HPV 16 E6/E7 up-regulate the expression of both HIF-1α and GLUT1 by inhibition of RRAD and activation of NF-κB in lung cancer cells

Gu, Na-Jin; Wu, Ming-Zhe; He, Ling; Wang, Xu-Bo; Wang, Shiyu; Qiu, Xue-Shan; Wang, En-Hua; Wu, Guang-Ping

doi:10.7150/jca.37070



International Journal of Biological Sciences

International Journal of Medical Sciences

Theranostics

Journal of Genomics

Nanotheranostics

Global reach, higher impact

Full Text | PDF

J Cancer 2019; 10(27):6903-6909. doi:10.7150/jca.37070 This issue Cite

Research Paper

HPV 16 E6/E7 up-regulate the expression of both HIF-1α and GLUT1 by inhibition of RRAD and activation of NF-κB in lung cancer cells

Na-Jin Gu¹, Ming-Zhe Wu², Ling He¹, Xu-Bo Wang¹, Shiyu Wang³, Xue-Shan Qiu¹, En-Hua Wang¹, Guang-Ping Wu^1✉

1. Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang 110001, China
2. Department of Gynecology, The First Hospital of China Medical University, Shenyang 110001, China
3. Geisinger Commonwealth School of Medicine; Scranton, PA18510, USA

Citation:

Gu NJ, Wu MZ, He L, Wang XB, Wang S, Qiu XS, Wang EH, Wu GP. HPV 16 E6/E7 up-regulate the expression of both HIF-1α and GLUT1 by inhibition of RRAD and activation of NF-κB in lung cancer cells. J Cancer 2019; 10(27):6903-6909. doi:10.7150/jca.37070. https://www.jcancer.org/v10p6903.htm

Other styles

Abstract

Chronic infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. In our previous studies, we found that HPV16 E6/E7 up-regulated HIF-1α at protein level and further up-regulated GLUT1 at both protein and mRNA levels in well-established lung cancer cell lines. In one of our further mechanism study, the results demonstrated that HPV16 E6/E7 up-regulated the expression of GLUT1 through HPV-LKB1-HIF-1α-GLUT1 axis. However, there are multiple pathways involved in HPV16 E6/E7 regulation of HIF-1α expression. In current study, using double directional genetic manipulation in well-established lung cancer cell lines, we showed that both E6 and E7 down-regulated the expression of RRAD at both protein and mRNA levels. Like LKB1, RRAD is one of the cancer suppressor genes. The loss of RRAD further activated NF-κB by promoted cytoplasmic p65 translocated to nucleus, and up-regulated the expression level of the p-p65 in nucleus. Furthermore, p-p65 up regulated HIF-1α and GLUT1 at both protein and mRNA levels. Thus, we proposed HPV16 E6/E7 up-regulated the expression of GLUT1 through HPV-RRAD-p65- HIF-1α- GLUT1 axis. In conclusion, we demonstrated for the first time that E6 and E7 promoted the expression of HIF-1α and GLUT1 by relieving the inhibitory effect of RRAD which resulted in the activation of NF-κB by promoting cytoplasmic p65 translocated to nucleus, and up-regulated the expression of the p-p65 in nucleus in lung cancer cells. Our findings provided new evidence to support the critical role of RRAD in the pathogenesis of HPV-related lung cancer, and suggested novel therapeutic targets.

Keywords: Human papillomavirus (HPV), Ras-related associated with diabetes (RRAD), NF-κB, Hypoxia- inducible factor 1α (HIF-1α), glucose transporter 1 (GLUT1)

Citation styles

APA

Gu, N.J., Wu, M.Z., He, L., Wang, X.B., Wang, S., Qiu, X.S., Wang, E.H., Wu, G.P. (2019). HPV 16 E6/E7 up-regulate the expression of both HIF-1α and GLUT1 by inhibition of RRAD and activation of NF-κB in lung cancer cells. Journal of Cancer, 10(27), 6903-6909. https://doi.org/10.7150/jca.37070.

ACS

Gu, N.J.; Wu, M.Z.; He, L.; Wang, X.B.; Wang, S.; Qiu, X.S.; Wang, E.H.; Wu, G.P. HPV 16 E6/E7 up-regulate the expression of both HIF-1α and GLUT1 by inhibition of RRAD and activation of NF-κB in lung cancer cells. J. Cancer 2019, 10 (27), 6903-6909. DOI: 10.7150/jca.37070.

NLM

CSE

Gu NJ, Wu MZ, He L, Wang XB, Wang S, Qiu XS, Wang EH, Wu GP. 2019. HPV 16 E6/E7 up-regulate the expression of both HIF-1α and GLUT1 by inhibition of RRAD and activation of NF-κB in lung cancer cells. J Cancer. 10(27):6903-6909.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.