ICs) by decreasing expression of β-catenin via E2F1-induced microRNA (miR)-4496 up-regulation. Ultimately, low expression of PLD1 coupled with a low level of CC-IC markers was predictive of a good prognosis in CRC patients, suggesting in vivo relevance. Collectively, our data reveal that PLD1 has a crucial role in intestinal tumorigenesis via its modulation of the E2F1-miR-4496-β-catenin signaling pathway. Modulation of PLD1 expression and activity represents a promising therapeutic strategy for the treatment of intestinal tumorigenesis.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Dong Woo
authors.initials: DW
authors.lastname: Kang
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Chi Yeol
authors.initials: CY
authors.lastname: Choi
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, and Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Cho
authors.affiliation: Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Huasong
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, and Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea Department of Biotechnology, College of Life Science and Biotechnology, and Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea Department of Biotechnology, College of Life Science and Biotechnology, and Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea minds@pusan.ac.kr.
authors.forename: Do Sik
authors.initials: do S
authors.lastname: Min
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001397:Azoxymethane; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D016264:Dextran Sulfate; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010739:Phospholipase D / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D046888:Tissue Array Analysis; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C000622117:MIRN4496 microRNA, human; D035683:MicroRNAs; D051176:beta Catenin; D016264:Dextran Sulfate; D010739:Phospholipase D; C106801:phospholipase D1; D001397:Azoxymethane