MiR-148a Attenuates Paclitaxel Resistance of Hormone-refractory, Drug-resistant Prostate Cancer PC3 Cells by Regulating MSK1 Expression.
MiR-148a Attenuates Paclitaxel Resistance of Hormone-refractory, Drug-resistant Prostate Cancer PC3 Cells by Regulating MSK1 Expression.
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DOI：
10.1074/jbc.m109.079525
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发表时间：
2010-06-18
影响因子：
4.8
通讯作者：
Ito, Masafumi
中科院分区：
文献类型：
--
作者：
Fujita, Yasunori;Kojima, Keitaro;Ito, Masafumi
MicroRNA 参与癌症发病机制并充当肿瘤抑制基因或癌基因。最近有报道称，miR-148a 表达在多种类型的癌症中下调。然而，miR-148a 在前列腺癌中的功能作用和靶基因仍然未知。在本报告中，我们发现与 PrEC 正常人前列腺上皮细胞和 LNCaP 激素敏感前列腺癌细胞相比，PC3 和 DU145 激素难治性前列腺癌细胞中 miR-148a 表达水平较低。转染miR-148a前体可抑制PC3细胞的细胞生长、细胞迁移和侵袭，并增加对抗癌药物紫杉醇的敏感性。计算机辅助算法预测丝裂原和应激激活蛋白激酶 MSK1 作为 miR-148a 的潜在靶标。事实上，miR-148a 过度表达降低了 MSK1 的表达。使用荧光素酶报告基因检测，我们确定 MSK1 是 miR-148a 的直接靶标。然而，通过 siRNA 抑制 MSK1 表达，对 PC3 细胞的恶性表型影响很小或没有影响。在 PC3PR 细胞（从 PC3 细胞建立的紫杉醇耐药细胞系）中，miR-148a 抑制细胞生长、细胞迁移和侵袭，并减弱对紫杉醇的耐药性。 MiR-148a 通过直接靶向 PC3PR 细胞中的 3'-UTR 来降低 MSK1 表达。此外，MSK1 敲低降低了 PC3PR 细胞的紫杉醇耐药性，表明 miR-148a 部分通过调节 MSK1 表达来减弱激素难治性、耐药性 PC3PR 细胞的紫杉醇耐药性。我们的研究结果表明，miR-148a 作为肿瘤抑制因子发挥着多种作用，并且可以成为激素难治性前列腺癌特别是耐药性前列腺癌的有前景的治疗靶点。
MicroRNAs are involved in cancer pathogenesis and act as tumor suppressors or oncogenes. It has been recently reported that miR-148a expression is down-regulated in several types of cancer. The functional roles and target genes of miR-148a in prostate cancer, however, remain unknown. In this report, we showed that miR-148a expression levels were lower in PC3 and DU145 hormone-refractory prostate cancer cells in comparison to PrEC normal human prostate epithelial cells and LNCaP hormone-sensitive prostate cancer cells. Transfection with miR-148a precursor inhibited cell growth, and cell migration and invasion, and increased the sensitivity to anti-cancer drug paclitaxel in PC3 cells. Computer-aided algorithms predicted mitogen-and stress-activated protein kinase, MSK1, as a potential target of miR-148a. Indeed, miR-148a overexpression decreased expression of MSK1. Using luciferase reporter assays, we identified MSK1 as a direct target of miR-148a. Suppression of MSK1 expression by siRNA, however, showed little or no effects on malignant phenotypes of PC3 cells. In PC3PR cells, a paclitaxel-resistant cell line established from PC3 cells, miR-148a inhibited cell growth, and cell migration and invasion, and also attenuated the resistance to paclitaxel. MiR-148a reduced MSK1 expression by directly targeting its 3'-UTR in PC3PR cells. Furthermore, MSK1 knockdown reduced paclitaxel-resistance of PC3PR cells, indicating that miR-148a attenuates paclitaxel-resistance of hormone-refractory, drug-resistant PC3PR cells in part by regulating MSK1 expression. Our findings suggest that miR-148a plays multiple roles as a tumor suppressor and can be a promising therapeutic target for hormone-refractory prostate cancer especially for drug-resistant prostate cancer.