Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma
College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea
College of Health Science, Cheongju University, Cheongju 28503, Korea
Author to whom correspondence should be addressed.
These authors are equally contributed to this work.
Int. J. Mol. Sci. 2019, 20(9), 2309; https://doi.org/10.3390/ijms20092309
Received: 25 April 2019 / Revised: 8 May 2019 / Accepted: 8 May 2019 / Published: 10 May 2019
(This article belongs to the Special Issue Molecular Pathology of Lung and Thoracic Cancers)
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.