MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents.
MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents.
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DOI：
10.1158/1535-7163.mct-08-1046
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发表时间：
2009-05
影响因子：
5.7
通讯作者：
Richer JK
中科院分区：
文献类型：
--
作者：
Cochrane DR;Spoelstra NS;Howe EN;Nordeen SK;Richer JK
转录因子ZEB1在上皮细胞中通常不表达。当在癌症中不适当表达时，ZEB 1会启动上皮向间充质的转化，因为它能够抑制E-钙粘蛋白和其他参与极性的基因。最近，ZEB1和ZEB2已被确定为microRNA-200c家族的直接靶点。我们发现，miR-200c水平在分化良好的子宫内膜癌、乳腺癌和卵巢癌细胞系中很高，但在分化不良的癌细胞中极低。miR-200c的低表达或缺失导致ZEB1的异常表达和随后的E-钙粘蛋白的抑制。miR-200c对这些细胞的恢复恢复了E-钙粘蛋白，并显着降低了迁移和侵袭。微阵列分析显示，除了ZEB1和ZEB2之外，其他间充质基因（如FN 1，NTRK2和QKI）也是miR-200c的预测直接靶点，它们确实被外源性miR-200c抑制。一种这样的基因，III类β-微管蛋白（TUBB3），其编码通常仅在神经元细胞中发现的微管蛋白同种型，是miR-200c的直接靶标。这一发现具有特别重要的意义，因为我们表明miR-200c的恢复使对微管靶向药物的敏感性增加了85%。由于TUBB3的表达是许多类型的实体瘤中对微管结合化疗剂耐药的常见机制，因此miR-200 c恢复对此类药物的化疗敏感性的能力可以通过其减少TUBB3的能力来解释。由于miR-200c对于维持上皮身份、行为和对化疗的敏感性至关重要，我们建议将其作为侵袭性耐药癌症的治疗策略进行进一步研究。
The transcription factor ZEB1 is normally not expressed in epithelial cells. When inappropriately expressed in carcinomas, ZEB1 initiates epithelial to mesenchymal transition due to its ability to repress E-cadherin and other genes involved in polarity. Recently, ZEB1 and ZEB2 have been identified as direct targets of the microRNA-200c family. We find that miR-200c levels are high in well-differentiated endometrial, breast and ovarian cancer cell lines, but extremely low in poorly-differentiated cancer cells. Low or absent miR-200c results in aberrant expression of ZEB1 and consequent repression of E-cadherin. Reinstatement of miR-200c to such cells restores E-cadherin and dramatically reduces migration and invasion. Microarray profiling reveals that in addition to ZEB1 and ZEB2, other mesenchymal genes (such as FN1, NTRK2, and QKI), which are also predicted direct targets of miR-200c, are indeed inhibited by addition of exogenous miR-200c. One such gene, class IIIβ-tubulin (TUBB3), which encodes a tubulin isotype normally found only in neuronal cells, is a direct target of miR-200c. This finding is of particular significance because we show that restoration of miR-200c increases sensitivity to microtubule-targeting agents by up to 85%. Since expression of TUBB3 is a common mechanism of resistance to microtubule-binding chemotherapeutic agents in many types of solid tumors, the ability of miR-200c to restore chemosensitivity to such agents may be explained by its ability to reduce TUBB3. Because miR-200c is crucial for maintenance of epithelial identity, behavior, and sensitivity to chemotherapy, we propose that it warrants further investigation as a therapeutic strategy for aggressive, drug-resistant cancers.