Skip to main content

Advertisement

SpringerLink
Log in

Clinical significance of β2-adrenergic receptor expression in patients with surgically resected gastric adenocarcinoma

  • Original Article
  • Published:
Tumor Biology

Abstract

The β2-adrenergic receptor (β2-AR) is highly expressed in various human neoplasms and has been considered a novel therapeutic target of cancer treatment. However, the clinicopathological significance of β2-AR expression in patients with gastric cancer (GC) remains unclear. The aim of this study was to explore β2-AR expression and its prognostic significance. A total of 331 patients with surgically resected GC were evaluated. Tumor sections were stained immunohistochemically for β2-AR. And, we confirmed β2-AR expression in the GC cell lines by Western blot. β2-AR was highly expressed in 30.5 % of GC patients. Expression was significantly associated with age, T factor, tumor differentiation, histology of non-signet cells, lymphatic permeation, and vascular invasion. And, all the GC cell lines expressed β2-AR. On univariate analysis, age, disease stage, T factor, N factor, lymphatic permeation, vascular invasion, and β2-AR expression were significantly associated with overall survival. Although the multivariate analysis did not indicate that β2-AR expression was independently prognostic of survival, high-level β2-AR expression was associated with significantly poorer survival of GC patients with well or moderately differentiated tumors. β2-AR expression was a significant predictor of tumor aggressiveness in, and poorer survival of, patients with GC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Desai AM, Pareek M, Nightingale PG, Fielding JW. Improving outcomes in gastric cancer over 20 years. Gastric Cancer. 2004;7:196–201 .discussion 201-203

    Article  PubMed  Google Scholar 

  2. Aronow WS. Current role of beta-blockers in the treatment of hypertension. Expert Opin Pharmacol. 2010;11:2599–607.

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. Entschladen F, Drell IV TL, Lang K, Joseph J, Zaenker KS. Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters. Lancet Oncol. 2004;5:254–8.

    Article  CAS  PubMed  Google Scholar 

  5. Thaker PH, Han LY, Kamat AA, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12:939–44.

    Article  CAS  PubMed  Google Scholar 

  6. Ramberg H et al. Hormonal regulation of beta 2-adrenergic receptor level in prostate cancer. Prostate. 2008;68:1133–42.

    Article  CAS  PubMed  Google Scholar 

  7. Yang EV 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.

    Article  CAS  PubMed  Google Scholar 

  8. Shang ZJ et al. Expression of beta 2-adrenergic receptor in oral squamous cell carcinoma. J Oral Pathol M ed. 2009;38:371–6.

    Article  CAS  Google Scholar 

  9. Shi M et al. The beta 2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Res Treat. 2011;125:351–62.

    Article  CAS  PubMed  Google Scholar 

  10. Chen D et al. The beta 2-adrenergic receptor is a potential prognostic biomarker for human hepatocellular carcinoma after curative resection. Ann Surg Oncol. 2012;19:3556–65.

    Article  PubMed  Google Scholar 

  11. Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol. 2011;29:2645–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Barron TI, Connolly RM, Sharp L, et al. Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol. 2011;29:2635–44.

    Article  CAS  PubMed  Google Scholar 

  13. Shi M, Liu D, Duan H, Han C, Wei B, Qian L, et al. Catecholamine up-regulates MMP-7 expression by activating AP-1 and STAT3 in gastric cancer. Mol Cancer. 2010;12(9):269.

    Google Scholar 

  14. Ming S, Zhengyan Y, Meiru H, Dan L, Yabin H, Lu Q, et al. Catecholamine-induced β2-adrenergic receptor activation mediates desensitization of gastric cancer cells to Trastuzumab by upregulating MUC4 expression. J Immunol. 2013;190:5600–8.

    Article  Google Scholar 

  15. Satoshi M, Atsushi N, Kazuhiro N, Akira M, Hiroto M, Kazuya Y, et al. Clinicopathological factors associated with HER2 status in gastric cancer: results from a prospective multicenter observational cohort study in a Japanese population (JFMC44-1101). Gastric Cancer. 2015; in press.

  16. Bravo-Calderon DM, Oliveira DT, Marana AN, Nonogaki S, Carvalho AL, Kowalski LP. Prognostic significance of beta-2 adrenergic receptor in oral squamous cell carcinoma. Cancer Biomarkers: Sec A Dis Mark. 2010;10:51–9.

    Google Scholar 

  17. Wenjuan Y, Yujun L, Ceng Y. Association of single nucleotide polymorphisms of beta 2-adrenergic receptor gene with clinicopathological features of pancreatic carcinoma. Acta Histochem. 2013;115:198–203.

    Article  PubMed  Google Scholar 

  18. Shan T, Cui X, Lin W, Li Y, Chen X, Wu T. Novel regulatory program for norepinephrine-induced epithelial-mesenchymal transition in gastric adenocarcinoma cell lines. Cancer Sci. 2014;7:847–56.

    Article  Google Scholar 

  19. Gomes LR, Terra LF, Sogayar MCL. Epithelial-mesenchymal transition: implications in cancer progression and metastasis. Curr Pharm Biotechnol. 2011;12:1881–90.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Palm D, Lang K, Niggemann B, Drell IV TL, 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.

    Article  CAS  PubMed  Google Scholar 

  22. De Giorgi V, Grazzini M, Gandini S, Benemei S, Lotti T, Marchionni N, Geppetti P. Treatment with beta-blockers and reduced disease progression in patients with thick melanoma. Arch Intern Med. 2011;171:779–81.

    PubMed  Google Scholar 

  23. Lemeshow S, Sorensen HT, Phillips G, Yang EV, Antonsen S, Riis AH, Lesinski GB, Jackson R, Glaser R. Beta-blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol Biomark Prev. 2011;20:2273–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Ms. Yuka Matsui for her technical assistance during manuscript submission. And, we thank Ms. Tuya Bai and Ms. Hailin Bao for their technical assistance during Western blotting. We deeply appreciate the help given by Prof. Masahiko Nishiyama of the Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, who critically reviewed the manuscript.

Author information

Authors and Affiliations

  1. Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Kengo Takahashi, Taisuke Sato, Norifumi Takahashi, Hiroomi Ogawa, Daisuke Yoshinari & Izumi Takeyoshi

  2. Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Kyoichi Kaira & Takayuki Asao

  3. Department of Dermatology, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Akira Shimizu

  4. Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Takehiko Yokobori

  5. Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Tetsunari Oyama

Authors
  1. Kengo Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyoichi Kaira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akira Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Taisuke Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Norifumi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroomi Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daisuke Yoshinari
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takehiko Yokobori
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takayuki Asao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Izumi Takeyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tetsunari Oyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kyoichi Kaira.

Ethics declarations

Conflicts of interest

None.

Ethical statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Gunma University Hospital) and with the Helsinki Declaration of 1964 and later versions.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Takahashi, K., Kaira, K., Shimizu, A. et al. Clinical significance of β2-adrenergic receptor expression in patients with surgically resected gastric adenocarcinoma. Tumor Biol. 37, 13885–13892 (2016). https://doi.org/10.1007/s13277-016-5139-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5139-2

Keywords

Search

Navigation