Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.
Department of Anesthesiology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, 516001, P. R. China.
Cancer Commun (Lond). 2020 Dec;40(12):694-710. doi: 10.1002/cac2.12103. Epub 2020 Oct 5.
Dopamine and dopamine receptor D1 (DRD1), a member of the dopamine receptor family, have been indicated to play important roles in cancer progression, but dopamine secretion in hepatocellular carcinoma (HCC) and the effects of DRD1 on HCC remain unclear. This study was designed to explore the contribution of the dopaminergic system to HCC and determine the relationship between DRD1 and prognosis in HCC patients.
The dopamine metabolic system was monitored using enzyme-linked immunosorbent assays (ELISAs). The expression of DRD1 was detected by microarray analysis, immunohistochemistry (IHC), and quantitative real-time PCR (qRT-PCR). Stable DRD1 knockout and overexpression cell lines were established for investigation. Transwell, colony formation, and Cell Counting Kit 8 (CCK8) assays were performed to assess the malignant behaviors of cancer cells. The cAMP/PI3K/AKT/ cAMP response element-binding (CREB) signaling pathway was evaluated by Western blot. This pathway, which is agitated by DRD1 in striatal neurons, had been proven to participate in tumor progression. Xenograft HCC tumors were generated for in vivo experiments.
Dopamine secretion increased locally in HCC due to an imbalance in dopamine metabolism, including the upregulation of dopa decarboxylase (DDC) and the downregulation of monoamine oxidase A (MAOA). Dopamine promoted the proliferation and metastasis of HCC. DRD1 was highly expressed in HCC tissues and positive DRD1 expression was related to a poor prognosis in HCC patients. The upregulation of DRD1 agitated malignant activities, including proliferation and metastasis in HCC by regulating the cAMP/PI3K/AKT/CREB pathway, and the downregulation of DRD1 had opposing effects. The effects of dopamine on HCC was reversed by depleting DRD1. SCH23390, a selective DRD1 antagonist, inhibited the proliferation and metastasis of HCC cells both in vitro and in vivo.
Dopamine secretion was locally increased in HCC and promoted HCC cell proliferation and metastasis. DRD1 was found to exert positive effects on HCC progression and play a vital role in the dopamine system, and could be a potential therapeutic target and prognostic biomarker for HCC.
多巴胺和多巴胺受体 D1（DRD1）作为多巴胺受体家族的一员，被表明在癌症进展中发挥重要作用，但肝癌（HCC）中的多巴胺分泌以及 DRD1 对 HCC 的影响仍不清楚。本研究旨在探讨多巴胺能系统对 HCC 的贡献，并确定 DRD1 与 HCC 患者预后之间的关系。
使用酶联免疫吸附测定（ELISA）监测多巴胺代谢系统。通过微阵列分析、免疫组织化学（IHC）和实时定量 PCR（qRT-PCR）检测 DRD1 的表达。建立稳定的 DRD1 敲除和过表达细胞系进行研究。使用 Transwell、集落形成和细胞计数试剂盒 8（CCK8）测定评估癌细胞的恶性行为。通过 Western blot 评估 cAMP/PI3K/AKT/cAMP 反应元件结合（CREB）信号通路。该通路在纹状体神经元中被 DRD1 激活，已被证明参与肿瘤进展。生成 HCC 肿瘤的异种移植用于体内实验。
由于多巴胺代谢失衡，包括多巴脱羧酶（DDC）上调和单胺氧化酶 A（MAOA）下调，HCC 中局部多巴胺分泌增加。多巴胺促进 HCC 的增殖和转移。DRD1 在 HCC 组织中高表达，DRD1 阳性表达与 HCC 患者预后不良相关。DRD1 的上调通过调节 cAMP/PI3K/AKT/CREB 通路促进 HCC 的恶性活动，包括增殖和转移，而 DRD1 的下调则具有相反的作用。通过耗尽 DRD1，多巴胺对 HCC 的作用被逆转。SCH23390，一种选择性 DRD1 拮抗剂，在体外和体内均抑制 HCC 细胞的增殖和转移。
HCC 中局部多巴胺分泌增加，并促进 HCC 细胞增殖和转移。DRD1 对 HCC 进展有积极影响，在多巴胺系统中发挥重要作用，可能成为 HCC 的潜在治疗靶点和预后生物标志物。
