HPV 16 E6/E7 Promote the Glucose Uptake of GLUT1 in Lung Cancer Through Downregulation of TXNIP Due to Inhibition of PTEN Phosphorylation.

Jia-Yi Tang,Xue-Shan Qiu,Ling He,Guang-Ping Wu,Dong-Yu Li,En-Hua Wang

doi:10.3389/fonc.2020.559543

Abstract

High-risk human papillomavirus (HPV) infection play an important role in the development of lung cancer. Our previously study showed that E6 and E7 in HPV16 upregulated the expression of GLUT1 in lung cancer cells. However, whether they can promote the glucose uptake by GLUT1 and the underlying molecular mechanism has not been identified. It has been reported that thioredoxin interacting protein (TXNIP) regulates both the expression of GLUT1 and its glucose uptake. We speculate that high risk HPV16 infection may be closely related to TXNIP expression. Therefore, we associate HPV16 with TXNIP to explore the potential molecular mechanism of their regulation of GLUT1 expression and glucose uptake. Using double directional genetic manipulation in lung cancer cells, we showed that HPV16 E6/E7 proteins downregulated the expression of p-PTEN in lung cancer cells, the knockdown of PTEN further inhibited the expression of TXNIP, the inhibition of TXNIP further promoted the accumulation of HIF-1α by inhibiting the translocation of nuclear HIF-1α to the cytoplasm, and subsequently upregulated the expression of GLUT1 at the protein and mRNA levels. More interestingly, we found that the knockdown of TXNIP played a decisive role to promote the glucose uptake by GLUT1. Together, these findings suggested that the PTEN-TXNIP-HIF-1α axis might be related to the E6/E7-mediated expression of GLUT1 and its glucose uptake.

Highlights

In 1980, Syrjänen first proposed the hypothesis of the role of human papillomavirus (HPV) infection in the occurrence of bronchosquamous cell carcinoma [1]
Results showed that the overexpression of E6 or E7 significantly downregulated the expression of p-phosphatase and tensin homolog (PTEN) and thioredoxin interacting protein (TXNIP) at both protein and mRNA levels but upregulated the expression of HIF-1a at the protein level only and of GLUT1 at both the protein and mRNA levels
We had reported that the overexpression of HPV16 E6/E7 resulted in the upregulation of GLUT1 at protein and mRNA levels in lung cancer cells [14, 15]

Summary

Introduction

In 1980, Syrjänen first proposed the hypothesis of the role of HPV infection in the occurrence of bronchosquamous cell carcinoma [1]. With the rapid development of molecular biology technology and the deepening of lung cancer research, researchers found that HPV16 is the main type of infection, in which E6 and E7 proteins are the main oncogenes, and only long-term persistent infection is closely related to the occurrence of lung cancer [2,3,4,5]. The molecular mechanisms that regulate phosphorylation of PTEN at S380—in response to the high-risk HPV16 E6/E7 oncogene—in lung cancer, are remain unclear. Activated PTEN has been reported to be function as a tumor suppressor which was negatively regulated in the Akt/PKB signaling pathway. Shen et al, had suggested that PTEN might indirectly upregulate TXNIP at the protein level by inhibiting the phosphorylation of Akt, which triggered the activation of TXNIP in liver cancer [9]. The PTEN-mediated regulation of TXNIP in lung cancer remains unknown

Methods

Results

Conclusion