外泌体介导HIF-1α跨细胞调控HMOX1参与前列腺癌亚克隆间阿比特龙耐药性播散的作用及机制研究

Exosome, a new-found vehicle for intercellular communication，has been demonstrated to be responsible for progression of prostate cancer. However, no studies have reported whether exosomes play a role in the process of abiraterone-resistance transformation. Our preliminary study found that abiraterone-sensitive parental prostate cancer cells （AA-S-PCa）got the resistance after indirectly co-cultured with abiraterone-resistance prostate cancer cells （AA-R-PCa）; the results of quantitative PCR showed that the expressions of HIF-1α and HMOX1 are increased both in the AA-R-PCa cells and in the AA-S parental cells co-cultured with AA-R-PCa cells. Combining with the bioinformatics prediction, we hypothesis that the AA-R subclones will propagate the resistance ability to AA-S subclones via exosome-transmitted HIF-1α activating the HMOX1 in AA-S subclones. From the molecular, cellular, tissue and animal levels, our study will testify the effect of exosomes in propagating abiraterone-resistance among prostate cancer subclones and the role of HMOX1 on the sensitivity of abiraterone, and explore the mechanisms of exosome-transmitted HIF-1α modulating the HMOX1 in transcellular pathway. This study will explore for the first time the process and concrete mechanisms that exosomes participate in the development of abiraterone-resistance in prostate cancer, providing the new insights for treating the abiraterone-resistance prostate cancer.

外泌体作为一种新型的细胞间信息交流载体在前列腺癌恶变过程中发挥重要作用，但尚没有报道是否参与阿比特龙耐药的形成。我们前期研究发现将阿比特龙敏感的原代前列腺癌亲本细胞（AA-S-PCa）与阿比特龙耐药前列腺癌（AA-R-PCa）细胞间接共培养后，可使亲本细胞获得耐药特性；定量PCR结果显示HIF-1α和HMOX1均在AA-R-PCa细胞和共培养后的亲本细胞中高表达，结合生物信息学预测，我们提出假说：耐药细胞亚克隆通过外泌体转运HIF-1α调控非耐药细胞亚克隆内HMOX1，播散阿比特龙耐药性。本项目拟从分子、细胞、组织以及动物水平等多层次明确外泌体介导前列腺癌细胞亚克隆间阿比特龙耐药性播散的作用，确定HMOX1表达对阿比特龙敏感性的影响并揭示外泌体递送HIF-1α跨细胞调控HMOX1的机制。本研究将首次探讨外泌体参与前列腺癌阿比特龙耐药形成的过程及机制，为治疗阿比特龙抵抗性前列腺癌提供新思路。

前列腺癌是男性最常见的恶性肿瘤之一，我国前列腺癌的发病率也逐年上升，而且转移性前列腺癌占了1/3。对于转移性高危前列腺癌或者去势抵抗性前列腺癌，目前临床使用最广泛的是阿比特龙。但阿比特龙使用一段时间后可出现耐药情况。解决阿比特龙耐药问题可提高患者的预后。外泌体作为一种新型的细胞间信息交流载体已经被证实在前列腺癌恶变过程中发挥重要作用，但尚没有报道是否参与阿比特龙耐药的形成。本项目利用体内体外实验结合分子实验等首次明确外泌体介导前列腺癌细胞亚克隆间阿比特龙耐药性播散的作用，确定前列腺癌细胞内HMOX1表达上调与阿比特龙耐药性的产生密切相关，明确了阿比特龙耐药前列腺癌细胞可以通过其分泌的外泌体递送HIF-1α促进阿比特龙敏感前列腺癌亚克隆产生耐药性，并且初步验证了HIF-1α对HMOX1的调控作用.我们的研究结果证明了外泌体可以通过递送HIF-1α跨细胞调控HMOX1促进前列腺癌细胞产生阿比特龙耐药的作用。本研究首次探讨了外泌体参与前列腺癌阿比特龙耐药形成的过程及机制，为未来治疗阿比特龙抵抗性前列腺癌提供新思路。