PSGR通过外泌体途径促进前列腺癌骨转移前niche形成的作用机制研究

Prostate Cancer (PCa), is one of most common malignant tumor of male in the world. Clinical treatment of advanced PCa is not satisfying, especially for metastatic PCa, of which the prognosis is very poor, its five-year survival rate is less than 30%. Bone metastases is the most common type of metastatic PCa, but the mechanism of bone metastasis is not yet clear, and treatment options are relatively limited. Exosomes as an important part of the liquid biopsy, are the reliable source of biomarkers for early diagnosis and assessment of prognosis, as well as the ideal way for targeted drug delivery, accounting for an important prospect of clinical application. In recent years, exosomes were found to be a precursor for metastasis of malignant tumor by promoting the formation of pre-metastatic niche, our preliminary results found that compared with the localized PCa, prostate specific G protein coupled receptor (PSGR) was overexpressed in exosomes derived from the urine of PCa patients with bone metastases, giving a hint that exosomes may participate in the process of bone metastasis of PCa. To test this hypothesis, we intends to investigate the molecular mechanism of PSGR contained exosomes enhancing the invasion of neighbor PCa cells through paracrine, and the formation of bone pre-metastatic niche after the receptor cells in bone microenvironment accepting exosomes derived from the PCa. To clarify the mechanism underlying exosomes` role in the development of bone metastases of PCa.

前列腺癌是全球男性高发肿瘤之一，临床上治疗中晚期前列腺患者是难点，尤其是转移性 前列腺癌五年生存率不到30%，骨转移是前列腺癌最常见的转移类型，但是骨转移的发生机制 尚不清楚，治疗手段相对局限。外泌体作为液体活检的重要部分，是用于早期诊断和判断预后 的生物标记物的可靠来源，也是靶向给药的理想途径，近年来研究发现外泌体可以通过促进转 移前niche形成参与恶性肿瘤的定植转移，我们前期结果发现前列腺特异性G蛋白偶联受体与前 列腺癌恶性表型相关，且相对于局限性前列腺癌患者，在前列腺癌骨转移患者尿来源外泌体中 过量表达，提示其可能参与前列腺癌骨转移的发生发展过程。本项目拟进一步研究外泌体携带 PSGR通过旁分泌作用增强周围肿瘤细胞侵袭力的分子机制，以及骨微环境中前列腺癌外泌体的 受体细胞接纳外泌体后形成骨转移前niche的具体机制，以阐明外泌体促进前列腺癌骨转移发 生和发展中的作用机制。

前列腺癌是全球男性高发肿瘤之一，临床上治疗中晚期前列腺患者是难点，尤其是转移性前列腺癌五年生存率不到30%，骨转移是前列腺癌最常见的转移类型，但是骨转移的发生机制尚不清楚，治疗手段相对局限。外泌体作为液体活检的重要部分，是用于早期诊断和判断预后的生物标记物的可靠来源，也是靶向给药的理想途径，近年来研究发现外泌体可以通过促进转移前niche形成参与恶性肿瘤的定植转移。我们前期结果发现前列腺特异性G蛋白偶联受体与前列腺癌恶性表型相关，且相对于局限性前列腺癌患者，在前列腺癌骨转移患者尿来源外泌体中过量表达，提示其可能参与前列腺癌骨转移的发生发展过程。本研究证明了过表达PSGR的PC3细胞源外泌体孵育LNCaP细胞、RWPE-1细胞后，促进LNCaP细胞、RWPE-1细胞的EMT进程和细胞干性，重塑其转录组表达谱；PSGR过表达的PC3细胞衍生的外泌体增强了hFOB1.19成骨能力，通过转录组测序揭示了外泌体PSGR在PCa转移骨微环境中的分子机制，为前列腺癌骨转移的早期诊断及新型靶向药物的研发提理论基础。