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Isoprenaline induces epithelial–mesenchymal transition in gastric cancer cells

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Abstract

The emerging role of stress-related signaling in regulating cancer development and progression has been recognized. However, whether stress serves as a mechanism to promote gastric cancer metastasis is not clear. Here, we show that the β2-AR agonist, isoprenaline, upregulates expression levels of CD44 and CD44v8-10 in gastric cancer cells. CD44, a cancer stem cell-related marker, is expressed at high levels in gastric cancer tissues, which strongly correlates with the occurrence of epithelial–mesenchymal transition (EMT)-associated phenotypes both in vivo and in vitro. Combined with experimental observations in two human gastric cancer cell lines, we found that β2-AR signaling can initiate EMT. It led to an increased expression of mesenchymal markers, such as α-SMA, vimentin, and snail at mRNA and protein levels, and conversely a decrease in epithelial markers, E-cadherin and β-catenin. Isoprenaline stimulation of β2-AR receptors activates the downstream target STAT3, which functions as a positive regulator and mediated the phenotypic switch toward a mesenchymal cell type in gastric cancer cells. Our data provide a mechanistic understanding of the complex signaling cascades involving stress-related hormones and their effects on EMT. In light of our observations, pharmacological interventions targeting β2-AR-STAT3 signaling can potentially be used to ameliorate stress-associated influences on gastric cancer development and progression.

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References

  1. Lozano R et al (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2095–2128

    Article  PubMed  Google Scholar 

  2. Price MA et al (2001) The role of psychosocial factors in the development of breast carcinoma: part II. Life event stressors, social support, defense style, and emotional control and their interactions. Cancer 91(4):686–697

    Article  CAS  PubMed  Google Scholar 

  3. Price MA et al (2001) The role of psychosocial factors in the development of breast carcinoma: part I. The cancer prone personality. Cancer 91(4):679–685

    Article  CAS  PubMed  Google Scholar 

  4. Reiche EM, Nunes SO, Morimoto HK (2004) Stress, depression, the immune system, and cancer. Lancet Oncol 5(10):617–625

    Article  CAS  PubMed  Google Scholar 

  5. Antoni MH et al (2006) The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer 6(3):240–248

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Sood AK et al (2010) Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J Clin Invest 120(5):1515–1523

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Thaker PH et al (2006) Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 12(8):939–944

    Article  CAS  PubMed  Google Scholar 

  8. Shi M et al (2011) The beta2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Res Treat 125(2):351–362

    Article  CAS  PubMed  Google Scholar 

  9. Shi M et al (2013) Catecholamine-induced beta2-adrenergic receptor activation mediates desensitization of gastric cancer cells to trastuzumab by upregulating MUC4 expression. J Immunol 190(11):5600–5608

    Article  CAS  PubMed  Google Scholar 

  10. Shi M et al (2010) Catecholamine up-regulates MMP-7 expression by activating AP-1 and STAT3 in gastric cancer. Mol Cancer 9:269

    Article  PubMed Central  PubMed  Google Scholar 

  11. Liu H et al (2010) Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci USA 107(42):18115–18120

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Liu R et al (2007) The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 356(3):217–226

    Article  CAS  PubMed  Google Scholar 

  13. Mani SA et al (2008) The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Yang J, Weinberg RA (2008) Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14(6):818–829

    Article  CAS  PubMed  Google Scholar 

  15. Rhim AD et al (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148(1–2):349–361

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Landen CJ et al (2007) Neuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer. Cancer Res 67(21):10389–10396

    Article  CAS  PubMed  Google Scholar 

  17. Rokavec M et al (2014) IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest 124(4):1853–1867

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Liu RY et al (2014) JAK/STAT3 signaling is required for TGF-beta-induced epithelial–mesenchymal transition in lung cancer cells. Int J Oncol 44(5):1643–1651

    CAS  PubMed  Google Scholar 

  19. Gregory PA et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10(5):593–601

    Article  CAS  PubMed  Google Scholar 

  20. Shorning BY, Griffiths D, Clarke AR (2011) Lkb1 and Pten synergise to suppress mTOR-mediated tumorigenesis and epithelial–mesenchymal transition in the mouse bladder. PLoS ONE 6(1):e16209

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Noseda M et al (2004) Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation. Circ Res 94(7):910–917

    Article  CAS  PubMed  Google Scholar 

  22. Sanchez-Tillo E et al (2012) EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cell Mol Life Sci 69(20):3429–3456

    Article  CAS  PubMed  Google Scholar 

  23. Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol 15(3):178–196

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Iseri OD et al (2014) Beta-adrenoreceptor antagonists reduce cancer cell proliferation, invasion, and migration. Pharm Biol 52(11):1374–1381

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Natural Science Foundation of China, No. 30901564, No. 81101883, No. 81372067, No. 81121004, No. 81230041; National Basic Science and Development Programme (973 Programme) No. 2012CB518105; Beijing Novel Program, No. 2008B53, No. 2009A38; Science and technology support program of Hebei Province of China, No. 13277779D; and the Key Subjects in Universities and Colleges of Hebei Province of China (pathology and pathophysiology).

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    Authors and Affiliations

    1. Department of General Surgery, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, People’s Republic of China

      Yan-Jie Lu & Bo Wei

    2. Key Research Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of skin injury, Repair and Regeneration, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, 100048, People’s Republic of China

      Zhi-Jun Geng & Xiao-Bing Fu

    3. Department of General Surgery, The 266th hospital of Chinese PLA, Chengde, 067000, Hebei, People’s Republic of China

      Yan-Jie Lu & Xiang-Yang Zhao

    4. Department of Pathology, Cancer Research Laboratory, Chengde Medical College, Chengde, 067000, Hebei, People’s Republic of China

      Yan-Jie Lu & Yu-Hong Li

    5. Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Trauma Center of Postgraduate Medical School, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China

      Xiao-Yan Sun & Xiao-Bing Fu

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    1. Yan-Jie Lu
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    Correspondence to Xiang-Yang Zhao or Bo Wei.

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    Yan-Jie Lu and Zhi-Jun Geng have contributed equally to this work.

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    Supplementary Fig. S1

    CD44 expressed negatively correlated with β-catenin in gastric cancer.Representative fluorescence images showing the double-labeling of CD44 withepithelial marker β-catenin in peri-cancerous (A), cancerous (B) and metastatic gastriccancer tissue samples (C). In normal gastric mucosa epithelial cells β-catenin washighly expressed (A) and downregulated in cancerous tissue (B) and lymphaticmetastasis (C). In cancerous tissue where CD44 was expressed at high levels, theexpression of β-catenin was downregulated and was inversely correlated with thedistribution patterns of CD44. In contrast, in cancerous tissues where CD44 showed lowexpression, β-catenin was expressed at high levels in the membrane of cancerous gastricepithelial cells. A similar result can be obtained in lymphatic metastasis that CD44 washighly expressed and β-catenin expression was nearly absent. A–C, Bar 25 μm. (TIFF 14184 kb)

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    Lu, YJ., Geng, ZJ., Sun, XY. et al. Isoprenaline induces epithelial–mesenchymal transition in gastric cancer cells. Mol Cell Biochem 408, 1–13 (2015). https://doi.org/10.1007/s11010-015-2477-0

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    • DOI: https://doi.org/10.1007/s11010-015-2477-0

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