Reduced MAGI3 level by HPV18E6 contributes to Wnt/β‐catenin signaling activation and cervical cancer progression

Abstract

Human papillomavirus type 18 (HPV18) has high carcinogenic power in invasive cervical cancer (ICC) development. However, the underlying mechanism remains elusive. The carcinogenic properties of HPV18 require the PDZ-binding motif of its E6 oncoprotein (HPV18 E6) to degrade its target PSD95/Dlg/ZO-1 (PDZ) proteins. In this study, we demonstrated that the PDZ protein membrane-associated guanylate kinase, WW and PDZ domain containing 3 (MAGI3) inhibited the Wnt/b-catenin pathway, and subsequently cervical cancer (CC) cell migration and invasion, via decreasing b-catenin levels. By reducing MAGI3 protein levels, HPV18 E6 promoted CC cell migration and invasion through activation of Wnt/bcatenin signaling. Furthermore, HPV18 rather than HPV16 was preferentially associated with the downregulation of MAGI3 and activation of the Wnt/b-catenin pathway in CC. These findings shed light on the mechanism that gives HPV18 its high carcinogenic potential in CC progression.Cervical cancer (CC) is the fourth most prominent type of cancer in women [1]. Infection with high-risk types of human papillomaviruses (HR-HPVs) is the main cause for the transformation of normal cervical epithelium to cervical intraepithelial neoplasia (CIN) and progression to invasive cervical cancer (ICC) [2,3]. The 5-year overall survival for early-stage patients (stage I) of CC reaches 88%, and this percentage Abbreviations CC, cervical cancer; CIN, cervical intraepithelial neoplasia; CIS, carcinoma in situ; FDR, false discovery rate; GSEA, gene set enrichment analysis; HG-CIN, high-grade cervical intraepithelial neoplasia; HPV16, human papillomavirus type 16; HPV18, human papillomavirus type 18; HR-HPVs, high-risk types of human papillomaviruses; ICC, invasive cervical cancer; IHC, immunohistochemistry; MAGI3, membraneassociated guanylate kinase, WW and PDZ domain containing 3; NHERF1, Na + /H + exchanger regulatory factor 1; PBM, PDZ-binding motif; PDZ, PSD95/Dlg/ZO-1; TCGA, The Cancer Genome Atlas.

High-Risk Genotypes of Human Papillomavirus at Diverse Anogenital Sites among Chinese Women: Infection Features and Potential Correlation with Cervical Intraepithelial Neoplasia

“…Based on colposcopy and pathology studies, we found consistent results, with nearly half (48.7%) of participants with cervical lesions (CIN 1+) and 11.6% with CIN 2+ lesions requiring further treatment, such as cervical conization [ 68 ]. From the literature, it is suggested that cervical HPV 16 and HPV 18 are associated with 70% of all cases of invasive cervical cancer, and HPV 16 is the most common high-risk subtype, causing over half of all cervical cancer cases [ 69 , 70 ]. Our results showed that cervical HPV 16/18 detection was still not sufficient for predicting CIN 2+ lesions, with 1/3 CIN 2+ patients not covered.…”

Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

“…Activation of the Wnt pathway increases cytoplasmic β‐catenin, subsequently fueling the activation of cyclin genes, culminating in cellular division, growth, and uncontrolled proliferation. HPV18 E6 diminishes MAGI3 levels, contributing to Wnt /β‐catenin signaling activation 125 . E6 proteins from HR‐HPV and LR‐HPV activate the Wnt/ β‐catenin pathway by degrading NHERF1 through E6AP 126 .…”

“…HPV18 E6 diminishes MAGI3 levels, contributing to Wnt /β‐catenin signaling activation. 125 E6 proteins from HR‐HPV and LR‐HPV activate the Wnt/ β‐catenin pathway by degrading NHERF1 through E6AP. 126 Besides, HPV‐18 E6 oncoprotein and its spliced isoform E6*I regulate the Wnt/β‐catenin cell signaling pathway through upregulating TCF‐4 transcriptional factors.…”

The clinical course of untreated CIN2 (HPV16/18+) under active monitoring: A protocol of systematic reviews and meta-analysis

“…[ 9 , 10 ] HPV16 and HPV18 are associated with 70% of all cases of invasive CC, and HPV16 is the most common high-risk subtype, causing over half of all CC cases. [ 11 , 12 ] In 2012, the American Society for Colposcopy and Cervical Lesions and the American College of Obstetricians and Gynecologists issued guidelines clearly stating that people infected with HPV16 and HPV18 should undergo colposcopy even if cytology is negative. [ 13 ] However, fewer than 10% of patients with high-risk HPV subtypes have an infection lasting more than 2 years.…”