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Published in: Annals of Surgical Oncology 11/2012

01-10-2012 | Hepatobiliary Tumors

The Beta2-Adrenergic Receptor is a Potential Prognostic Biomarker for Human Hepatocellular Carcinoma After Curative Resection

Authors: Dongtai Chen, MD, Wei Xing, MD, Jian Hong, MD, PhD, Meibing Wang, MD, Yang Huang, MD, Cuizhen Zhu, MD, Yunfei Yuan, MD, Weian Zeng, MD, PhD

Published in: Annals of Surgical Oncology | Issue 11/2012

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Abstract

Background

The beta2-adrenergic receptor (Beta2-AR) is overexpressed and highly associated with poor prognosis in many malignancies. Nevertheless, the role of Beta2-AR in hepatocellular carcinoma (HCC) has not been thoroughly elucidated. The aim of this study is to investigate the expression of Beta2-AR and its clinicopathological/prognostic value in HCC patients after curative resection.

Materials and Methods

Semiquantitative reverse transcription PCR (RT-PCR) and real-time quantitative PCR (qPCR) were used to measure Beta2-AR RNA expression in 60 pairs of HCC tumors and matched nontumorous tissues. Beta2-AR expression was detected in HCC cell lines by Western blot analysis. Furthermore, we investigated Beta2-AR expression in correlation with the clinicopathological features and analyzed the potential prognostic significance of Beta2-AR in 192 HCC patients by immunohistochemistry (IHC).

Results

Upregulation of Beta2-AR mRNA was significantly higher in HCC tumor tissues than in their paired nontumorous liver specimens. The expression of Beta2-AR protein was detected in five HCC cell lines. Positive Beta2-AR protein expression was significantly associated with a high α-fetoprotein (AFP) level (P = 0.001), large tumor size (P < 0.001), tumor encapsulation (P = 0.002), vascular invasion (P = 0.004), microsatellite formation (P = 0.002), and poor differentiation (P < 0.001). In univariate and multivariate analyses, Beta2-AR was an excellent predictive factor for both recurrence-free survival and overall survival (OS). Beta2-AR expression status was associated with poor prognosis independent of AFP, tumor-node-metastasis stage and Edmondson stage.

Conclusions

The Beta2-AR is a potential prognostic biomarker for survival and tumor recurrence in HCC patients after curative resection.
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Literature
1.
go back to reference Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRef Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRef
2.
go back to reference McGlynn KA, Tarone RE, El-Serag HB. A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States. Cancer Epidemiol Biomarkers Prev. 2006;15:1198–203.PubMedCrossRef McGlynn KA, Tarone RE, El-Serag HB. A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States. Cancer Epidemiol Biomarkers Prev. 2006;15:1198–203.PubMedCrossRef
3.
go back to reference Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, et al. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol. 2007;25:3069–75.PubMedCrossRef Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, et al. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol. 2007;25:3069–75.PubMedCrossRef
4.
go back to reference Maki T, Kontula K, Harkonen M. The beta-adrenergic system in man: physiological and pathophysiological response. Regulation of receptor density and functioning. Scand J Clin Lab Invest Suppl. 1990;201:25–43.PubMedCrossRef Maki T, Kontula K, Harkonen M. The beta-adrenergic system in man: physiological and pathophysiological response. Regulation of receptor density and functioning. Scand J Clin Lab Invest Suppl. 1990;201:25–43.PubMedCrossRef
5.
go back to reference Maudsley S, Pierce KL, Zamah AM, Miller WE, Ahn S, Daaka Y, et al. The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor. J Biol Chem. 2000;275:9572–80.PubMedCrossRef Maudsley S, Pierce KL, Zamah AM, Miller WE, Ahn S, Daaka Y, et al. The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor. J Biol Chem. 2000;275:9572–80.PubMedCrossRef
6.
go back to reference Entschladen F, Drell TL 4th, Lang K, Joseph J, Zaenker KS. Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters. Lancet Oncol. 2004;5:254–8.PubMedCrossRef Entschladen F, Drell TL 4th, Lang K, Joseph J, Zaenker KS. Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters. Lancet Oncol. 2004;5:254–8.PubMedCrossRef
7.
go back to reference Entschladen F, Drell TLt, Lang K, Joseph J, Zaenker KS. Neurotransmitters and chemokines regulate tumor cell migration: potential for a new pharmacological approach to inhibit invasion and metastasis development. Curr Pharm Des. 2005;11:403–11.PubMedCrossRef Entschladen F, Drell TLt, Lang K, Joseph J, Zaenker KS. Neurotransmitters and chemokines regulate tumor cell migration: potential for a new pharmacological approach to inhibit invasion and metastasis development. Curr Pharm Des. 2005;11:403–11.PubMedCrossRef
8.
go back to reference Ramberg H, Eide T, Krobert KA, Levy FO, Dizeyi N, Bjartell AS, et al. Hormonal regulation of beta2-adrenergic receptor level in prostate cancer. Prostate. 2008;68:1133–42.PubMedCrossRef Ramberg H, Eide T, Krobert KA, Levy FO, Dizeyi N, Bjartell AS, et al. Hormonal regulation of beta2-adrenergic receptor level in prostate cancer. Prostate. 2008;68:1133–42.PubMedCrossRef
9.
go back to reference Yang EV, Kim SJ, Donovan EL, Chen M, Gross AC, Webster Marketon JI, et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun. 2009;23:267–75.PubMedCrossRef Yang EV, Kim SJ, Donovan EL, Chen M, Gross AC, Webster Marketon JI, et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun. 2009;23:267–75.PubMedCrossRef
10.
go back to reference Shang ZJ, Liu K, Liang de F. Expression of beta2-adrenergic receptor in oral squamous cell carcinoma. J Oral Pathol Med. 2009;38:371–6.PubMedCrossRef Shang ZJ, Liu K, Liang de F. Expression of beta2-adrenergic receptor in oral squamous cell carcinoma. J Oral Pathol Med. 2009;38:371–6.PubMedCrossRef
11.
go back to reference Shi M, Liu D, Duan H, Qian L, Wang L, Niu L, et al. The beta2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Res Treat. 2011;125:351–62.PubMedCrossRef Shi M, Liu D, Duan H, Qian L, Wang L, Niu L, et al. The beta2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Res Treat. 2011;125:351–62.PubMedCrossRef
12.
go back to reference Schuller HM. Beta-adrenergic signaling, a novel target for cancer therapy? Oncotarget. 2010;1:466–9.PubMed Schuller HM. Beta-adrenergic signaling, a novel target for cancer therapy? Oncotarget. 2010;1:466–9.PubMed
13.
go back to reference Chen L, Yuan YF, Li Y, Chan TH, Zheng BJ, Huang J, et al. Clinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion. Gut. 2011;60:534–43.PubMedCrossRef Chen L, Yuan YF, Li Y, Chan TH, Zheng BJ, Huang J, et al. Clinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion. Gut. 2011;60:534–43.PubMedCrossRef
14.
go back to reference Tung-Ping Poon R, Fan ST, Wong J. Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg. 2000;232:10–24.PubMedCrossRef Tung-Ping Poon R, Fan ST, Wong J. Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg. 2000;232:10–24.PubMedCrossRef
15.
go back to reference El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.PubMedCrossRef El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.PubMedCrossRef
16.
17.
go back to reference Takezaki T, Hamajima N, Matsuo K, Tanaka R, Hirai T, Kato T, et al. Association of polymorphisms in the beta-2 and beta-3 adrenoceptor genes with risk of colorectal cancer in Japanese. Int J Clin Oncol. 2001;6:117–22.PubMedCrossRef Takezaki T, Hamajima N, Matsuo K, Tanaka R, Hirai T, Kato T, et al. Association of polymorphisms in the beta-2 and beta-3 adrenoceptor genes with risk of colorectal cancer in Japanese. Int J Clin Oncol. 2001;6:117–22.PubMedCrossRef
18.
go back to reference Soresi M, Magliarisi C, Campagna P, Leto G, Bonfissuto G, Riili A, et al. Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer Res. 2003;23:1747–53.PubMed Soresi M, Magliarisi C, Campagna P, Leto G, Bonfissuto G, Riili A, et al. Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer Res. 2003;23:1747–53.PubMed
19.
go back to reference Johnson PJ. The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis. 2001;5:145–59.PubMedCrossRef Johnson PJ. The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis. 2001;5:145–59.PubMedCrossRef
20.
go back to reference Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40:667–76.PubMedCrossRef Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40:667–76.PubMedCrossRef
21.
go back to reference Pullar CE, Isseroff RR. The beta 2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms. J Cell Sci. 2006;119:592–602.PubMedCrossRef Pullar CE, Isseroff RR. The beta 2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms. J Cell Sci. 2006;119:592–602.PubMedCrossRef
22.
go back to reference Yuan A, Li Z, Li X, Yi S, Wang S, Cai Y, et al. The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells. Oncol Rep. 2010;23:151–7.PubMed Yuan A, Li Z, Li X, Yi S, Wang S, Cai Y, et al. The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells. Oncol Rep. 2010;23:151–7.PubMed
23.
go back to reference Liu X, Wu WK, Yu L, Li ZJ, Sung JJ, Zhang ST, et al. Epidermal growth factor-induced esophageal cancer cell proliferation requires transactivation of beta-adrenoceptors. J Pharmacol Exp Ther. 2008;326:69–75.PubMedCrossRef Liu X, Wu WK, Yu L, Li ZJ, Sung JJ, Zhang ST, et al. Epidermal growth factor-induced esophageal cancer cell proliferation requires transactivation of beta-adrenoceptors. J Pharmacol Exp Ther. 2008;326:69–75.PubMedCrossRef
24.
go back to reference Guo K, Ma Q, Wang L, Hu H, Li J, Zhang D, et al. Norepinephrine-induced invasion by pancreatic cancer cells is inhibited by propranolol. Oncol Rep. 2009;22:825–30.PubMed Guo K, Ma Q, Wang L, Hu H, Li J, Zhang D, et al. Norepinephrine-induced invasion by pancreatic cancer cells is inhibited by propranolol. Oncol Rep. 2009;22:825–30.PubMed
25.
go back to reference Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol. 2002;12:258–66.PubMedCrossRef Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol. 2002;12:258–66.PubMedCrossRef
27.
go back to reference Drell TL 4th, Joseph J, Lang K, Niggemann B, Zaenker KS, Entschladen F. Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat. 2003;80:63–70.PubMedCrossRef Drell TL 4th, Joseph J, Lang K, Niggemann B, Zaenker KS, Entschladen F. Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat. 2003;80:63–70.PubMedCrossRef
28.
go back to reference Sood AK, Bhatty R, Kamat AA, Landen CN, Han L, Thaker PH, et al. Stress hormone-mediated invasion of ovarian cancer cells. Clin Cancer Res. 2006;12:369–75.PubMedCrossRef Sood AK, Bhatty R, Kamat AA, Landen CN, Han L, Thaker PH, et al. Stress hormone-mediated invasion of ovarian cancer cells. Clin Cancer Res. 2006;12:369–75.PubMedCrossRef
29.
go back to reference Masur K, Niggemann B, Zanker KS, Entschladen F. Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res. 2001;61:2866–9.PubMed Masur K, Niggemann B, Zanker KS, Entschladen F. Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res. 2001;61:2866–9.PubMed
30.
go back to reference Lang K, Drell TL 4th, Lindecke A, Niggemann B, Kaltschmidt C, Zaenker KS, et al. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer. 2004;112:231–8.PubMedCrossRef Lang K, Drell TL 4th, Lindecke A, Niggemann B, Kaltschmidt C, Zaenker KS, et al. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer. 2004;112:231–8.PubMedCrossRef
31.
go back to reference Palm D, Lang K, Niggemann B, Drell TL 4th, Masur K, Zaenker KS, et al. The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers. Int J Cancer. 2006;118:2744–9.PubMedCrossRef Palm D, Lang K, Niggemann B, Drell TL 4th, Masur K, Zaenker KS, et al. The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers. Int J Cancer. 2006;118:2744–9.PubMedCrossRef
32.
go back to reference Powe DG, Voss MJ, Zanker KS, Habashy HO, Green AR, Ellis IO, et al. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget. 2010;1:628–38.PubMed Powe DG, Voss MJ, Zanker KS, Habashy HO, Green AR, Ellis IO, et al. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget. 2010;1:628–38.PubMed
33.
go back to reference Powe DG, Entschladen F. Targeted therapies: using beta-blockers to inhibit breast cancer progression. Nat Rev Clin Oncol. 2011;8:511–2.PubMedCrossRef Powe DG, Entschladen F. Targeted therapies: using beta-blockers to inhibit breast cancer progression. Nat Rev Clin Oncol. 2011;8:511–2.PubMedCrossRef
Metadata
Title
The Beta2-Adrenergic Receptor is a Potential Prognostic Biomarker for Human Hepatocellular Carcinoma After Curative Resection
Authors
Dongtai Chen, MD
Wei Xing, MD
Jian Hong, MD, PhD
Meibing Wang, MD
Yang Huang, MD
Cuizhen Zhu, MD
Yunfei Yuan, MD
Weian Zeng, MD, PhD
Publication date
01-10-2012
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 11/2012
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-012-2396-1

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