Lin28 mediates paclitaxel resistance by modulating p21, Rb and Let-7a miRNA in breast cancer cells.
Lin28 mediates paclitaxel resistance by modulating p21, Rb and Let-7a miRNA in breast cancer cells.
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Lin28 通过调节乳腺癌细胞中的 p21、Rb 和 Let-7a miRNA 介导紫杉醇耐药性
DOI：
10.1371/journal.pone.0040008
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Teng L
中科院分区：
文献类型：
--
作者：
Lv K;Liu L;Wang L;Yu J;Liu X;Cheng Y;Dong M;Teng R;Wu L;Fu P;Deng W;Hu W;Teng L
对化疗的抗性是有效治疗癌症的主要障碍。Lin 28已被证明有助于化疗后的肿瘤复发;然而，Lin 28与化疗耐药性之间的关系仍然未知。在这项研究中，我们研究了Lin 28与紫杉醇耐药性的关系，并确定了Lin 28在人乳腺癌细胞系和肿瘤组织中的潜在作用机制。我们发现Lin 28的表达水平与紫杉醇治疗的耐药性密切相关。高度表达Lin 28的T47 D癌细胞系比具有低水平Lin 28表达的MCF 7、Bcap-37或SK-BR-3癌细胞系对紫杉醇更耐药。Lin 28高表达T47 D细胞中Lin 28的敲低增加了对紫杉醇治疗的敏感性，而Lin 28在乳腺癌细胞中的稳定表达有效地减弱了对紫杉醇治疗的敏感性，导致紫杉醇的IC 50值显著增加。Lin 28转染也显著抑制紫杉醇诱导的细胞凋亡。我们还发现Lin 28在新辅助化疗后的肿瘤组织或局部复发或转移的乳腺癌组织中的表达显著增加。进一步的研究表明，p21、Rb和Let-7 miRNA是Lin 28的分子靶点。Lin 28在乳腺癌细胞中的过表达显著诱导p21和Rb的表达，并抑制Let-7 miRNA的水平。我们的研究结果表明，Lin 28的表达可能是乳腺癌紫杉醇耐药的机制之一，Lin 28可能是克服乳腺癌紫杉醇耐药的潜在靶点。
Resistance to chemotherapy is a major obstacle for the effective treatment of cancers. Lin28 has been shown to contribute to tumor relapse after chemotherapy; however, the relationship between Lin28 and chemoresistance remained unknown. In this study, we investigated the association of Lin28 with paclitaxel resistance and identified the underlying mechanisms of action of Lin28 in human breast cancer cell lines and tumor tissues. We found that the expression level of Lin28 was closely associated with the resistance to paclitaxel treatment. The T47D cancer cell line, which highly expresses Lin28, is more resistant to paclitaxel than the MCF7, Bcap-37 or SK-BR-3 cancer cell lines, which had low-level expression of Lin28. Knocking down of Lin28 in Lin28 high expression T47D cells increased the sensitivity to paclitaxel treatment, while stable expression of Lin28 in breast cancer cells effectively attenuated the sensitivity to paclitaxel treatment, resulting in a significant increase of IC50 values of paclitaxel. Transfection with Lin28 also significantly inhibited paclitaxel-induced apoptosis. We also found that Lin28 expression was dramatically increased in tumor tissues after neoadjuvant chemotherapy or in local relapse or metastatic breast cancer tissues. Moreover, further studies showed that p21, Rb and Let-7 miRNA were the molecular targets of Lin28. Overexpression of Lin28 in breast cancer cells considerably induced p21 and Rb expression and inhibited Let-7 miRNA levels. Our results indicate that Lin28 expression might be one mechanism underlying paclitaxel resistance in breast cancer, and Lin28 could be a potential target for overcoming paclitaxel resistance in breast cancer.
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影响因子：
7.2
作者：
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通讯作者：
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3
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4.3
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