Department of Urology and Andrology, The First Affiliated Hospital of Guangzhou Medical University; Guangdong Provincial Key Laboratory of Urology, Guangzhou, Guangdong Province, China.
Medical school, University of South China, Hengyang, Hunan Province, China.
Mol Cancer Res. 2020 Mar;18(3):501-513. doi: 10.1158/1541-7786.MCR-19-0278. Epub 2019 Nov 13.
Distant metastasis, predominantly to bone, is the leading cause of morbidity and mortality in prostate cancer. However, the mechanisms underlying prostate cancer metastases remain unknown. Prostate cancer cells exhibited discrete adhesion to bone marrow endothelial cells (BMEC), resulting in osteotropic metastasis. Prior data showed an increased metastatic propensity of prostate stem cell antigen (PSCA)-positive prostate cancer cells. The current study sought to characterize the roles of PSCA in the adhesion of prostate cancer cells to BMECs. Cell adhesion was assessed using the adhesion assay and transendothelial migration. The expression and regulation of integrins were evaluated by qRT-PCR, Western blot, promoter-luciferase activity, and chromatin immunoprecipitation (ChIP). Functionally, the potential interacting partners of PSCA in prostate cancer cells were identified by coimmunoprecipitation and mass spectrometry (MS) analysis. The association of PSCA expression with bone metastasis was further analyzed in an model and prostate cancer patients. We found that overexpression of PSCA enhanced the adhesion capability of prostate cancer cells to BMECs through upregulating integrin-α4 expression, concurrent with transcriptionally activated NF-κB. Growth factor progranulin (PGRN) was identified as a potential interacting partner of PSCA in prostate cancer cells. Functional studies showed that downregulation of PGRN and PSCA with siRNAs in prostate cancer cells significantly suppressed the integrin-α4 expression and the adhesion to BMECs , respectively, which were restorable by exogenous PGRN. Importantly, PSCA depletion significantly reduced tumors' presence in the bone of a mouse model. Furthermore, PSCA expression is elevated in prostate cancer tissue, and significantly associated with increased Gleason score, advanced stage, bone metastasis, and poor prognosis in prostate cancer patients. We conclude that PSCA/PGRN promoted the adhesion of prostate cancer cells to BMECs through NF-κB/integrin-α4 pathways, to facilitate metastases. IMPLICATIONS: The findings presented here suggest PSCA/PGRN as a potential therapeutic target for prostate cancer metastases, especially for bone metastasis.
远处转移，主要是骨骼，是前列腺癌发病率和死亡率的主要原因。然而，前列腺癌转移的机制尚不清楚。前列腺癌细胞与骨髓内皮细胞（BMEC）有明显的黏附，导致成骨转移。先前的数据表明，前列腺干细胞抗原（PSCA）阳性的前列腺癌细胞有更高的转移倾向。本研究旨在研究 PSCA 在前列腺癌细胞与 BMEC 黏附中的作用。通过黏附实验和跨内皮迁移实验评估细胞黏附。通过 qRT-PCR、Western blot、启动子-荧光素酶活性和染色质免疫沉淀（ChIP）评估整合素的表达和调节。通过免疫共沉淀和质谱（MS）分析鉴定 PSCA 在前列腺癌细胞中的潜在相互作用伙伴。在动物模型和前列腺癌患者中进一步分析 PSCA 表达与骨转移的关系。我们发现 PSCA 的过表达通过上调整合素-α4 的表达增强了前列腺癌细胞与 BMEC 的黏附能力，同时转录激活 NF-κB。生长因子颗粒蛋白（PGRN）被鉴定为前列腺癌细胞中 PSCA 的一个潜在相互作用伙伴。功能研究表明，前列腺癌细胞中 PGRN 和 PSCA 的下调用 siRNAs 显著抑制了整合素-α4 的表达和对 BMEC 的黏附，而外源性 PGRN 可恢复这种作用。重要的是，PSCA 耗竭显著减少了小鼠模型中肿瘤在骨中的存在。此外，在前列腺癌组织中 PSCA 表达上调，与前列腺癌患者的 Gleason 评分升高、晚期、骨转移和预后不良显著相关。我们得出结论，PSCA/PGRN 通过 NF-κB/整合素-α4 途径促进了前列腺癌细胞与 BMEC 的黏附，从而促进了转移。意义：本研究结果表明，PSCA/PGRN 可能成为前列腺癌转移，特别是骨转移的潜在治疗靶点。
