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Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma

Fusion genes have been identified as oncogenes in several solid tumors including lung, colorectal, and stomach cancers. Here, we characterized the fusion gene, VAPA-Rab31, discovered from RNA-sequencing data of a patient with lung adenocarcinoma who did not harbor activating mutations in EGFR, KRAS...

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Autores principales: Yoon, Daseul, Bae, Kieun, Kim, Jin-Hee, Choi, Yang-Kyu, Yoon, Kyong-Ah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539523/
https://www.ncbi.nlm.nih.gov/pubmed/31083279
http://dx.doi.org/10.3390/ijms20092309
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author Yoon, Daseul
Bae, Kieun
Kim, Jin-Hee
Choi, Yang-Kyu
Yoon, Kyong-Ah
author_facet Yoon, Daseul
Bae, Kieun
Kim, Jin-Hee
Choi, Yang-Kyu
Yoon, Kyong-Ah
author_sort Yoon, Daseul
collection PubMed
description Fusion genes have been identified as oncogenes in several solid tumors including lung, colorectal, and stomach cancers. Here, we characterized the fusion gene, VAPA-Rab31, discovered from RNA-sequencing data of a patient with lung adenocarcinoma who did not harbor activating mutations in EGFR, KRAS and ALK. This fusion gene encodes a protein comprising the N-terminal region of vesicle-associated membrane protein (VAMP)-associated protein A (VAPA) fused to the C-terminal region of Ras-related protein 31 (Rab31). Exogenous expression of VAPA-Rab31 in immortalized normal bronchial epithelial cells demonstrated the potential transforming effects of this fusion gene, including increased colony formation and cell proliferation in vitro. Also, enhanced tumorigenicity upon VAPA-Rab31 was confirmed in vivo using a mouse xenograft model. Metastatic tumors were also detected in the liver and lungs of xenografted mice. Overexpression of VAPA-Rab31 upregulated anti-apoptotic protein Bcl-2 and phosphorylated CREB both in cells and xenograft tumors. Reduced apoptosis and increased phosphorylation of CREB and Erk were observed in VAPA-Rab31-overexpressing cells after bortezomib treatment. Elevated Bcl-2 level via activated CREB contributed to the resistance to the bortezomib-induced apoptosis. Our data suggest the oncogenic function of the novel fusion gene VAPA-Rab31 via upregulated Bcl-2 and activated CREB in lung cancer.
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spelling pubmed-65395232019-06-04 Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma Yoon, Daseul Bae, Kieun Kim, Jin-Hee Choi, Yang-Kyu Yoon, Kyong-Ah Int J Mol Sci Article Fusion genes have been identified as oncogenes in several solid tumors including lung, colorectal, and stomach cancers. Here, we characterized the fusion gene, VAPA-Rab31, discovered from RNA-sequencing data of a patient with lung adenocarcinoma who did not harbor activating mutations in EGFR, KRAS and ALK. This fusion gene encodes a protein comprising the N-terminal region of vesicle-associated membrane protein (VAMP)-associated protein A (VAPA) fused to the C-terminal region of Ras-related protein 31 (Rab31). Exogenous expression of VAPA-Rab31 in immortalized normal bronchial epithelial cells demonstrated the potential transforming effects of this fusion gene, including increased colony formation and cell proliferation in vitro. Also, enhanced tumorigenicity upon VAPA-Rab31 was confirmed in vivo using a mouse xenograft model. Metastatic tumors were also detected in the liver and lungs of xenografted mice. Overexpression of VAPA-Rab31 upregulated anti-apoptotic protein Bcl-2 and phosphorylated CREB both in cells and xenograft tumors. Reduced apoptosis and increased phosphorylation of CREB and Erk were observed in VAPA-Rab31-overexpressing cells after bortezomib treatment. Elevated Bcl-2 level via activated CREB contributed to the resistance to the bortezomib-induced apoptosis. Our data suggest the oncogenic function of the novel fusion gene VAPA-Rab31 via upregulated Bcl-2 and activated CREB in lung cancer. MDPI 2019-05-10 /pmc/articles/PMC6539523/ /pubmed/31083279 http://dx.doi.org/10.3390/ijms20092309 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yoon, Daseul
Bae, Kieun
Kim, Jin-Hee
Choi, Yang-Kyu
Yoon, Kyong-Ah
Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma
title Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma
title_full Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma
title_fullStr Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma
title_full_unstemmed Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma
title_short Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma
title_sort oncogenic effect of the novel fusion gene vapa-rab31 in lung adenocarcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539523/
https://www.ncbi.nlm.nih.gov/pubmed/31083279
http://dx.doi.org/10.3390/ijms20092309
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