Department of Biology, University of North Carolina at Charlotte, Charlotte, NC, USA.
Oncogenesis. 2013 Jun 17;2(6):e51. doi: 10.1038/oncsis.2013.16.
MUC1 (CD227), a membrane tethered mucin glycoprotein, is overexpressed in >60% of human pancreatic cancers (PCs), and is associated with poor prognosis, enhanced metastasis and chemoresistance. The objective of this study was to delineate the mechanism by which MUC1 induces drug resistance in human (BxPC3 and Capan-1) and mouse (KCKO, KCM) PC cells. We report that PC cells that express high levels of MUC1 exhibit increased resistance to chemotherapeutic drugs (gemcitabine and etoposide) in comparison with cells that express low levels of MUC1. This chemo resistance was attributed to the enhanced expression of multidrug resistance (MDR) genes including ABCC1, ABCC3, ABCC5 and ABCB1. In particular, levels of MRP1 protein encoded by the ABCC1 gene were significantly higher in the MUC1-high PC cells. In BxPC3 and Capan-1 cells MUC1 upregulates MRP1 via an Akt-dependent pathway, whereas in KCM cells MUC1-mediated MRP1 upregulation is via an Akt-independent mechanism. In KCM, BxPC3 and Capan-1 cells, the cytoplasmic tail motif of MUC1 associates directly with the promoter region of the Abcc1/ABCC1 gene, indicating a possible role of MUC1 acting as a transcriptional regulator of this gene. This is the first report to show that MUC1 can directly regulate the expression of MDR genes in PC cells, and thus confer drug resistance.
MUC1（CD227）是一种膜结合的粘蛋白糖蛋白，在超过 60%的人类胰腺癌（PC）中过表达，与预后不良、增强转移和化疗耐药有关。本研究的目的是阐明 MUC1 诱导人（BxPC3 和 Capan-1）和鼠（KCKO、KCM）PC 细胞耐药的机制。我们报告说，表达高水平 MUC1 的 PC 细胞对化疗药物（吉西他滨和依托泊苷）的耐药性比表达低水平 MUC1 的细胞更强。这种化疗耐药性归因于多药耐药（MDR）基因的表达增强，包括 ABCC1、ABCC3、ABCC5 和 ABCB1。特别是，ABCC1 基因编码的 MRP1 蛋白的水平在 MUC1 高表达的 PC 细胞中显著升高。在 BxPC3 和 Capan-1 细胞中，MUC1 通过 Akt 依赖性途径上调 MRP1，而在 KCM 细胞中，MUC1 介导的 MRP1 上调是通过 Akt 非依赖性机制。在 KCM、BxPC3 和 Capan-1 细胞中，MUC1 的细胞质尾巴基序与 Abcc1/ABCC1 基因的启动子区域直接结合，表明 MUC1 作为该基因的转录调节剂可能发挥作用。这是第一个报道表明 MUC1 可以直接调节 PC 细胞中 MDR 基因的表达，从而赋予耐药性。
