Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients.
Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients.
复制标题
原钙粘蛋白 B9 促进对比卡鲁胺的耐药性，并与前列腺癌患者的生存相关。
作者：
Sekino Y;Oue N;Mukai S;Shigematsu Y;Goto K;Sakamoto N;Sentani K;Hayashi T;Teishima J;Matsubara A;Yasui W.
前列腺癌（PCa）是世界范围内常见的恶性肿瘤，是男性癌症死亡的第二大原因。晚期前列腺癌的标准治疗是雄激素剥夺治疗（ADT）。虽然ADT（包括比卡鲁胺治疗）最初是有效的，但对比卡鲁胺的耐药性经常发生，并导致去势抵抗性PCa的发展。因此，迫切需要澄清比卡鲁胺耐药机制。我们设计了这项研究，以评估编码原钙粘蛋白B9的pcdhb9的表达和功能。方法采用免疫组化和qRT - PCR检测PCDHB9的表达。观察PCDHB9过表达或低表达对细胞生长、迁移、粘附的影响。为了评估PCDHB9在PCa中的介导作用，我们使用PCDHB9转染的DU145进行了基因表达分析。我们检测了PCDHB9抑制对比卡鲁胺耐药的影响。结果qRT - PCR结果显示pcdhb9在前列腺癌组织中的表达明显高于非肿瘤前列腺组织。在152例临床局限性前列腺癌中，免疫组化显示59%的前列腺癌原钙粘蛋白B9阳性。Kaplan‐Meier分析显示，原钙粘蛋白B9的高表达与根治性前列腺切除术后PSA复发有关。功能分析显示PCDHB9调节细胞迁移和粘附。我们还通过基因表达分析发现PCDHB9诱导ITGB6的表达。MTT法检测PCDHB9抑制对比卡鲁胺敏感性的影响。pcdhb9sirna转染的PCa细胞ic50值显著低于阴性siRNA转染的对照细胞。此外，74例接受雄激素消耗治疗（包括比卡鲁胺治疗）的PCa患者的原钙粘蛋白B9免疫组化染色表明，原钙粘蛋白B9的高表达与较差的总生存率显著相关。结论PCDHB9在前列腺癌的进展和比卡鲁胺耐药过程中起重要作用。总的来说，我们的结果表明PCDHB9靶向治疗可能比单独使用比卡鲁胺更有效。
Background Prostate cancer (PCa) is a common malignancy worldwide and is the second leading cause of cancer death in men. The standard therapy for advanced PCa is androgen deprivation therapy (ADT). Although ADT, including bicalutamide treatment, is initially effective, resistance to bicalutamide frequently occurs and leads to the development of castration‐resistant PCa. Thus, clarifying the mechanisms of bicalutamide resistance is urgently needed. We designed this study to assess the expression and function ofPCDHB9, which encodes the protocadherin B9 protein.Methods The expression of PCDHB9 was determined using immunohistochemistry and a qRT‐PCR. The effects of the overexpression or knockdown of PCDHB9 on cell growth, migration, adhesion were evaluated. To evaluate the PCDHB9‐mediated effects in PCa, we performed a gene expression analysis using DU145 transfected with PCDHB9. We examined the effects of PCDHB9 inhibition on bicalutamide resistance.Results The qRT‐PCR revealed that the expression ofPCDHB9was much higher in PCa than that in non‐neoplastic prostate tissues. In 152 clinically localized PCa cases immunohistochemistry showed that 59% of PCa cases were positive for protocadherin B9. A Kaplan‐Meier analysis showed that the high expression of protocadherin B9 was associated with PSA recurrence after radical prostatectomy. A functional analysis showed that PCDHB9 modulated cell migration and adhesion. We also found that PCDHB9 induced the expression of ITGB6 based on a gene expression analysis. The effect of PCDHB9 inhibition on bicalutamide sensitivity was examined using MTT assays. The IC50value ofPCDHB9siRNA‐transfected PCa cells was significantly lower than that of negative control siRNA‐transfected cells. Furthermore, immunohistochemical staining of protocadherin B9 in 74 PCa patients who were treated with androgen depletion therapy, including bicalutamide treatment, demonstrated that the high expression of protocadherin B9 was significantly associated with poor overall survival.Conclusions PCDHB9 plays an important role in the progression of PCa and bicalutamide resistance. Collectively, our results suggest that PCDHB9 targeted therapy may be more effective than bicalutamide alone.