β‑adrenergic receptor activation promotes the proliferation of HepG2 cells via the ERK1/2/CREB pathways

Lin,Xingcheng; Lin,Xingcheng; He,Jingjing; He,Jingjing; Liu,Fuhong; Liu,Fuhong; Li,Lehui; Li,Lehui; Sun,Longhua; Sun,Longhua; Niu,Liyan; Niu,Liyan; Xi,Haolin; Xi,Haolin; Zhan,Yuan; Zhan,Yuan; Liu,Xiaohua; Liu,Xiaohua; Hu,Ping; Hu,Ping

doi:10.3892/ol.2023.14106

β‑adrenergic receptor activation promotes the proliferation of HepG2 cells via the ERK1/2/CREB pathways

Authors:
- Xingcheng Lin
- Jingjing He
- Fuhong Liu
- Lehui Li
- Longhua Sun
- Liyan Niu
- Haolin Xi
- Yuan Zhan
- Xiaohua Liu
- Ping Hu
View Affiliations

Affiliations: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330001, P.R. China, Department of Respiratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Huan Kui College, Nanchang University, Nanchang, Jiangxi 330001, P.R. China, Queen Mary School, Nanchang University, Nanchang, Jiangxi 330001, P.R. China, Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Nursing, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: October 17, 2023 https://doi.org/10.3892/ol.2023.14106
Article Number: 519
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Primary liver cancer is one of the most frequently diagnosed malignant tumors seen in clinics, and typically exhibits aggressive invasive behaviors, a poor prognosis, and is associated with high mortality rates. Long‑term stress exposure causes norepinephrine (NE) release and activates the β‑Adrenergic receptor (β‑AR), which in turn exacerbates the occurrence and development of different types of cancers; however, the molecular mechanisms of β‑AR in liver cancer are not fully understood. In the present study, reverse transcription (RT)‑PCR and RT‑quantitative PCR showed that β‑AR expression was upregulated in human liver cancer cells (HepG2) compared with normal liver cells (LO2). Moreover, NE treatment promoted the growth of HepG2 cells, which could be blocked by propranolol, a β‑AR antagonist. Notably, NE had no significant effect on the migration and epithelial‑mesenchymal transition in HepG2 cells. Further experiments revealed that NE increased the phosphorylation levels of the extracellular signal‑regulated kinase 1/2 (ERK1/2) and cyclic adenosine monophosphate response element‑binding protein (CREB), while inhibition of ERK1/2 and CREB activation significantly blocked NE‑induced cell proliferation. In summary, the findings of the present study suggested that β‑adrenergic receptor activation promoted the proliferation of HepG2 cells through ERK1/2/CREB signaling pathways.

View Figures

View References

1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Wang Y, Shen J, Feng S, Liang R, Lai J, Li D, Peng B, Wang Z, Huang C and Kuang M: Hepatic resection versus transarterial chemoembolization in infiltrative hepatocellular carcinoma: A multicenter study. J Gastroenterol Hepatol. 35:2220–2228. 2020. View Article : Google Scholar : PubMed/NCBI
3	Kim JJ, McFarlane T, Tully S and Wong WWL: Lenvatinib versus sorafenib as first-line treatment of unresectable hepatocellular carcinoma: A cost-utility analysis. Oncologist. 25:e512–e519. 2020. View Article : Google Scholar : PubMed/NCBI
4	Li J, Zhou M, Liu F, Xiong C, Wang W, Cao Q, Wen X, Robertson JD, Ji X, Wang YA, et al: Hepatocellular carcinoma: Intra-arterial delivery of doxorubicin-loaded hollow gold nanospheres for photothermal ablation-chemoembolization therapy in rats. Radiology. 281:427–435. 2016. View Article : Google Scholar : PubMed/NCBI
5	Li X, Ramadori P, Pfister D, Seehawer M, Zender L and Heikenwalder M: The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer. 21:541–557. 2021. View Article : Google Scholar : PubMed/NCBI
6	Dai S, Mo Y, Wang Y, Xiang B, Liao Q, Zhou M, Li X, Li Y, Xiong W, Li G, et al: Chronic stress promotes cancer development. Front Oncol. 10:14922020. View Article : Google Scholar : PubMed/NCBI
7	Antoni MH and Dhabhar FS: The impact of psychosocial stress and stress management on immune responses in patients with cancer. Cancer. 125:1417–1431. 2019. View Article : Google Scholar : PubMed/NCBI
8	Krizanova O, Babula P and Pacak K: Stress, catecholaminergic system and cancer. Stress. 19:419–428. 2016. View Article : Google Scholar : PubMed/NCBI
9	Xia Y, Wei Y, Li ZY, Cai XY, Zhang LL, Dong XR, Zhang S, Zhang RG, Meng R, Zhu F and Wu G: Catecholamines contribute to the neovascularization of lung cancer via tumor-associated macrophages. Brain Behav Immun. 81:111–121. 2019. View Article : Google Scholar : PubMed/NCBI
10	Seiler A, Sood AK, Jenewein J and Fagundes CP: Can stress promote the pathophysiology of brain metastases? A critical review of biobehavioral mechanisms. Brain Behav Immun. 87:860–880. 2020. View Article : Google Scholar : PubMed/NCBI
11	Bastos DB, Sarafim-Silva BAM, Sundefeld M, Ribeiro AA, Brandao JDP, Biasoli ER, Miyahara GI, Casarini DE and Bernabe DG: Circulating catecholamines are associated with biobehavioral factors and anxiety symptoms in head and neck cancer patients. PLoS One. 13:e02025152018. View Article : Google Scholar : PubMed/NCBI
12	Zhang X, Zhang Y, He Z, Yin K, Li B, Zhang L and Xu Z: Chronic stress promotes gastric cancer progression and metastasis: An essential role for ADRB2. Cell Death Dis. 10:7882019. View Article : Google Scholar : PubMed/NCBI
13	Zhang B, Wu C, Chen W, Qiu L, Li S, Wang T, Xie H, Li Y, Li C and Li L: The stress hormone norepinephrine promotes tumor progression through beta2-adrenoreceptors in oral cancer. Arch Oral Biol. 113:1047122020. View Article : Google Scholar : PubMed/NCBI
14	Li XQ, Peng WT, Shan S, Wu JJ, Li N, Du JJ, Sun JC, Chen TT, Wei W and Sun WY: beta-arrestin2 regulating beta2-adrenergic receptor signaling in hepatic stellate cells contributes to hepatocellular carcinoma progression. J Cancer. 12:7287–7299. 2021. View Article : Google Scholar : PubMed/NCBI
15	Cole SW and Sood AK: Molecular pathways: Beta-adrenergic signaling in cancer. Clin Cancer Res. 18:1201–1206. 2012. View Article : Google Scholar : PubMed/NCBI
16	Nilsson MB, Le X and Heymach JV: β-adrenergic signaling in lung cancer: A potential role for beta-blockers. J Neuroimmune Pharmacol. 15:27–36. 2020. View Article : Google Scholar : PubMed/NCBI
17	Zhang Y, Zanos P, Jackson IL, Zhang X, Zhu X, Gould T and Vujaskovic Z: Psychological stress enhances tumor growth and diminishes radiation response in preclinical model of lung cancer. Radiother Oncol. 146:126–135. 2020. View Article : Google Scholar : PubMed/NCBI
18	Zhou J, Liu Z, Zhang L, Hu X, Wang Z, Ni H, Wang Y and Qin J: Activation of beta2-adrenergic receptor promotes growth and angiogenesis in breast cancer by down-regulating PPARγ. Cancer Res Treat. 52:830–847. 2020. View Article : Google Scholar : PubMed/NCBI
19	Moraes RM, Elefteriou F and Anbinder AL: Response of the periodontal tissues to β-adrenergic stimulation. Life Sci. 281:1197762021. View Article : Google Scholar : PubMed/NCBI
20	Qian W, Lv S, Li J, Chen K, Jiang Z, Cheng L, Zhou C, Yan B, Cao J, Ma Q and Duan W: Norepinephrine enhances cell viability and invasion, and inhibits apoptosis of pancreatic cancer cells in a Notch-1-dependent manner. Oncol Rep. 40:3015–3023. 2018.PubMed/NCBI
21	Du P, Zeng H, Xiao Y, Zhao Y, Zheng B, Deng Y, Liu J, Huang B, Zhang X, Yang K, et al: Chronic stress promotes EMT-mediated metastasis through activation of STAT3 signaling pathway by miR-337-3p in breast cancer. Cell Death Dis. 11:7612020. View Article : Google Scholar : PubMed/NCBI
22	Liu C, Yang Y, Chen C, Li L, Li J, Wang X, Chu Q, Qiu L, Ba Q, Li X and Wang H: Environmental eustress modulates beta-ARs/CCL2 axis to induce anti-tumor immunity and sensitize immunotherapy against liver cancer in mice. Nat Commun. 12:57252021. View Article : Google Scholar : PubMed/NCBI
23	Liu J, Qu L, Wan C, Xiao M, Ni W, Jiang F, Fan Y, Lu C and Ni R: A novel β2-AR/YB-1/β-catenin axis mediates chronic stress-associated metastasis in hepatocellular carcinoma. Oncogenesis. 9:842020. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L, Rusu A, Irimie A, Atanasov AG, Slaby O, et al: A comprehensive review on MAPK: A promising therapeutic target in cancer. Cancers (Basel). 11:16182019. View Article : Google Scholar : PubMed/NCBI
26	Han J, Jiang Q, Ma R, Zhang H, Tong D, Tang K, Wang X, Ni L, Miao J, Duan B, et al: Norepinephrine-CREB1-miR-373 axis promotes progression of colon cancer. Mol Oncol. 14:1059–1073. 2020. View Article : Google Scholar : PubMed/NCBI
27	Pan C, Wu J, Zheng S, Sun H, Fang Y, Huang Z, Shi M, Liang L, Bin J, Liao Y, et al: Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β2 -AR/MACC1 axis. Cancer Commun (Lond). 41:1049–1070. 2021. View Article : Google Scholar : PubMed/NCBI
28	Sakakitani S, Podyma-Inoue KA, Takayama R, Takahashi K, Ishigami-Yuasa M, Kagechika H, Harada H and Watabe T: Activation of beta2-adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells. Cancer Sci. 112:155–167. 2021. View Article : Google Scholar : PubMed/NCBI
29	Wang X, Wang Y, Xie F, Song ZT, Zhang ZQ, Zhao Y, Wang SD, Hu H, Zhang YS and Qian LJ: Norepinephrine promotes glioma cell migration through up-regulating the expression of Twist1. BMC Cancer. 22:2132022. View Article : Google Scholar : PubMed/NCBI
30	Mravec B, Horvathova L and Hunakova L: Neurobiology of cancer: The role of beta-adrenergic receptor signaling in various tumor environments. Int J Mol Sci. 21:79582020. View Article : Google Scholar : PubMed/NCBI
31	Bamodu OA, Chang HL, Ong JR, Lee WH, Yeh CT and Tsai JT: Elevated PDK1 expression drives PI3K/AKT/MTOR signaling promotes radiation-resistant and dedifferentiated phenotype of hepatocellular carcinoma. Cells. 9:7462020. View Article : Google Scholar : PubMed/NCBI
32	Villanueva A: Hepatocellular carcinoma. N Engl J Med. 380:1450–1462. 2019. View Article : Google Scholar : PubMed/NCBI
33	Pu J, Zhang X, Luo H, Xu L, Lu X and Lu J: Adrenaline promotes epithelial-to-mesenchymal transition via HuR-TGFbeta regulatory axis in pancreatic cancer cells and the implication in cancer prognosis. Biochem Biophys Res Commun. 493:1273–1279. 2017. View Article : Google Scholar : PubMed/NCBI
34	Xiao MB, Jin DD, Jiao YJ, Ni WK, Liu JX, Qu LS, Lu CH, Ni RZ, Jiang F and Chen WC: β2-AR regulates the expression of AKR1B1 in human pancreatic cancer cells and promotes their proliferation via the ERK1/2 pathway. Mol Biol Rep. 45:1863–1871. 2018. View Article : Google Scholar : PubMed/NCBI
35	Decker AM, Jung Y, Cackowski FC, Yumoto K, Wang J and Taichman RS: Sympathetic signaling reactivates quiescent disseminated prostate cancer cells in the bone marrow. Mol Cancer Res. 15:1644–1655. 2017. View Article : Google Scholar : PubMed/NCBI
36	He JJ, Zhang WH, Liu SL, Chen YF, Liao CX, Shen QQ and Hu P: Activation of β-adrenergic receptor promotes cellular proliferation in human glioblastoma. Oncol Lett. 14:3846–3852. 2017. View Article : Google Scholar : PubMed/NCBI
37	Deng J, Jiang P, Yang T, Huang M, Xie J, Luo C, Qi W, Zhou T, Yang Z, Zou Y, et al: beta2adrenergic receptor signaling promotes neuroblastoma cell proliferation by activating autophagy. Oncol Rep. 42:1295–1306. 2019.PubMed/NCBI
38	Gagliardi PA, Puliafito A and Primo L: PDK1: At the crossroad of cancer signaling pathways. Semin Cancer Biol. 48:27–35. 2018. View Article : Google Scholar : PubMed/NCBI
39	Shan T, Cui X, Li W, Lin W, Li Y, Chen X and Wu T: Novel regulatory program for norepinephrine-induced epithelial-mesenchymal transition in gastric adenocarcinoma cell lines. Cancer Sci. 105:847–856. 2014. View Article : Google Scholar : PubMed/NCBI
40	Bhat AA, Syed N, Therachiyil L, Nisar S, Hashem S, Macha MA, Yadav SK, Krishnankutty R, Muralitharan S, Al-Naemi H, et al: Claudin-1, a double-edged sword in cancer. Int J Mol Sci. 21:5692020. View Article : Google Scholar : PubMed/NCBI