Dopamine receptor D3 is related to prognosis in human hepatocellular carcinoma and inhibits tumor growth.
Dopamine receptor D3 is related to prognosis in human hepatocellular carcinoma and inhibits tumor growth.
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多巴胺受体 D3 与人肝细胞癌的预后相关并抑制肿瘤生长
DOI：
10.1186/s12885-022-10368-y
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发表时间：
2022-12-02
期刊：
影响因子：
3.8
通讯作者：
Chen, Dongtai
中科院分区：
文献类型：
--
作者：
Yan, Yan;Chen, Yonghua;Pan, Jiahao;Xing, Wei;Li, Qiang;Wang, Yan;Gei, Liba;Yuan, Yunfei;Xie, Jingdun;Zeng, Weian;Chen, Dongtai
研究背景多巴胺受体在肿瘤进展中发挥重要作用。然而，多巴胺受体D3(DRD3)在肝细胞癌中的作用尚不清楚。方法采用免疫组织化学和实时定量聚合酶链式反应检测DRD3的表达。通过分析选定的数据库，包括cBioPortal和Kaplan-Meier绘图仪，研究DRD3在患者中的预后价值。CCK8法检测细胞生长，Transwell法检测癌细胞迁移和侵袭能力。用Western印迹分析和ELISA法检测cAMP/ERK/CREB信号通路。结果DRD3mRNA在非肿瘤组织中的表达明显高于肿瘤组织。DRD3蛋白低表达与无复发生存期(RFS)和总生存期(OS)差有关。Kaplan-Meier分析显示，DRD3mRNA的高表达与较好的OS、RFS、疾病特异性生存(DSS)和无进展生存(PFS)相关。CBioPortal分析显示，含有DRD3基因突变的改变组表现出较差的OS、RFS、DSS和PFS。根据CCK8和Transwell检测，稳定高表达DRD3的细胞株(ex-DRD3-SK-Hep-1)表现出较弱的增殖、迁移和侵袭行为。DRD3激动剂PD128907抑制肝癌细胞的增殖、迁移和侵袭，而DRD3拮抗剂U99194促进肝癌细胞的增殖、迁移和侵袭。Western印迹和ELISA法分析表明，稳定的DRD3敲除细胞系(sh-DRD3-PLC/PRF/5)和U99194均能增加cAMP、p-ERK和p-CREB的蛋白水平，而ex-DRD3-SK-Hep-1和PD128907则降低cAMP、p-ERK和p-CREB的蛋白水平。ERK拮抗剂SCH772984可阻断U99194对肝癌细胞恶性生物学行为的影响。在体内，PD128907抑制肿瘤生长，U99194促进肿瘤生长。结论DRD3表达下调与肝细胞癌的发生发展密切相关，DRD3可作为肝细胞癌的独立预后因素。此外，DRD3激动剂可能是治疗肝癌的一种有前途的策略。
BackgroundDopamine receptors have been reported to play important roles in cancer progression. However, the role of dopamine receptor D3 (DRD3) in hepatocellular carcinoma (HCC) remains unclear.MethodsThe expression of DRD3 was detected by immunohistochemistry and real-time qPCR. The prognostic value of DRD3 in patients was investigated by analyzing selected databases, including cBioPortal and Kaplan–Meier plotter. Cell growth was tested by CCK8 assay, and Transwell assays were performed to assess cancer cell migration and invasion. The cAMP/ERK/CREB signaling pathway was evaluated by Western blot analysis and ELISA. An HCC xenograft model was established for in vivo experiments.ResultsDRD3 mRNA expression was significantly higher in nontumor tissues than in tumor tissues. Lower protein expression of DRD3 was related to poor recurrence-free survival (RFS) and overall survival (OS). Kaplan–Meier plotter analysis showed that higher expression of DRD3 mRNA was associated with better OS, RFS, disease-specific survival (DSS), and progression-free survival (PFS). cBioPortal analysis revealed that the alteration group, which harbored genetic mutations in DRD3, exhibited poor OS, RFS, DSS and PFS. According to CCK8 and Transwell assays, stable DRD3 overexpression cell line (ex-DRD3-SK-HEP-1) showed weaker proliferation, migration and invasion behaviors. PD128907, a DRD3 agonist, suppressed proliferation, migration and invasion in HCC cell lines, while U99194, a DRD3 antagonist, enhanced proliferation, migration and invasion in HCC cell lines. Western blot analysis and ELISA revealed that stable DRD3 knock-down cell line (sh-DRD3-PLC/PRF/5) and U99194 both increased the protein levels of cAMP, p-ERK and p-CREB; on the other hand, ex-DRD3-SK-HEP-1 and PD128907 decreased the protein levels of cAMP, p-ERK and p-CREB. SCH772984, an ERK antagonist, abolished the effect of U99194 on the malignant biological behaviors of HCC cells. In vivo, PD128907 suppressed tumor growth, and U99194 enhanced tumor growth.ConclusionOur results suggest that down-regulation of DRD3 is strongly involved in the progression of HCC, and DRD3 might be consider as an independent prognostic factor for HCC. Furthermore, DRD3 agonists may be a promising strategy for HCC therapy.
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DOI：
10.1016/s0140-6736(18)32203-7
发表时间：
2018-11-10
期刊：
Lancet (London, England)
影响因子：
--
作者：
GBD 2017 Causes of Death Collaborators
通讯作者：
GBD 2017 Causes of Death Collaborators
影响因子：
14.9
作者：
Kanehisa M;Furumichi M;Sato Y;Ishiguro-Watanabe M;Tanabe M
通讯作者：
Tanabe M
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
29.4
作者：
Jandaghi, Pouria;Najafabadi, Hamed S.;Hoheisel, Joerg D.
通讯作者：
Hoheisel, Joerg D.
细胞外调节的激酶：从RAS到ERK底物的信号传导以控制生物学结果。
影响因子：
--
作者：
Eblen ST
通讯作者：
Eblen ST