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.
