Infection by High-Risk Human Papillomaviruses, Epithelial-to-Mesenchymal Transition and Squamous Pre-Malignant or Malignant Lesions of the Uterine Cervix: A Series of Chained Events?

Giovanni Barillari,Andrea Modesti,Vittorio Manzari,Roberto Bei

doi:10.3390/ijms222413543

Abstract

Wound healing requires static epithelial cells to gradually assume a mobile phenotype through a multi-step process termed epithelial-to-mesenchymal transition (EMT). Although it is inherently transient and reversible, EMT perdures and is abnormally activated when the epithelium is chronically exposed to pathogens: this event deeply alters the tissue and eventually contributes to the development of diseases. Among the many of them is uterine cervical squamous cell carcinoma (SCC), the most frequent malignancy of the female genital system. SCC, whose onset is associated with the persistent infection of the uterine cervix by high-risk human papillomaviruses (HR-HPVs), often relapses and/or metastasizes, being resistant to conventional chemo- or radiotherapy. Given that these fearsome clinical features may stem, at least in part, from the exacerbated and long-lasting EMT occurring in the HPV-infected cervix; here we have reviewed published studies concerning the impact that HPV oncoproteins, cellular tumor suppressors, regulators of gene expression, inflammatory cytokines or growth factors, and the interactions among these effectors have on EMT induction and cervical carcinogenesis. It is predictable and desirable that a broader comprehension of the role that EMT inducers play in SCC pathogenesis will provide indications to flourish new strategies directed against this aggressive tumor.

Highlights

Epithelial cells lining human organs are tightly joined together by means of adherens junctions, are connected to the extracellular matrix via membrane receptors, are oriented according to an apical–basal polarity, and have a limited life span [1].In multilayered epithelia, dead cells are replaced by young ones arising from the differentiation of stem cells located in the basal layers [1]
On the other hand, when overexpressed and/or hyperactivated, Snail, Slug, and Zeb1 can directly counteract p53 and pRb activity, further downregulating tumor suppressive miRs, and rendering epithelial cells susceptible to malignant transformation [33,34]. In agreement with these findings, the concurrent inactivation of p53 and pRB has been shown to give rise to mesenchymal-like tumors in animal models [116]. All these findings indicate that the E5, E6, and E7 oncoproteins of the high-risk human papillomaviruses (HR-HPVs) cooperate in inducing the proliferation and trans-differentiation of cervical epithelial cells
squamous cell carcinoma (SCC) of the uterine cervix is a leading cause of death among women worldwide, its onset can be prevented in the first instance by anti-HPV vaccination [275] and, in the second instance, through screening programs for the detection and surveillance of squamous precancerous lesions [58,276]

Summary

Introduction

Epithelial cells lining human organs are tightly joined together by means of adherens junctions, are connected to the extracellular matrix via membrane receptors, are oriented according to an apical–basal polarity, and have a limited life span [1]. Cells that have survived the harm proliferate due to the ending of contact inhibition and, at the same time, migrate to the site of damage [1,2] For this to happen, epithelial cells change their phenotype from static to mobile through the EMT process [1,3]. E5 inhibits epithelial cell differentiation by downregulating the expression of the fibroblast growth factor receptor (FGFR)2b [68,69,70] Because of all these activities, E5 favors the proliferation of immature basal cells and, at the same time, hampers their differentiation (Table 1) [68,69,70]

Activity

Concluding Remarks and Future Directions