Study On The Roles And Underlying Mechanisms Of MUC1 In Tumor Initiating Cells Regulation

Tumor initiating cells(TICs)are thought to be responsible for causing tumor formation,chemotherapy resistance and tumor relapse.Although multiple studies have reported that chemotherapy leads to TICs enrichment in tumor tissues,the regulation of TICs by drugs is still an unsolved core problem in cancer research.Mucin1(MUC1)is abnormally overexpressed in multiple cancers and its abnormal expression is associated with tumor malignancy and poor prognosis.We previously found that high expression of MUC1 induced acquired chemoresistance.However,the role and mechanism of MUC1 on TICs after chemotherapy has not been elucidated.This paper studies the role and mechanism of MUC1 in TICs regulation,especially about the regulation mechanism of TICs after chemotherapy,which is mainly divided into 4 parts.Firstly,using tumor cell lines and corresponding paclitaxel-resistant cells,we demonstrate that MUC1 induces the expansion of TICs population in chemoresistant cancer cells via loss-and gain-of function approaches.Secondly,mechanism study reveals MUC1 expression results in activation of epidermal growth factor receptor(EGFR),which augments interleukin-6(IL-6)transcription through directly binding to CAMP response element binding protein(CREB)and Glucocorticoid receptor β(GRβ)sites in the promoter,and thereby stimulates TICs expansion.In accordance,inhibition of EGFR or blockage of IL-6 results in the significant reduction of TICs chemoresistant.Moreover,coadministration of EGFR inhibitor overcomes the resistance of TICs to paclitaxel and tumor recurrence in vivo.Thirdly,analysis of 20 paired pre-and post-neoadjuvant chemotherapy tumor specimens from cervical cancer patients,reveals that the activation of MUC1-EGFR-IL-6 signaling after chemotherapy,showing a positive correlation between the expression of MUC1/EGFR,EGFR/IL-6 and EGFR/IL-6.Consistently,mining TCGA datasets we finds that high expression of MUC1 positively relates to poor outcome of patients,what’s more,database analysis also uncovers a significant correlation between activation of MUC1-EGFR-IL-6signaling with poor disease-free survival in chemo-treated cervical cancer patients.Finally,we investigates the function and mechanism of MUC1 on TICs without drug treatment.We find that MUC1 promotes the symmetrical division of TICs.Preliminary mechanism study shows that MUC1 is highly expressed in mitosis phase,and protein phosphatase 2A(PP2A)inhibitors blocks MUC1-induced TICs proliferation,suggesting that PP2 A plays a role in promoting symmetrical division of TICs by MUC1.Collectively,this study not only reveals the role of MUC1 in promoting TICs enrichment with chemotherapy,but also elucidates a novel mechanism that MUC1 induced enrichment of TICs via EGFR-CREB/GRβ-IL-6 signaling pathway,and discovers that MUC1 promotes the symmetrical division of TICs through PP2 A.Providing novel strategies for treatment and prevention of tumor.