Increased Expression of P-Glycoprotein and Doxorubicin Chemoresistance of Metastatic Breast Cancer Is Regulated by miR-298
Increased Expression of P-Glycoprotein and Doxorubicin Chemoresistance of Metastatic Breast Cancer Is Regulated by miR-298
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DOI：
10.1016/j.ajpath.2012.02.024
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发表时间：
2012-06-01
影响因子：
6
通讯作者：
Dash, Srikanta
中科院分区：
文献类型：
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作者：
Bao, Lili;Hazari, Sidhartha;Dash, Srikanta
MicroRNAs （miRNAs）是一种短的非编码RNA分子，可调节与癌症有关的许多基因的表达；因此，它们提供了很好的诊断和治疗靶点。我们开发了多柔比星耐药和敏感的转移性人乳腺癌细胞系（MDA-MB-231），以研究miRNAs调控的化疗耐药机制。我们发现阿霉素仅局限于细胞质，无法到达耐药肿瘤细胞的细胞核，因为细胞核中MDR1/ p -糖蛋白（P-gp）的表达增加。阿霉素敏感和耐药乳腺癌细胞之间的miRNA阵列显示，在阿霉素耐药的人乳腺癌细胞中，miR-298的表达降低与P-gp的表达增加有关。在瞬时转染实验中，miR-298直接结合到MDR1 3'非翻译区，并以剂量依赖的方式调节萤火虫荧光素酶报告基因的表达。miR-298的过表达下调了P-gp的表达，增加了阿霉素耐药乳腺癌细胞中阿霉素的核积累和细胞毒性。此外，miR-298的下调增加了P-gp的表达，并在敏感的乳腺癌细胞中诱导了阿霉素耐药性。总之，这些结果表明naiR-298直接调节P-gp的表达，并与转移性人乳腺癌的化疗耐药机制有关。因此，miR-298在预测人乳腺癌阿霉素化疗耐药方面具有诊断和治疗潜力。（中华病理学杂志，2012,180:2490-2503;http://dx.doi.org/10.1016/j.ajpath.2012.02.024）
MicroRNAs (miRNAs) are short, noncoding RNA molecules that regulate the expression of a number of genes involved in cancer; therefore, they offer great diagnostic and therapeutic targets. We have developed doxorubicin-resistant and -sensitive metastatic human breast cancer cell lines (MDA-MB-231) to study the chemoresistant mechanisms regulated by miRNAs. We found that doxorubicin localized exclusively to the cytoplasm and was unable to reach the nuclei of resistant tumor cells because of the increased nuclear expression of MDR1/P-glycoprotein (P-gp). An miRNA array between doxorubicin-sensitive and -resistant breast cancer cells showed that reduced expression of miR-298 in doxorubicin-resistant human breast cancer cells was associated with increased expression of P-gp. In a transient transfection experiment, miR-298 directly bound to the MDR1 3' untranslated region and regulated the expression of firefly luciferase reporter in a dose-dependent manner. Overexpression of miR-298 down-regulated P-gp expression, increasing nuclear accumulation of doxorubicin and cytotoxicity in doxorubicin-resistant breast cancer cells. Furthermore, down-regulation of miR-298 increased P-gp expression and induced doxorubicin resistance in sensitive breast cancer cells. In summary, these results suggest that naiR-298 directly modulates P-gp expression and is associated with the chemoresistant mechanisms of metastatic human breast cancer. Therefore, miR-298 has diagnostic and therapeutic potential for predicting doxorubicin chemoresistance In human breast cancer. (Am J Pathol 2012, 180:2490-2503; http://dx.doi.org/10.1016/j.ajpath.2012.02.024)