Impact of nuclear YAP1 expression in residual cancer after neoadjuvant chemohormonal therapy with docetaxel for high-risk localized prostate cancer
Impact of nuclear YAP1 expression in residual cancer after neoadjuvant chemohormonal therapy with docetaxel for high-risk localized prostate cancer
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DOI：
10.1186/s12885-020-06844-y
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发表时间：
2020-04-15
期刊：
影响因子：
3.8
通讯作者：
Habuchi, Tomonori
中科院分区：
文献类型：
--
作者：
Matsuda, Yoshinori;Narita, Shintaro;Habuchi, Tomonori
虽然多西他赛为基础的激素化疗（CHT）是去势抵抗性前列腺癌（CRPC）的标准治疗方法之一，但相关的生物标志物和CRPC耐药的确切机制尚不清楚。我们研究了化疗激素抵抗与类固醇受体和Hippo通路蛋白表达之间的关系，使用多西他赛耐药前列腺癌（PCa）细胞系和接受手术和不接受新辅助治疗的人PCa组织。方法制备多西他赛耐药亚群（22Rv1-DR），检测Hippo通路蛋白表达及YAP1抑制对细胞特性的影响。采用来自70个高危局部PCa组织的203个核心的组织芯片来评估类固醇受体和Hippo通路蛋白的表达。结果核YAP （nYAP）在22Rv-1 - dr中的表达高于亲本22Rv-1， YAP1的敲低抑制了22Rv1-DR的细胞增殖。类固醇受体和Hippo通路蛋白的表达在三个不同的新佐剂组中有所不同，nYAP1的表达在CHT组中最高。新辅助CHT术后残余癌中nYAP1高的患者生化复发率明显高于nYAP1低的患者。在多变量分析中，高nYAP1是BCR的独立预后因素。结论在多西他赛基CHT治疗的高危患者中，snyap表达是一个潜在的生物标志物。类固醇受体和Hippo通路蛋白可能在晚期前列腺癌的化学激素抵抗中发挥作用。
BackgroundAlthough docetaxel-based chemohormonal therapy (CHT) is one of the standard treatments for castration-resistant prostate cancer (CRPC), pertinent biomarkers and precise mechanisms involved in the resistance for CHT for CRPC remain unknown. We investigated the relationship between chemohormonal resistance and the expression of steroid receptors and Hippo pathway proteins using a docetaxel-resistant prostate cancer (PCa) cell line and human PCa tissues in patients who underwent surgery with and without neoadjuvant therapy.MethodsA docetaxel-resistant subline (22Rv1-DR) was generated to assess Hippo pathway protein expression and the effect of YAP1 inhibition on cellular characteristics. A tissue microarray with 203 cores from 70 high-risk localized PCa tissues was performed to assess steroid receptor and Hippo pathway protein expressions.ResultsNuclear YAP (nYAP) expression was higher in 22RV-1-DR than in parental 22Rv-1 and YAP1 knockdown suppressed cell proliferation of 22Rv1-DR. Steroid receptor and Hippo pathway protein expressions varied among three different neoadjuvant groups, and nYAP1 expression was the highest in the CHT group. The patients with high nYAP in residual cancer after neoadjuvant CHT had a significantly higher biochemical recurrence (BCR) rate than those with low nYAP1. On multivariate analysis, the high nYAP1 was an independent prognostic factor for BCR.ConclusionsnYAP expression is a potential biomarker in high-risk patients treated with docetaxel-based CHT. Steroid receptors and Hippo pathway proteins may play a role in the chemohormonal resistance in advanced PCa.