EP1.14-14 MUC1 Confers Chemotherapy Resistance of Tumor-Initiating Cells Through EGFR-IL-6 Axis

Abstract

Tumor initiating cells (TICs) are responsible for causing chemotherapy resistance and tumor relapse, but the mechanisms have not been elucidated. This study aims to explore the role of mucin 1 (MUC1) in chemotherapy resistance of TICs and its clinical significance. The relationships between expression of MUC1 and clinical outcomes were analyzed by multiple databases. The MUC1 expression and function in chemoresistant TICs were investigated in vitro and in vivo through gain-of and loss-of function strategies. The potential downstream targets of MUC1 were analyzed using chromatin immunoprecipitation and luciferase reporter assay. The prognostic value of MUC1 signaling was evaluated using IHC. High expression of MUC1 positively related with poor outcome of cancer patients. Elevation of MUC1 in chemoresistant cancer cells concomitant with TICs enrichment. Mechanistically, MUC1 induces the expansion of TICs population through activation of EGFR, which augments interleukin-6 (IL-6) transcription. Inhibition of EGFR-IL-6 signaling significantly abolishes expansion of chemoresistant TICs. Furthermore, coadministration of EGFR inhibitor overcomes the resistance of TICs to paclitaxel both in vitro and in vivo. Analysis of cervical cancer patients reveales that the expression of MUC1, EGFR and IL-6 are considerably increased after chemotherapy, showing a positive correlation between the expression of MUC1, EGFR and IL-6. Consistently, mining TCGA datasets uncovered a significant positive correlation between activation of MUC1-EGFR-IL-6 signaling pathway and poor disease-free survival in chemo-treated cervical cancer patients. MUC1 confers chemotherapy resistance of TICs through EGFR-mediated transcriptional regulation of IL-6.