SPARCL1基因功能多态性对于内分泌治疗后去势抵抗性前列腺癌发生风险的影响及作用机制研究

The role of chemotherapy in metastatic prostate cancer is supported by the updated by the guidelines. The ability to predict response to primary androgen deprivation therapy (ADT) and risk of castration-resistant would be invaluable due to the toxic effects. Previous studies suggest that SPARCL1 was been implicated castration-resistant prostate cancer (CRPC) via androgen receptor and non-androgen receptor signalling way as matricellular protein in tumor microenvironment. We establish SPARCL1 knockout prostate cancer cell line using the CRISPR/Cas9 system and further confirm that SPARCL1 knockout increase prostate cancer cell proliferation and PSA expression. Three functional SNPs in the SPARCL1 gene were associated with time to progression and risk of CRPC. Given the role of SPARCL1 in the tumor microenvironment, SPARCL1 polymorphisms have the potential to modify its expression or function and subsequently lead to CRPC. This study aimed to reveal the association between genetic variations in SPARCL1 and the risk of CRPC and underlying biological mechanisms. Also, these findings will help to identify the high risk patients who benefit most from chemotherapy.

指南更新彰显了内分泌治疗联合早期化疗在转移性前列腺癌中的价值。然而考虑到化疗副反应等因素，寻找预测患者内分泌治疗预后和去势抵抗性前列腺癌（CRPC）发生风险的生物标记物成为当务之急。多项研究提示前列腺癌微环境中细胞基质蛋白SPARCL1可能通过AR途径和非AR途径对CRPC发生发展起关键作用。前期研究中我们采用CRISPR/Cas9技术敲除SPARCL1基因后发现前列腺癌细胞增殖能力和PSA表达显著增高，相反SPARCL1过表达细胞系的增殖能力和PSA表达显著下降。并且3个SPARCL1基功能性多态位点与内分泌治疗预后及CRPC发生相关，其机制可能与机体微环境中SPARCL1表达/功能差异有关。在此，我们拟明确SPARCL1基因多态性对内分泌治疗预后和CRPC发生风险的预测价值，揭示SPARCL1基因多态性在CRPC发生中的作用机制，为临床上遴选CRPC高危患者和采取个体化治疗提供参考。

指南更新彰显了内分泌治疗联合早期化疗在转移性前列腺癌中的价值。然而考虑到化疗副反应等因素，寻找预测患者内分泌治疗预后和去势抵抗性前列腺癌（CRPC）发生风险的生物标记物成为当务之急。多项研究提示前列腺癌微环境中细胞基质蛋白SPARCL1可能通过AR途径和非AR途径对CRPC发生发展起关键作用。研究结果显示SPARCL1蛋白在前列腺癌中的表达下调，敲除SPARCL1促进前列腺癌细胞增殖并上调PSA mRNA表达，过表达SPARCL1抑制前列腺癌细胞增殖并下调PSA mRNA表达，敲除SPARCL1后促进前列腺癌细胞进入S期，过表达SPARCL1后前列腺癌细胞阻滞在G0-G1期。并且SPARCL1基因功能性多态位点rs1049539和rs1130643与内分泌治疗预后及CRPC发生具有相关性，其机制可能与机体微环境中SPARCL1表达/功能差异有关。本研究一方面弥补了当前基于临床病理指标预测内分泌治疗预后的缺陷，为临床上遴选发生CRPC高危患者和采取个体化治疗提供理论基础，也为制定早期干预策略如联合化疗等提供依据，另一方面为进一步研究CRPC的发生、发展和治疗提供新的方向。