We are using cell culture and mouse models to understand the role of gammaherpesviruses in the pathogenesis of lung adenocarcinoma.
IL-17 promotes lung tumorigenesis. Known human lung carcinogens including tobacco smoke, asbestos and silica establish aT helper 17 (Th17) inflammatory environment in the lung. Consistent with this observation, our published findings showed that overexpression of IL-17A (the hallmark cytokine of Th17 inflammation) in the lungs of mice promotes inflammation and accelerates the growth of lung tumors. In cell culture, treatment of murine lung tumor cells with IL-17 enhanced expression of tumorigenic mediators by altering the association of SRSF1, a mRNA splicing factor, with target mRNAs.
Gammaherpesviruses and Th17 inflammation. In southeast Asia, a high prevalence of lung adenocarcinoma in never smokers is coincident geographically with a strong association between the gammaherpesvirus, Epstein-Barr virus (EBV), and nasopharyngeal carcinoma. This correlation prompted us to ask if EBV hasa similar tumor promoting role in lung adenocarcinoma. We showed that lung delivery of a recombinant adenovirus that expresses Zta (Ad-Zta), the transcriptional activator of EBVlytic replication, induced Th17 inflammation. In accord, infection of lung epithelial cells with Ad-Zta induced the expression of mRNAs encoding the 2 subunits of IL-23, a central upstream Th17 cytokine. Moreover, the genomes of some gammaherpesviruses encode Th17 cytokines, suggesting that Th17 inflammation may be integral to gammaherpesvirus replication. Recent literature demonstrated that IL-17A reactivated EBV in cells latently infected with the virus. The association of Th17inflammation with the pathogenesis of both lung cancer and gamma-herpesviruses supports our premise that Th17 inflammation induced by gammaherpesvirus infection/reactivation promotes lung tumorigenesis. To test this relationship, we model K-Ras-driven lung adenocarcinoma in mice (K-RasLA1mice) and determine whether gammaherpesvirus MHV68 infection/reactivation elicits Th17 cytokine production and exacerbates disease progression. Our preliminary findings are consistent with our postulate that gammaherpesvirus infection elicits Th17 cytokine production that incidentally favors lung tumorigenesis.
ORCID identifier
0000-0002-4540-8099
MyNCBI Link
Selected Publications
Morris, G.F., Price, D.H. and Marzluff, W.F. Synthesis of U1 RNA in a DNA-dependent system from sea urchin embryos. Proceedings of the National Academy of Sciences USA 83: 3674-3678 (1986). PMID: 3459149
Morris, G.F. and Mathews, M.B. Regulation of proliferating cell nuclear antigen during the cell cycle. Journal of Biological Chemistry 264: 13856-13864 (1989). PMID: 2569465
Morris, G.F., Bischoff, J.R., and Mathews, M.B. Transcriptional activation of the human proliferating cell nuclear antigen promoter by p53. Proceedings of the National Academy of Sciences 93: 895-899 (1996). PMID: 8570655
Xu, J. and Morris, G.F. p53-mediated regulation of proliferating cell nuclear antigen (PCNA) expression in cells exposed to ionizing radiation. Molecular and Cellular Biology 19:12-20 (1999). PMID: 9858527
Shan, B., Xu, J., Zhuo, Y., Morris, C.A. and Morris, G.F. Induction of p53-dependentactivation of the human PCNA gene in chromatin by ionizing radiation. Journal of Biological Chemistry 278,44009-44017 (2003). PMID: 12947108
Ghosh, S., Mendoza, T., Ortiz, L.A., Hoyle, G.W., Fermin, C.D., Brody, A.R., Friedman, M. and Morris, G.F. Enhanced bleomycin sensitivity in mice expressing dominant negative p53 from the surfactant protein C promoter. American Journal of Respiratory and Critical Care Medicine 166: 890-897 (2002). PMID: 12231503
Xu, B., Guenther, J.F., Pociask, D.A., Wang, Y., Kolls, J.K., You, Z., Shan, B., Sullivan, D.E., Morris, G.F. Promotion of lung tumor growth by interleukin-17. American Journal of Physiology, Lung Cellular and Molecular Physiology 307(6):L497-508 (2014). PMID: 25038189
Morris, G. F., S. Danchuk, Y. Wang, B. Xu, R. J. Rando, A. R. Brody, B. Shan and D. E. Sullivan. Cigarette smoke represses the innate immune response to asbestos. Physiol Rep 3(12), (2015). PMID: 26660560
Kheir, F.,M. Zhao, M. J. Strong, Y. Yu, A. Nanbo, E. K. Flemington, G. F. Morris, K. Reiss, L. Li and Z. Lin (2019). "Detection of Epstein-Barr Virus Infectionin Non-Small Cell Lung Cancer." Cancers (Basel) 11(6). PMID:31159203.
Liu, Y. Z., C. A. Miller, Y. Zhuang,S. S. Mukhopadhyay, S. Saito, E. B. Overton and G. F. Morris (2020). "The Impact of the Deepwater Horizon Oil Spill upon Lung Health-Mouse Model-BasedRNA-Seq Analyses." Int J Environ Res Public Health 17(15) PMID: 32751227.
“Topics” (Keywords/Tags)
Gammaherpesvirus
Lung adenocarcinoma
Mutant K-Ras
Type 3inflammation
Myeloid-derived Suppressor Cells
MHV68
IL-17
Th17inflammation
Epstein-Barr virus
Mouse lung tumor model
mK-Ras-LE cells
Link to lab website:
