Department of Gastrointestinal Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
PLoS One. 2012;7(7):e40008. doi: 10.1371/journal.pone.0040008. Epub 2012 Jul 9.
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.
化疗耐药是癌症有效治疗的主要障碍。Lin28 已被证明有助于化疗后肿瘤复发；然而，Lin28 与化疗耐药之间的关系尚不清楚。在这项研究中，我们研究了 Lin28 与紫杉醇耐药的相关性，并确定了 Lin28 在人乳腺癌细胞系和肿瘤组织中的作用机制。我们发现 Lin28 的表达水平与紫杉醇治疗耐药密切相关。高表达 Lin28 的 T47D 癌细胞系比 MCF7、Bcap-37 或 SK-BR-3 癌细胞系对紫杉醇更耐药，后者 Lin28 表达水平较低。在 Lin28 高表达的 T47D 细胞中敲低 Lin28 增加了对紫杉醇治疗的敏感性，而在乳腺癌细胞中稳定表达 Lin28 则有效降低了对紫杉醇治疗的敏感性，导致紫杉醇的 IC50 值显著增加。Lin28 的转染也显著抑制了紫杉醇诱导的细胞凋亡。我们还发现，新辅助化疗后或局部复发或转移性乳腺癌组织中 Lin28 的表达显著增加。此外，进一步的研究表明 p21、Rb 和 Let-7 miRNA 是 Lin28 的分子靶点。Lin28 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。我们的结果表明，Lin28 表达可能是乳腺癌紫杉醇耐药的一种机制，Lin28 可能是克服乳腺癌紫杉醇耐药的潜在靶点。
