Role of Wingless Integrated - Glycogen Synthase Kinase3β Mediated Signaling in Cervical Cancer Progression and Resistance

Abstract

Background: Cervical Squamous Cell Carcinoma (CSCC) is one of the most prevalent newlinecancers, with an increasing number of new newlinecases worldwide. Human papillomavirus newlinecancers and often becomes newline(HPV) infection is the newlinemost common newlinegynecological newlineaggressive, with rapid proliferation, invasion/migration, and drug resistance. The role and newlineexpression of proteins such as GSK3B and ALDH is still unclear in cervical cancer. Also, newlineexpression and single nucleotide polymorphisms (SNPs) newlineof TLR4/9, CYP1Al and XRCC newlinegenes are vital for cervical squamous cell carcinoma (CSCC) newlinebut considerably vary in newlinedifferent populations. newlineMaterials and methods: In this study, fresh human CSCC tissue specimens, comprising of newlineadjacent normal (AN), cervical intraepithelial neoplasia (CINI-3), primary CSCC, newlineinvasive CSCC and drugs (chemo-radiation)-resistant cervical tumor (DRCT) tissues were newlineincluded. HPV-positive (HeLa, SiHa), HPV-negative (C33A), and cisplatin-resistant newline(CisR- newlineHeLa/-SiHa/-C33A) cell lines were used for newlinein vitro studies. HPV16/18 newlineoncoproteins E6/E7, pERK1/2, and glycogen synthase kinase-3 (GSK3), ALDH and the newlineMMP-9/-2 newline(MMPs) metalloproteinases matrix newlineassessed using newlineimmunohistochemistry, RT-PCR, WB, and gelatin zymography. For the SNPs (TLR4/9, newlineCYP1Yl and XRCC1-4) study and TF binding (to the ALDH1A1 promoter), the allele newlinewere newlineResults: HPVI6/18 infection was observed in 16.7% of the CIN1-3, 77.8% of the CSCC, newlineand 89.7% of DRCT samples. Total and inactive GSK3ß expressions were associated with newlineoverall CSCC progression (p =0.039 and p = 0.024, respectively) and chemoresistance (p newline= 0.004 and p = 0.014, respectively). Positive correlations were observed, between the newlineexpression of E6 and pGSK3ß expression (p = 0.013); E6 and CSCC progression (p lt newline0.0001ydrug resistance (p = 0.0001). CisR-HeLa-siHa was more dependent on newlineDGSK3B. and activation of GSK3 by SMIs (iAkt), treatment with nimbolide, or newlineknockdown of E6/E7 reduced cisplatin resistance and promoted apoptosis.