Aberrant Expression of Citrate Synthase is Linked to Disease Progression and Clinical Outcome in Prostate Cancer
Aberrant Expression of Citrate Synthase is Linked to Disease Progression and Clinical Outcome in Prostate Cancer
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柠檬酸合酶的异常表达与前列腺癌的疾病进展和临床结果相关
DOI：
10.2147/cmar.s255817
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发表时间：
2020-01-01
影响因子：
3.3
通讯作者：
Zhong, Weide
中科院分区：
文献类型：
--
作者：
Cai, Zhiduan;Deng, Yulin;Zhong, Weide
目的柠檬酸合酶（Citrate synthase，CS）是柠檬酸循环中的限速酶，能催化草酰乙酸和乙酰辅酶A生成柠檬酸。CS已被发现在多种癌症中被上调，并且其在前列腺癌（PCa）中的表达和临床意义仍然未知。方法在本研究中，我们在TMA队列和公共癌症数据库（癌症基因组乳腺癌-前列腺癌，TCGA-PRAD）中检查CS表达水平与前列腺癌患者临床病理特征之间的关系。构建CS基因敲减的前列腺癌细胞系，研究CS基因下调对前列腺癌细胞增殖、集落形成、迁移、侵袭和细胞周期的影响。并在小鼠体内研究CS下调对肿瘤生长的影响。此外，在CS敲低细胞系中检测代谢组学和线粒体功能。结果CS在PCa组织中的表达明显高于正常组织（P < 0.05）。CS上调与高Gleason评分（P < 0.05）、晚期病理分期（P < 0.001）和生化复发（P < 0.001）显著相关。功能上，CS表达降低抑制PCa细胞增殖、集落形成、迁移、侵袭和细胞周期，并抑制体内肿瘤生长。此外，CS下调对PCa细胞的脂质代谢和线粒体功能产生潜在的抑制作用。结论CS表达上调可能与PCa的侵袭性进展和预后不良有关，其机制可能与CS影响细胞脂质代谢和线粒体功能有关。
Purpose Citrate synthase (CS) is a rate-limiting enzyme in the citrate cycle and is capable of catalyzing oxaloacetate and acetyl-CoA to citrate. CS has been uncovered to be upregulated in a variety of cancers, and its expression and clinical significance in prostate cancer (PCa) remain unknown. Methods In this study, we examined the association between CS expression level and clinicopathological features of prostate cancer patients in a TMA cohort and the public cancer database (The Cancer Genome Atlas-Prostate Adenocarcinoma, TCGA-PRAD). The CS knockdown cell lines were constructed to study the effects of CS downregulation on proliferation, colony formation, migration, invasion, and cell cycle of prostate cancer cells in vitro. And the effect of CS downregulation on tumor growth in mice was studied in vivo. In addition, the metabolomics and mitochondrial function were detected in the CS knockdown cell lines. Results CS expression level in PCa tissues was higher than that in normal tissues (P < 0.05). CS upregulation was significantly associated with high Gleason score (P < 0.05), advanced pathological stage (P < 0.001), and biochemical recurrence (P < 0.001). Functionally, decreased expression of CS inhibited PCa cell proliferation, colony formation, migration, invasion and cell cycle in vitro, and inhibited tumor growth in vivo. In addition, CS downregulation exerted potential inhibitory effects on the lipid metabolism and mitochondrial function of PCa cells. Conclusion In conclusion, these findings suggested that CS upregulation may contribute to the aggressive progression and poor prognosis of PCa patients, which might be partially associated with its influences on the cell lipid metabolism and mitochondrial function.