Abstract
HPV 16 E6 upregulates hTERT expression in lung cancer cells. However, the underlying molecular mechanism is unclear. In this paper, E6, LKB1, SP1, and hTERT mRNA expression levels were detected in brushing cells of patients with lung cancer (n = 106) and with benign lung disease (n = 68) by qRT-PCR. The mRNA expression levels of E6, SP1, and hTERT were significantly increased in the malignant group compared with the benign group (P < 0.01). Conversely, the mRNA expression level of LKB1 was significantly decreased in the malignant group (P < 0.01). Furthermore, the correlation between E6, Sp1, hTERT, and LKB1 was performed, our results indicated that E6, Sp1, and hTERT with positive, but LKB1 with negative correlation (P < 0.01). To investigate the potential relationship between these genes, using double directional genetic manipulation, we showed that overexpression of E6 in H1299 cells down-regulated LKB1 mRNA and protein expression but up-regulated SP1 and hTERT as well as the transcriptional activity of Sp1. In contrast, knockdown of E6 in A549 cells by short-interference RNAs (siRNAs) up-regulated LKB1 expression, but down-regulated SP1 and hTERT expression as well as Sp1 activity. LKB1 loss upregulated both SP1 and hTERT at the protein and mRNA level as well as SP1 activity. To verify that the role of E6 on hTERT was mediated by SP1, siRNA knockdown of SP1 was performed on both H1299 and A549 cell lines. Inhibition of SP1 downregulated hTERT expression. Our results indicate that HPV16 E6 indirectly upregulated the expression of hTERT by inhibition of LBK1 expression and upregulation of Sp1 expression, thus suggesting a HPV-LKB1-SP1-hTERT axis for the tumorigenesis of lung cancer. Our study also provides new evidence to support the critical role of SP1 and LKB1 in the pathogenesis of HPV-related lung cancer, and suggests novel therapeutic targets.
Highlights
Human papillomaviruses (HPV) is a cyclic double stranded DNA virus, which is associated with a variety of human diseases
E6, specificity protein 1 (SP1), and human telomerase reverse transcriptase (hTERT) mRNA were significantly increased in the malignant group than the benign group, whereas Liver kinase B1 (LKB1) mRNA was significantly decreased in the malignant group (P < 0.01)
SP1 mRNA was strongly positively correlated with E6 and hTERT mRNA (P < 0.01), whereas LKB1 mRNA was negatively correlated with E6, SP1, and hTERT mRNA (P < 0.01)
Summary
Human papillomaviruses (HPV) is a cyclic double stranded DNA virus, which is associated with a variety of human diseases. The persistent infection of high-risk HPV is closely related, for instance, to the occurrence of cervical cancer [1]. In 1979, Syrjanen first hypothesized that HPV infection might play an important role in the occurrence of lung cancer [2]. We hypothesized that high risk HPV16 infection may be associated with inactivation of LKB1 in the development of lung cancer. It is necessary to link HPV16 and LKB1 together to explore the combined role and the molecular mechanism in the occurrence of lung cancer, to search for genes and their regulation of promoting cancer progression, and to provide a new approach for the treatment of HPV related lung cancer
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