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Nat Commun. 2015 Aug 3;6:7839. doi: 10.1038/ncomms8839.

Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers.

Author information

1
Department of Molecular Microbiology and Immunology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
2
Department of Radiology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.
3
Key Laboratory of Carcinogenesis and Translational Research, Department of Colorectal Surgery, Peking University Cancer Hospital &Institute, Beijing 100142, China.
4
Department of Surgical Oncology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
5
Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40506, USA.
6
Department of Pathology, Keck Medical School, University of Southern California, Los Angeles, California 90033, USA.

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.

PMID:
26234763
PMCID:
PMC4526116
DOI:
10.1038/ncomms8839
[Indexed for MEDLINE]
Free PMC Article

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