Overexpression of claspin promotes docetaxel resistance and is associated with prostate-specific antigen recurrence in prostate cancer.
Overexpression of claspin promotes docetaxel resistance and is associated with prostate-specific antigen recurrence in prostate cancer.
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DOI：
10.1002/cam4.4113
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发表时间：
2021-08
期刊：
影响因子：
4
通讯作者：
Yasui W
中科院分区：
文献类型：
--
作者：
Babasaki T;Sentani K;Sekino Y;Kobayashi G;Thang Pham Q;Katsuya N;Akabane S;Taniyama D;Hayashi T;Shiota M;Oue N;Teishima J;Matsubara A;Yasui W
尽管多西他赛（DTX）在去势抵抗性前列腺癌（CRPC）患者中具有显著的生存获益，但对DTX的耐药性不可避免地发生。因此，阐明DTX抵抗的机制可能会改善CRPC患者的生存率。Claspin在DNA复制应激和损伤反应中起着关键作用，是S期检查点的重要调节因子。CLSPN是一种致癌基因，在几种人类实体瘤中促进肿瘤增殖。然而，claspin在前列腺癌（PCa）中的临床意义尚未研究。本研究旨在阐明claspin在PCa中的作用及其与DTX抗性的关系。我们对89例PCa病例中claspin的表达进行了免疫组化分析，其中31例（35%）为claspin阳性。Claspin阳性病例与较高的Gleason评分、静脉浸润和神经周围浸润相关。Kaplan-Meier分析显示claspin高表达与前列腺特异性抗原（PSA）无复发预后不良相关。在公共数据库中，CLSPN高表达与PSA无复发预后差、Gleason评分、T分期、淋巴结转移、CRPC和转移性PCa相关。在DU 145和PC 3细胞系中，通过siRNA敲低Claspin降低细胞增殖，上调DTX敏感性，并抑制Akt、Erk 1/2和CHK 1磷酸化的表达。此外，claspin表达在DTX抗性DU 145（DU 145-DR）中比在亲本DU 145细胞中上调得多。Claspin敲低显著上调DU 145 ‐DR细胞对DTX的敏感性。这些结果表明claspin在PCa肿瘤进展和DTX抗性中起重要作用。Claspin过表达与PSA无复发预后不良相关。Claspin敲低显著上调DU 145多西他赛耐药细胞对多西他赛的敏感性。
Although docetaxel (DTX) confers significant survival benefits in patients with castration‐resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S‐phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin‐positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan–Meier analysis showed that high claspin expression was related to poor prostate‐specific antigen (PSA) relapse‐free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse‐free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX‐resistant DU145 (DU145‐DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145‐DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance. Claspin overexpression was related to poor PSA relapse‐free prognosis. Claspin knockdown significantly upregulated the sensitivity to docetaxel in DU145 docetaxel‐resistant cells.
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影响因子：
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作者：
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