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Oncogene:厦门大学李博安课题组揭示Wnt信号促进乳腺癌多药耐药的下游分子机制

摘要 : 2016年2月15日,国际学术权威刊物自然出版集团旗下子刊、国际肿瘤学重要学术期刊《Oncogene》在线发表了厦门大学生命科学学院李博安教授课题组题为“Pygo2 activates MDR1 expression and mediates chemoresistance in breast cancer via the Wnt/β-catenin pathway”的研究论文。

 2016年2月15日,国际学术权威刊物自然出版集团旗下子刊、国际肿瘤学重要学术期刊《Oncogene》在线发表了厦门大学生命科学学院李博安教授课题组题为“Pygo2 activates MDR1 expression and mediates chemoresistance in breast cancer via the Wnt/β-catenin pathway”的研究论文。该研究首次揭示了Wnt信号在乳腺癌多药耐药中的作用及其下游分子机制,为乳腺癌耐药与复发的预测与治疗提供了一个新的标志物。

Wnt信号参与细胞的增殖、分化、肿瘤发生、转移等多个生物学过程,然而在乳腺癌多药耐药中的作用及其下游分子机制并不清楚。李博安教授课题组经过研究发现,Wnt信号在耐药细胞株中的强度较非耐药细胞株明显增强。进一步经过大规模筛选发现,Wnt信号新核心成员以及染色质效应因子Pygo2在耐药细胞中表达明显提高。Pygo2通过促进β-catenin细胞核内滞留并协同β-catenin直接激活多药耐药基因MDR1的表达而导致耐药的产生。在耐药细胞中敲减Pygo2的表达可以明显恢复耐药细胞对于多种化疗药物的敏感性,并明显减少耐药细胞的CD44+CD24-干细胞群,小鼠体内实验也证实了这个结果。重要的是,在对于化疗前后乳腺癌病人进行分析后发现,如果Pygo2与MDR1同步表达增高,那么病人术后1年复发率显著提高。

原文链接:

Pygo2 activates MDR1 expression and mediates chemoresistance in breast cancer via the Wnt/β-catenin pathway

原文摘要:

The Wnt/β-catenin pathway has important roles in chemoresistance and multidrug resistance 1 (MDR1) expression in some cancers, but its involvement in breast cancer and the underlying molecular mechanism are undefined. In this study, we demonstrated that the Wnt/β-catenin pathway is activated in chemoresistant breast cancer cells. Using a Wnt pathway-specific PCR array screening assay, we detected that Pygo2, a newly identified Wnt/β-catenin pathway component, was the most upregulated gene in the resistant cells. Additional experiments indicated that Pygo2 activated MDR1 expression in the resistant cells via the Wnt/β-catenin pathway. Moreover, the inhibition of Pygo2 expression restored the chemotherapeutic drug sensitivity of the resistant cells and reduced the breast cancer stem cell population in these cells in response to chemotherapy. importantly, these activities induced by Pygo2 were mediated by MDR1. We also determined the effect of Pygo2 on the sensitivity of breast tumors resistant to doxorubicin in a mouse model. Finally, RNA samples from 64 paired patient tumors (before and after chemotherapy) highly and significantly overexpressed Pygo2 and/or MDR1 after treatment, thus underlining a pivotal role for the Pygo2-mediated Wnt/β-catenin pathway in the clinical chemoresistance of breast cancer. Our data represent the first implication of the Wnt/β-catenin pathway in breast cancer chemoresistance and identify potential new targets to treat the recurrence of breast cancer.

来源: Oncogene 浏览次数:0

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