Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Details

Title
Increased dopamine and its receptor dopamine receptor D1 promote tumor growth in human hepatocellular carcinoma
Author
Yan, Yan 1 ; Pan, Jiahao 2 ; Chen, Yonghua 3 ; Xing, Wei 2 ; Li, Qiang 2 ; Wang, Dongyin 2 ; Zhou, Xiaoshuang 2 ; Xie, Jingdun 2 ; Miao, Changhong 4 ; Yuan, Yunfei 5 ; Zeng, Weian 2 ; Chen, Dongtai 2   VIAFID ORCID Logo 

1  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, P. R. China; Department of Anesthesiology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, P. R. China 
2  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, P. R. China 
3  Department of Anesthesiology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, P. R. China 
4  Department of Anesthesiology, Fudan University Zhongshan Hospital, Shanghai, P. R. China 
5  Department of Hepatobiliary Oncology, Sun Yat‐Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P. R. China 
Pages
694-710
Section
ORIGINAL ARTICLES
Publication year
2020
Publication date
Dec 2020
Publisher
John Wiley & Sons, Inc.
e-ISSN
2523-3548
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1002/cac2.12103
ProQuest document ID
2699961462
Copyright
© 2020. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.