MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner.
MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner.
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MUC1 通过以 EGFR 依赖性方式上调 ABCB1 诱导获得性化疗耐药
DOI：
10.1038/cddis.2017.378
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发表时间：
2017-08-10
影响因子：
9
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Jin W;Liao X;Lv Y;Pang Z;Wang Y;Li Q;Liao Y;Ye Q;Chen G;Zhao K;Huang L
化疗耐药性导致癌症复发和各种癌症类型的死亡率增加，迫切需要更好地了解其潜在机制。MUC 1在许多癌症中异常过表达，并与预后不良相关。然而，MUC 1在化疗耐药性中的功能意义尚未完全阐明。在这里，我们表明，MUC 1的表达是相当大的诱导细胞获得化疗耐药性在转录和翻译后水平。使用功能获得和丧失方法，我们证明了MUC 1在诱导耐药性中的关键作用。MUC 1通过刺激EGFR活化和核转位，增加ATP结合盒转运子B1（ABCB 1）的表达。值得注意的是，通过shRNA和抑制剂靶向抑制EGFR或ABCB 1有效逆转了化疗耐药性。此外，MUC 1-EGFR-ABCB 1抑制剂与紫杉醇的共同给药不仅显著阻断了肿瘤生长，而且还阻断了异种移植小鼠模型中的复发。我们的数据共同支持MUC 1通过以EGFR依赖性方式上调ABCB 1诱导获得性化疗耐药的模型，为在MUC 1阳性癌症中使用EGFR抑制剂预防化疗耐药提供了新的分子基础。
Chemoresistance contributes to cancer relapse and increased mortality in a variety of cancer types, raising a pressing need to better understand the underlying mechanism. MUC1 is abnormally overexpressed in numerous carcinomas and associated with poor prognosis. However, the functional significance of MUC1 in chemoresistance has not been fully elucidated. Here, we showed that MUC1 expression was considerably induced in cells that had acquired chemoresistance at both transcriptional and post-translational levels. Using gain-and loss-of function approaches, we demonstrated a critical role of MUC1 in induction of drug resistance. Through stimulation of EGFR activation and nuclear translocation, MUC1 increased the expression of ATP-binding cassette transporter B1 (ABCB1). Remarkably, targeted suppression of EGFR or ABCB1 by both shRNAs and inhibitors effectively reversed 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. Our data collectively support a model in which MUC1 induces acquired chemotherapy resistance by upregulating ABCB1 in an EGFR-dependent manner, providing a novel molecular basis of using the EGFR inhibitor in MUC1-positive cancers to prevent chemotherapy resistance.
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影响因子：
16.6
作者：
Chavez JD;Schweppe DK;Eng JK;Zheng C;Taipale A;Zhang Y;Takara K;Bruce JE
通讯作者：
Bruce JE
影响因子：
8
作者：
Dayde, D.;Guerard, M.;Gazzeri, S.
通讯作者：
Gazzeri, S.
影响因子：
3
作者：
Bark, H.;Choi, Cheol-Hee
通讯作者：
Choi, Cheol-Hee
影响因子：
78.5
作者：
Kufe, Donald W.
通讯作者：
Kufe, Donald W.
影响因子：
5.8
作者：
Fukuda, Yu;Schuetz, John D.
通讯作者：
Schuetz, John D.