Overexpression of SLC6A1 associates with drug resistance and poor prognosis in prostate cancer
Overexpression of SLC6A1 associates with drug resistance and poor prognosis in prostate cancer
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SLC6A1 过度表达与前列腺癌耐药和不良预后相关
DOI：
10.1186/s12885-020-06776-7
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发表时间：
2020-04-06
期刊：
影响因子：
3.8
通讯作者：
Zhong, Weide
中科院分区：
文献类型：
--
作者：
Chen, Chaojiang;Cai, Zhiduan;Zhong, Weide
溶质载体家族6成员1 （SLC6A1）已被确定为多种人类癌症的促癌基因，如透明细胞肾细胞癌和卵巢癌。然而，其在前列腺癌（PCa）中的作用尚未完全阐明。本研究旨在探讨SLC6A1在前列腺癌组织中的表达及临床意义，以及SLC6A1对前列腺癌多西他赛耐药的影响。方法采用组织芯片免疫组化技术检测前列腺癌组织中SLC6A1蛋白的表达谱。根据TCGA数据，统计评估SLC6A1蛋白表达与前列腺癌各种临床病理特征及患者预后的关系。体外和体内实验进一步确定SLC6A1失调在前列腺癌发生和耐药中的作用。结果TCGA数据集显示，SLC6A1在Gleason评分高、临床分期晚期、生化复发阳性患者中的表达明显高于对照组（p < 0.05）。单因素和多因素分析均表明，SLC6A1表达与前列腺癌患者的生化无复发生存率显著相关。此外，SLC6A1的强制表达能有效促进体外PCa细胞的增殖、迁移和侵袭。此外，抑制SLC6A1在体内抑制肿瘤生长。此外，低表达组的PCNA和MMP-9的免疫组化缺口明显低于NC组。最后，细胞活力显示，SLC6A1过表达明显促进了PCa细胞对多西紫杉醇（DTX）的耐药，且过表达组移植瘤与未处理组相比无明显减少。结论SLC6A1过表达可能与前列腺癌的侵袭性进展和较短的生化无复发生存期有关，并可能与多西他赛耐药有关。
BackgroundSolute Carrier Family 6 Member 1 (SLC6A1) has been identified as a cancer-promoting gene in various human cancers, such as clear cell renal cell carcinoma and ovarian cancer. However, its roles in prostate cancer (PCa) has not been fully elucidated. The aim of this study was to investigate the expression and clinical significance of SLC6A1 in PCa tissues and its effect on drug resistance to docetaxel in PCa.MethodsExpression patterns of SLC6A1 protein in PCa tissues were examined by immunohistochemistry based on Tissue microarray. Associations of SLC6A1 protein expression with various clinicopathological features and patients’ prognosis of PCa were also statistically evaluated based on TCGA data. Roles of SLC6A1 deregulation in prostate carcinogenesis and drug resistance was further determined in vitro and in vivo experiments.ResultsBased on TCGA Dataset, SLC6A1 expression was markedly higher in patients with high Gleason score, advanced clinical stage and positive biochemical recurrence than those with control features (allP< 0.05). Both unvariate and multivariate analyses demonstrated that SLC6A1 expression was significantly associated with biochemical recurrence-free survival in PCa patients. In addition, enforced expression of SLC6A1 effectively promoted cell proliferation, migration and invasion of PCa cells in vitro. Moreover, the inhibition of SLC6A1 suppressed the tumor growth in vivo. Additionally, immunohistochemical notches of PCNA and MMP-9 in the low-expression cluster were pointedly lower compared to those of NC group. Finally, the cell viability revealed that the overexpression of SLC6A1 obviously promoted the PCa cell resistant to docetaxel (DTX), and the transplanted tumor in the overexpression group had no significant reduction compared with the untreated group.ConclusionsOur data suggest that SLC6A1 overexpression may be associated with aggressive progression and short biochemical recurrence-free survival of PCa, and may be related to the resistance to docetaxel therapy.