Downregulation of cytokeratin 18 is associated with paclitaxel-resistance and tumor aggressiveness in prostate cancer
Downregulation of cytokeratin 18 is associated with paclitaxel-resistance and tumor aggressiveness in prostate cancer
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细胞角蛋白 18 的下调与前列腺癌的紫杉醇耐药性和肿瘤侵袭性相关
DOI：
10.3892/ijo.2016.3396
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发表时间：
2016-04-01
影响因子：
5.2
通讯作者：
Song, Yongsheng
中科院分区：
文献类型：
--
作者：
Yin, Bo;Zhang, Mo;Song, Yongsheng
紫杉醇经常作为去势抵抗性前列腺癌（PCa）患者的一线化疗药物。然而，获得性紫杉醇耐药几乎总是发生在初始反应之后，并且其发生的机制在很大程度上仍然未知。本研究的目的是鉴定与紫杉醇耐药相关的差异表达蛋白，并进一步探讨紫杉醇耐药的可能机制。通过比较已建立的稳定的紫杉醇耐药PCa细胞DU 145-TxR与亲本细胞DU 145的核基质蛋白（NMP）图谱，我们发现细胞角蛋白18（CK 18）在DU 145-TxR细胞中表达下调。通过实时荧光定量RT-PCR、免疫印迹和免疫荧光技术证实了DU 145-TxR细胞中CK 18在mRNA、NMP和总细胞蛋白水平上的下调，表明DU 145-TxR细胞中CK 18的下调是由于紫杉醇耐药所致的全局效应。此外，体内异种移植试验证实DU 145-TxR细胞具有较高的致瘤性，这表明这些紫杉醇耐药PCa细胞具有有效的癌症干细胞（CSC）样特性，并最终产生紫杉醇耐药性。此外，我们通过免疫组化确定，PCa组织中CK 18表达与肿瘤分级呈负相关，具有统计学意义，表明CK 18下调与肿瘤侵袭性可能相关。因此，进一步研究确定CK 18的潜在作用可能会导致新的治疗策略以及临床上有用的生物标志物PCa患者。
Paclitaxel frequently serves as the first-line chemotherapeutic agent for castration-resistant prostate cancer (PCa) patients. However, acquired paclitaxel-resistance almost always occurs after initial responses, and the mechanisms by which this occurs remain largely unknown. The goal of the present study was to identify differentially expressed protein(s) associated with paclitaxel-resistance and further explore the potential mechanisms involved in drug resistance. By comparing the nuclear matrix protein (NMP) patterns of DU145-TxR cells, the previously established stable paclitaxel-resistant PCa cells, with that of the parental DU145 cells using two-dimensional electrophoresis, we found that cytokeratin 18 (CK18) is downregulated in DU145-TxR cells. The downregulation of CK18 in DU145-TxR cells at mRNA, NMP and total cellular protein levels was validated by real-time RT-PCR, immunoblotting and immunofluorescence, indicating that the downregulation of CK18 was a global effect in DU145-TxR cells due to paclitaxel-resistance. Furthermore, in vivo assay of xenograft transplantation confirmed the higher tumorigenicity of DU145-TxR cells, suggesting that these paclitaxel-resistant PCa cells possessed potent cancer stem cell (CSC)-like properties and eventually developed paclitaxel-resistance. Moreover, we determined by immunohistochemistry that CK18 expression in PCa tissues was inversely correlated with tumor grade in a statistically significant fashion, indicating a potential association of the downregulation of CK18 with tumor aggressiveness. Therefore, further study to define the potential role of CK18 may lead to novel therapy strategies as well as clinically useful biomarker for PCa patients.