Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University School of Medicine, Toyoake, Japan.
Department of Urology, Asahi University Hospital, Gifu, Japan.
Prostate. 2024 Dec;84(16):1515-1524. doi: 10.1002/pros.24792. Epub 2024 Sep 15.
Androgen receptor signaling inhibitors(ARSIs) have been used to treat patients with metastatic prostate cancer (PC) and castration-resistant prostate cancer (CRPC). In this study, we aimed to identify novel serum extracellular vesicle (EV)-based biomarkers to diagnose ARSI-resistance and therapeutic targets for ARSI-resistant CRPC.
Total RNA contained in serum EVs from 5 cases of CRPC before ARSI treatment and after acquiring ARSI-resistance was subjected to RNA-sequencing. The expression changes of selected RNAs contained in EVs were confirmed in 48 cases of benign prostatic hyperplasia (BPH) and 107 PC using reverse transcription-quantitative PCR (RT-qPCR) and compared with tissue RNA expression using public datasets.
RNA-sequencing revealed that mitochondrial oxidative phosphorylation (OXPHOS)-related genes were increased in EVs after acquiring ARSI-resistance. Among them, RT-qPCR and datasets analysis demonstrated that SDHB mRNA was upregulated after acquiring ARSI-resistance in EVs and ARSI-exposed PC tissue compared to ARSI-naïve EVs and tissue, respectively. SDHB mRNA levels both in EVs and tissue were increased in localized PC compared with BPH and decreased in advanced PC. Tissue expression of SDHB mRNA was significantly correlated with those of other OXPHOS-related genes. SDHB mRNA in EVs (EV-SDHB) was elevated among 3 out of 7 ARSI-treating patients with stable PSA levels who later progressed to ARSI-resistant CRPC.
The levels of OXPHOS-related mRNAs in EVs correlated with those in PC tissue, among which SDHB mRNA was found to be a novel biomarker to diagnose ARSI-resistance. EV-SDHB may be useful for early diagnosis of ARSI-resistance.
雄激素受体信号抑制剂（ARSIs）已被用于治疗转移性前列腺癌（PC）和去势抵抗性前列腺癌（CRPC）患者。在这项研究中，我们旨在鉴定新的血清细胞外囊泡（EV）基于生物标志物，以诊断 ARSI 耐药和 ARSI 耐药性 CRPC 的治疗靶点。
用 ARSI 治疗前和获得 ARSI 耐药后的 5 例 CRPC 患者的血清 EV 中的总 RNA 进行 RNA-seq 分析。使用逆转录定量 PCR（RT-qPCR）在 48 例良性前列腺增生（BPH）和 107 例 PC 中对 EV 中包含的选定 RNA 的表达变化进行了确认，并使用公共数据集与组织 RNA 表达进行了比较。
RNA-seq 显示，获得 ARSI 耐药后，EV 中与线粒体氧化磷酸化（OXPHOS）相关的基因增加。其中，RT-qPCR 和数据集分析表明，与 ARSI 敏感的 EV 和组织相比，SDHB mRNA 在获得 ARSI 耐药后在 EV 和 ARSI 暴露的 PC 组织中上调。与 BPH 相比，局部 PC 中 EV 和组织中的 SDHB mRNA 水平均升高，而晚期 PC 中则降低。组织中 SDHB mRNA 的表达与其他 OXPHOS 相关基因的表达显著相关。在 7 名接受 ARSI 治疗的 PSA 水平稳定的患者中，有 3 名患者的 EV-SDHB 升高，后来进展为 ARSI 耐药性 CRPC。
EV 中与 OXPHOS 相关的 mRNAs 水平与 PC 组织中的水平相关，其中 SDHB mRNA 被发现是诊断 ARSI 耐药的新型生物标志物。EV-SDHB 可能有助于早期诊断 ARSI 耐药。
