Human telomerase reverse transcriptase regulates vascular endothelial growth factor expression via human papillomavirus oncogene E7 in HPV-18-positive cervical cancer cells

Abstract

Human papillomavirus (HPV) infection induces chronic and precancerous lesions and results in invasive cervical cancer. Human telomerase as well as inflammatory and angiogenic factors such as telomerase reverse transcriptase (hTERT) or vascular endothelial growth factor (VEGF) could play a role in regulating HPV-induced cervical cancer. This study investigated underlying molecular events in HPV-induced HPV-positive cervical cancer through hTERT and VEGF in vitro. Expressions of hTERT, a rate-limiting subunit of telomerase, and VEGF mRNA and proteins were, respectively, assessed by qRT-PCR, ELISA, and TRAP-ELISA in HPV-positive tissue samples and cervical cancer cell lines. To assess hTERT and VEGF secretion, hTERT overexpression and knockdown were conducted in HPV-18-positive Hela cells by hTERT cDNA and shRNA transfection, respectively. Then, the effect of HPV E6 and E7 on VEGF expressions was assessed in HPV-negative cervical cancer cells. Data have shown that VEGF expression levels are associated with hTERT expressions and telomerase activity in HPV-positive cervical cancer tissues and cells. Knockdown of hTERT expression down-regulated VEGF expressions, whereas overexpression of hTERT up-regulated VEGF expressions in HPV-18-positive Hela cells. Furthermore, HPV E7 oncoprotein was necessary for hTERT to up-regulate VEGF expressions in HPV-negative cervical cancer cells. Data from this current study indicate that HPV oncoproteins up-regulated hTERT and telomerase activity and in turn promoted VEGF expressions, which could be a key mechanism for HPV-induced cervical cancer development and progression.

Putative biomarkers for cervical cancer: SNVs, methylation and expression profiles

“…AKT and E2F are responsible for phosphorylation and activation of telomerase reverse transcriptase (TERT), an oncogene responsible for telomere elongation that allows the cells to evade apoptosis [102]. HPV16 E6 binds to the TERT promoter and induces its expression, leading to significant higher levels of TERT in the cervical cancer samples [103,104] as well as the upregulation of vascular endothelial growth factor (VEGF) [105], which contributes for tumour angiogenesis. Silencing of TERT leads to the suppression of cell proliferation, cell cycle, cell migration and invasion leading to the induction of apoptosis, thereby suppressing the growth of cervical cancer cells in vitro [106].…”

Phenyllactic acid promotes cell migration and invasion in cervical cancer via IKK/NF-κB-mediated MMP-9 activation

“…Persistent infection with specific human papillomaviruses (HPVs), such as high-risk (hr) HPV16 and HPV18, underlie the development of approximately 70% of cervical cancers [1]. The E6 and E7 proteins are the two major transforming proteins encoded by oncogenic HPVs, and the consistent expression of these two oncoproteins can immortalize human cervical epithelial cells, thus inducing the development of precancerous lesions, which could progress to cervical cancer if left untreated [2]. HPV E6 and E7 function by targeting host pathways that modulate many downstream effectors, thus resulting in alterations in relevant physiological processes that are considered hallmarks of cancer [3].…”

Dysregulation of Stemness Pathways in HPV Mediated Cervical Malignant Transformation Identifies Potential Oncotherapy Targets

“…Expression of integrins such as ITGB3 is also upregulated by HPV E6 (Yim et al, 2004 ), however, the mechanism is yet to be explored. Angiogenic protein VEGF, another top-scoring gene in our analysis, is involved in increasing vascular permeability and is also upregulated by E6 and E7 (Lopez-Ocejo et al, 2000 ; Li and Cui, 2015 ). Interestingly, E6 has been further shown to cause degradation of the polarity protein SCRIB (Gheit, 2019 ), and overexpression of SCRIB is associated with poor cervical cancer prognosis.…”