Study On The Function And Mechanism Of MUC1 In Cancer Chemoresistance

Chemoresistance contributes to cancer relapse and increased mortality in a variety of cancer types,raising a pressing need to better understand the underlying mechanism.Glycoprotein MUC1 is abnormally overexpressed in 70% of carcinomas and associates with chemoresistance.However,the functional significance of MUC1 in chemoresistance has not been fully elucidated.We carried out the research in the following parts.First,we used the cancer cell lines with high expression of MUC1 as research materials,we found that MUC1 contributed to chemoresistance though silence/ reexression of MUC1 and induction of drug resitance cell lines.Research showed that MUC1 not only increased the mRNA and protein level of ATP binding cassette transporter B1(ABCB1)but also enhanced the resistance to other ABCB1 sbustrate drugs.Further research demonstrated that MUC1 increased the expression of ABCB1 through triggering the activation and nuclear translocation of EGFR.MUC1 and EGFR mainly bound to ABCB1 promoter on-200~+200 sites,and activated the transcription of ABCB1.Remarkably,targeted inhibition of EGFR or ABCB1 by Erlotinib and verapamil effectively reversed MUC1-induced chemoresistance.Moreover,co-administration of the inhibitors of MUC1-EGFR-ABCB1 with paclitaxel significantly blocked not only tumor growth but also relapse in xenograft mouse model.Major currently used chemotherapy drugs target and upset cell mitosis,mitosis slippage is one of the most important factors causing chemotherapy resistance.The results showed that MUC1 was upregulated in mitosis phase in transcriptional level.MUC1 interacted with BubR1 and accelerated the dephosphorylation of BubR1 which resulted in escaping from paclitaxel induced mitosis arrest.Futher results showed that MUC1 directly interacted with PP2 A and increased of PP2 A enzymatic activity in mitosis.In presence of MUC1,PP2 A could dephosphorylate BubR1 leading to slippage from paclitaxel-induced mitosis arrest,the cancer cells acquired reisistance to microtubule inhibitor drugs.Further study showed that inhibition of PP2 A blocked the acceleration of p-BubR1 dephosphorylation and paclitaxel resistance induced by MUC1.Meanwhile,cancer stem cells(CSCs)are responsible for most of the drug resistance recurrence in cancer.We find that MUC1 could increase the CSCs frequency and enhance the CSCs enrichment.Further study showed that MUC1 could increase the transcription of IL6 and IL8.As IL6 and IL8 are reported to play important roles in cancer stem cells,more experiments are needed to explore whether MUC1 regulates the CSCs frequency through IL6 and IL8.In conclusions,our results reveal that MUC1 induces acquired chemotherapy resistance by activating MUC1-EGFR-ABCB1 pathway.Targeted inhibition of MUC1-EGFR-ABCB1 pathway effectively reverses MUC1-induced chemoresistance.Besides,we find that MUC1 could enhance the enzymatic activity of PP2 A and accelerate dephosphorylation of BubR1.Therefore,MUC1 promotes the mitosis exit and lead to resistance to microtubule inhibitors.Besides,MUC1 could enhance the self-renew ability and chemoresistance of cancer stem cell by up-regulation of inflammatory cytokines.Our research provides a novel molecular basis of chemoresistance and is of great value for clinical therapy in MUC1 positive cancer.