Dataset Information

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.

SUBMITTER: He S

PROVIDER: S-EPMC4526116 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

He Shanshan S Zhao Zhen Z Yang Yongfei Y O'Connell Douglas D Zhang Xiaowei X Oh Soohwan S Ma Binyun B Lee Joo-Hyung JH Zhang Tian T Varghese Bino B Yip Janae J Dolatshahi Pirooz Sara S Li Ming M Zhang Yong Y Li Guo-Min GM Ellen Martin Sue S Machida Keigo K Liang Chengyu C

Nature communications 20150803

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 ...[more]

PMID: 26234763

Similar Datasets

Project description:BackgroundAnti-EGFR antibody-based treatment is an important therapeutic strategy for advanced colorectal cancer (CRC); despite this, several mutations--including KRAS, BRAF, and PIK3CA mutations, and HER2 amplification--are associated with the mechanisms underlying the development of resistance to anti-EGFR therapy. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC.MethodsKRAS, BRAF, and PIK3CA mutations were determined by Cobas real-time polymerase chain reaction (PCR) in 191 advanced CRC patients with distant metastasis. Microsatellite instability (MSI) status was determined by a fragmentation assay and HER2 amplification was assessed by silver in situ hybridization. In addition, KRAS mutations were investigated by the Sanger sequencing method in 97 of 191 CRC cases.ResultsMutations in KRAS, BRAF, and PIK3CA were found in 104 (54.5%), 6 (3.1%), and 25 (13.1%) cases of advanced CRC, respectively. MSI-high status and HER2 amplification were observed in 3 (1.6%) and 16 (8.4%) cases, respectively. PIK3CA mutations were more frequently found in KRAS mutant type (18.3%) than KRAS wild type (6.9%) (P = 0.020). In contrast, HER2 amplifications and BRAF mutations were associated with KRAS wild type with borderline significance (P = 0.052 and 0.094, respectively). In combined analyses with KRAS, BRAF and HER2 status, BRAF mutations or HER2 amplifications were associated with the worst prognosis in the wild type KRAS group (P = 0.004). When comparing the efficacy of detection methods, the results of real time PCR analysis revealed 56 of 97 (57.7%) CRC cases with KRAS mutations, whereas Sanger sequencing revealed 49 cases (50.5%).ConclusionsKRAS mutations were found in 54.5% of advanced CRC patients. Our results support that subgrouping using PIK3CA and BRAF mutation or HER2 amplification status, in addition to KRAS mutation status, is helpful for managing advanced CRC patients.

Project description:Background:Glioma is a prevalent disease of the central nervous system with a high incidence and mortality rate. Many long noncoding RNAs (lncRNAs) have been determined to be critical regulators of glioma oncogenesis. However, the function and mechanism of LINC00963 in glioma have not been fully elucidated. Methods:The expression level of RNA was determined by qRT-PCR, and the protein level was determined by Western blot analysis. A luciferase activity assay was conducted to verify the interaction between miRNA and lncRNA or the target gene. The proliferation, cell cycle distribution, invasion, and migration were evaluated by MTT, EdU, flow cytometry, wound-healing and Transwell invasion assays, respectively. In vivo tumor growth was evaluated in a xenograft nude mouse model. Results:We found that LINC00963 was upregulated in glioma cells and tissues and associated with the poor prognosis of patients with glioma. Ectopic expression of LINC00963 promoted cell proliferation, cell cycle progression, migration, and invasion in vitro and tumorigenesis in vivo. Mechanistically, the results of luciferase activity and RNA pulldown assays validated that LINC00963 could act as a molecular sponge of miR-506. Reciprocal repression was found between LINC00963 and miR-506. In addition, BCAT1 was identified as a target of miR-506, and both the mRNA and protein levels of BCAT1 were reduced by miR-506. In tumor tissues, the expression of BCAT1 was negatively and positively correlated with miR-506 and LINC00963 expression, respectively. The reintroduction of BCAT1 in glioma cells abolished the tumor suppressive function of miR-506 by promoting cell viability and motility. The upregulated LINC00963 and BCAT1 were associated with the aggressive phenotypes of tumors. Conclusion:Our data revealed that LINC00963 confers oncogenic function in the progression of glioma and that the LINC00963/miR-506/BCAT1 axis may be a novel mechanism and therapeutic strategy for this disease.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets