Skip to main content
Erschienen 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

verfasst von: 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

Erschienen in: Annals of Surgical Oncology | Ausgabe 11/2012

Einloggen, um Zugang zu erhalten

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.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer. 2007;7:79–94.PubMedCrossRef Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer. 2007;7:79–94.PubMedCrossRef
17.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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
Metadaten
Titel
The Beta2-Adrenergic Receptor is a Potential Prognostic Biomarker for Human Hepatocellular Carcinoma After Curative Resection
verfasst von
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
Publikationsdatum
01.10.2012
Verlag
Springer-Verlag
Erschienen in
Annals of Surgical Oncology / Ausgabe 11/2012
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-012-2396-1

Weitere Artikel der Ausgabe 11/2012

Annals of Surgical Oncology 11/2012 Zur Ausgabe

Update Chirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

S3-Leitlinie „Diagnostik und Therapie des Karpaltunnelsyndroms“

CME: 2 Punkte

Prof. Dr. med. Gregor Antoniadis Das Karpaltunnelsyndrom ist die häufigste Kompressionsneuropathie peripherer Nerven. Obwohl die Anamnese mit dem nächtlichen Einschlafen der Hand (Brachialgia parästhetica nocturna) sehr typisch ist, ist eine klinisch-neurologische Untersuchung und Elektroneurografie in manchen Fällen auch eine Neurosonografie erforderlich. Im Anfangsstadium sind konservative Maßnahmen (Handgelenksschiene, Ergotherapie) empfehlenswert. Bei nicht Ansprechen der konservativen Therapie oder Auftreten von neurologischen Ausfällen ist eine Dekompression des N. medianus am Karpaltunnel indiziert.

Prof. Dr. med. Gregor Antoniadis
Berufsverband der Deutschen Chirurgie e.V.

S2e-Leitlinie „Distale Radiusfraktur“

CME: 2 Punkte

Dr. med. Benjamin Meyknecht, PD Dr. med. Oliver Pieske Das Webinar S2e-Leitlinie „Distale Radiusfraktur“ beschäftigt sich mit Fragen und Antworten zu Diagnostik und Klassifikation sowie Möglichkeiten des Ausschlusses von Zusatzverletzungen. Die Referenten erläutern, welche Frakturen konservativ behandelt werden können und wie. Das Webinar beantwortet die Frage nach aktuellen operativen Therapiekonzepten: Welcher Zugang, welches Osteosynthesematerial? Auf was muss bei der Nachbehandlung der distalen Radiusfraktur geachtet werden?

PD Dr. med. Oliver Pieske
Dr. med. Benjamin Meyknecht
Berufsverband der Deutschen Chirurgie e.V.

S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“

CME: 2 Punkte

Dr. med. Mihailo Andric
Inhalte des Webinars zur S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“ sind die Darstellung des Projektes und des Erstellungswegs zur S1-Leitlinie, die Erläuterung der klinischen Relevanz der Klassifikation EAES 2015, die wissenschaftliche Begründung der wichtigsten Empfehlungen und die Darstellung stadiengerechter Therapieoptionen.

Dr. med. Mihailo Andric
Berufsverband der Deutschen Chirurgie e.V.