Human papillomavirus and lung cancinogenesis: an overview

Abstract

Lung cancer is the most common cause of cancer deaths worldwide. Although tobacco smoking is considered to be the main risk factor and the most well-established risk factor for lung cancer, a number of patients who do not smoke have developed this disease. This number varies between 15 % to over one-half of lung cancer cases, and the deaths from lung cancer in non-smokers are increasing every year. There are many other agents that are thought to be etiological, including diesel exhaust exposure, metals, radiation, radon, hormonal factors, cooking oil, air pollution and infectious diseases, such as human papillomavirus (HPV). Studies in various parts of the world have detected HPV DNA at different rates in lung tumors. However, the role of HPV in lung cancer is still unclear. Thus, in this review, we investigated some molecular mechanisms of HPV protein activity in host cells, the entry of HPV into lung tissue and the possible route used by the virus to reach the lung cells.

Keywords: E6 HPV; E7 HPV; Human papillomavirus; Lung cancer; Molecular mechanism.

Fig. 1

Risk factors that are associated with lung cancer. Exposure to diesel exhaust fumes, exposure to heavy metals, radiation, radon, inhalation of cooking oil fumes, hormonal factors, air pollution, genetics and infectious factors

Fig. 2

Role of E6 protein in cell cycle progression from G1 phase to S phase. a The p53 protein interacts with DDX3 and activates the p21 protein that inhibits the cyclin/cdk complex. As a result, pRb is not phosphorylated and remains linking with E2F transcription factor, and the cell cycle remains in the G1 phase. b The HPV E6 inhibits the p53 interaction with DDX3. Thus, p21 is not activated. Hence, the complex cyclin A/CDK2 is free to phosphorylate pRb, and the E2F transcription factor is released and determines the cell cycle and S-phase entry

Fig. 3

Schematic representation of the p21 transcriptions by p53. The −2.325/2.260 region of the p21 promoter recruits p53. In turn, p53 recruits DDX3, and this interaction increases the affinity of Sp1 in the p21 promoter and increases the activation of the p21 transcription

Fig. 4

Angiogenesis caused by HPV E6 and E7. The HPV E6 and E7 induce the vascular endothelial growth factor (VEGF) through hypoxia-inducible factor 1α (HIF-1α). The greater degree of VEGF expression increases the number of microvessels, which leads to tumor angiogenesis

Fig. 5

E7 HPV causes the HDAC/pRb/E2F complex dissociation by interaction with pRb. Thus, HDAC is released to hypermethylate p16INK4 and, together with E2F, inactivates the tumor suppressor genes and activates the cellular proliferation genes, respectively, which leads to tumor progression