Abstract
BackgroundThe E6 oncoproteins of human papillomavirus (HPV) 16/18 are the critical drivers of cervical cancer (CC) progression. Extracellular vesicles (EVs) are emerging as critical mediators of cancer-tumor microenvironment (TME) communication. However, whether EVs contribute to HPV 16/18 E6-mediated impacts on CC progression remains unclear.MethodsA series of in vitro and in vivo assays were performed to elucidate the roles and mechanism of EV-Wnt7b in HPV E6-induced CC angiogenesis. The prognostic value of serum EV-Wnt7b was determined and a predictive nomogram model was established.ResultsHPV 16/18 E6 upregulated Wnt7b mRNA expression in four HPV 16/18-positive CC cell lines and their EVs. In vitro and in vivo experiments demonstrated that EV-Wnt7b mRNA was transferred to and modulated human umbilical vein endothelial cells (HUVECs) toward more proliferative and proangiogenic behaviors by impacting β-catenin signaling. Clinically, serum EV-Wnt7b levels were elevated in CC patients and significantly correlated with an aggressive phenotype. Serum EV-Wnt7b was determined to be an independent prognostic factor for CC overall survival (OS) and recurrence-free survival (RFS). Notably, we successfully established a novel predictive nomogram model using serum EV-Wnt7b, which showed good prediction of 1- and 3-year OS and RFS.ConclusionsOur results illustrate a potential crosstalk between HPV 16/18-positive CC cells and HUVECs via EVs in the TME and highlight the potential of circulating EV-Wnt7b as a novel predictive biomarker for CC prognosis.
Highlights
Despite the development of screening tests and therapies, cervical cancer (CC) remains one of the most lethal gynecological malignances worldwide, especially in developing countries [1]
Since the Wnt pathway can be activated by the human papillomavirus (HPV) E6 oncogene, a prerequisite for CC carcinogenesis, we determined whether Wnt3a, Wnt5a and Wnt7b mRNA can be dysregulated by HPV 16/18 E6
We found that the knockdown (KD) of HPV-E6 did not lead to a consistent expression change of Wnt3a and Wnt5a mRNA but lead to a consistently decreased Wnt7b mRNA expression in all the four HPV 16/18 positive cell lines (Fig. 1c)
Summary
Despite the development of screening tests and therapies, cervical cancer (CC) remains one of the most lethal gynecological malignances worldwide, especially in developing countries [1]. Qiu et al Journal of Experimental & Clinical Cancer Research (2020) 39:260 extracellular matrix, and endothelial cells, play important roles in regulating immune escape, tumor proliferation, metastasis and angiogenesis [6,7,8,9,10]. Angiogenesis has been widely accepted as a key event in tumor development because cancer cells rely on neovascularization for nutrition and oxygen supply to support continuous and sustained growth and metastasis [11]. Previous studies have implicated HPV in angiogenesis [14, 15], the detailed cellular and molecular events involved, especially how HPV mediates cancer-TME communication to influence angiogenesis, remain unclear. The E6 oncoproteins of human papillomavirus (HPV) 16/18 are the critical drivers of cervical cancer (CC) progression. Extracellular vesicles (EVs) are emerging as critical mediators of cancer-tumor microenvironment (TME) communication. Whether EVs contribute to HPV 16/18 E6-mediated impacts on CC progression remains unclear
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