title: Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers.
abstract: Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAG(FS) in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAG(FS) abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAG(FS) can trigger CRC metastatic spread through Rac1 activation and epithelial-to-mesenchymal transition, independently of autophagy. Interestingly, UVRAG(FS) expression renders cells more sensitive to standard chemotherapy regimen due to a DNA repair defect. These results identify UVRAG as a new MSI target gene and provide a mechanism for UVRAG participation in CRC pathogenesis and treatment response.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: O'Connell
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Soohwan
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Binyun
authors.initials: B
authors.lastname: Ma
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Joo-Hyung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Radiology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Bino
authors.initials: B
authors.lastname: Varghese
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Janae
authors.initials: J
authors.lastname: Yip
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Dolatshahi Pirooz
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Department of Colorectal Surgery, Peking University Cancer Hospital &Institute, Beijing 100142, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Surgical Oncology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40506, USA.
authors.forename: Guo-Min
authors.initials: GM
authors.lastname: Li
authors.affiliation: Department of Pathology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Sue
authors.initials: S
authors.lastname: Ellen Martin
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001343:Autophagy / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D053842:Microsatellite Instability; D018613:Microscopy, Confocal; D008875:Middle Aged; D000066450:Mouse Embryonic Stem Cells; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D009368:Neoplasm Transplantation; D047368:Tumor Burden / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C107953:RAC1 protein, human; D025521:Tumor Suppressor Proteins; C408122:UVRAG protein, human; D020830:rac1 GTP-Binding Protein; D005472:Fluorouracil