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Stat3 promotes invasion of esophageal squamous cell carcinoma through up-regulation of MMP2

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Abstract

Stat3 alters the expression of its downstream genes and is associated with tumor invasion and metastasis in several human cancers. Its role in esophageal squamous cell carcinoma (ESCC) has not been well characterized. We examined the tumor sections of 100 cases of ESCC by immunohistochemistry and observed significant overexpression of Stat3 in the cytoplasm of 89 % of ESCC cells and of phosphorylated Stat3 (p-Stat3) in the nuclei of 71 % of ESCC when compare with normal esophageal mucosa (72 %, p = 0.02; and 31 %, p = 0.001). Overexpression of Stat3 and p-Stat3 positively correlated with that of matrix metalloproteinase-2 (MMP2), a known regulator for cell migration, in 65 % of ESCC while only 26 % shown in benign esophageal mucosa. To further investigate the association of Stat3 with tumor metastasis in vitro, invasion of EC-1 cells (a human ESCC cell line) were investigated with Boyden chambers. The results showed that transfection of Stat3 not only promoted invasion of EC-1 cells but also significantly induced MMP2 expression in a dose-dependent manner. In contrast, suppressing expression of endogenous Stat3 mRNA and protein by Stat3 siRNA significantly reduced EC-1 cell invasion and MMP2 expression. A high-affinity Stat3-binding element was localized to the positions of 648–641 bp (TTCTCGAA) in the MMP2 promoter with electrophoretic mobility shift assay. Our results suggest that Stat3, p-Stat3, and MMP2 were overexpressed in ESCC and associated with invasion of ESCC; and Stat3 up-regulated expression of MMP2 in ESCC through directly binding to the MMP2 promoter.

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References

  1. Lu JC, Tao H, Zhang YQ et al (2008) Extent of prophylactic postoperative radiotherapy after radical surgery of thoracic esophageal squamous cell carcinoma. Dis Esophagus 21:502–507

    Article  PubMed  Google Scholar 

  2. Pai A, Sonawane S, Purandare NC et al (2008) Penile metastasis from esophageal squamous carcinoma after curative resection. Ann Thorac Cardiovasc Surg 14:238–241

    PubMed  Google Scholar 

  3. Darnell JE Jr (1997) STATs and gene regulation. Science 277:1630–1635

    Article  CAS  PubMed  Google Scholar 

  4. Santos CI, Costa-Pereira AP (2011) Signal transducers and activators of transcription—from cytokine signaling to cancer biology. Biochim Biophys Acta 1816:38–49

    CAS  PubMed  Google Scholar 

  5. Jatiani SS, Baker SJ, Silverman LR, Reddy EP (2010) Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes Cancer 1:979–993

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Hazan-Halevy I, Harris D, Liu Z et al (2010) STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood 115:2852–2863

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Rani MR, Croze E, Wei T et al (2010) STAT-phosphorylation-independent induction of interferon regulatory factor-9 by interferon-beta. J Interferon Cytokine Res 30:163–1670

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Escudero-Lourdes C, Medeiros MK, Cárdenas-González MC, Wnek SM, Gandolfi JA (2010) Low level exposure to monomethylarsonous acid-induced the over-production of inflammation-related cytokines and the activation of cell signals associated with tumor progression in an urothelial cell model. Toxicol Appl Pharmacol 244:162–173

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Abdulghani J, Gu L, Dagvadorj A et al (2008) Stat3 promotes metastatic progression of prostate cancer. Am J Pathol 172:1717–1728

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Bourguignon LYW, Peyrollier K, Xia W, Gilad E (2008) Hyaluronan–CD44 interaction activates stem cell marker nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J Biol Chem 283:17635–17651

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Zhang M, Zhu GY, Gao HY, Zhao SP, Xue Y (2011) Expression of tissue levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in gastric adenocarcinoma. J Surg Oncol 103:243–247

    Article  CAS  PubMed  Google Scholar 

  12. Roomi MW, Monterrey JC, Kalinovsky T, Rath M, Niedzwiecki A (2010) Inhibition of invasion and MMPs by a nutrient mixture in human cancer cell lines: a correlation study. Exp Oncol 32:243–248

    CAS  PubMed  Google Scholar 

  13. Groblewska M, Mroczko B, Gryko M, Kędra B, Szmitkowski M (2010) Matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases 2 in the diagnosis of colorectal adenoma and cancer patients. Folia Histochem Cytobiol 48:564–571

    PubMed  Google Scholar 

  14. He Y, Liu XD, Chen ZY et al (2007) Interaction between cancer cells and stromal fibroblasts is required for activation of the uPAR-uPA-MMP-2 cascade in pancreatic cancer metastasis. Clin Cancer Res 13:3115–3124

    Article  CAS  PubMed  Google Scholar 

  15. Gupta GP, Nguyen DX, Chiang AC et al (2007) Mediators of vascular remodeling co-opted for sequential steps in lung metastasis. Nature 446:765–770

    Article  CAS  PubMed  Google Scholar 

  16. Xie T, Wei D, Liu M et al (2004) Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 23:3550–3560

    Article  CAS  PubMed  Google Scholar 

  17. Arnold MM, Srivastava S, Fredenburgh J, Stockard CR, Myers RB, Grizzle WE (1996) Effects of fixation and tissue processing on immunohistochemical demonstration of specific antigens. Biotech Histochem 71:23–224

    Article  Google Scholar 

  18. Garner MM, Revzin A (1986) The use of gel electrophoresis to detect and study nucleic acid–protein interactions. Trends Biol Sci 11:395–396

    Article  CAS  Google Scholar 

  19. Fried MG (1989) Measurement of protein–DNA interaction parameters by electrophoresis mobility shift assay. Electrophoresis 10:366–376

    Article  CAS  PubMed  Google Scholar 

  20. Becker S, Groner B, Muller CW (1998) Three-dimensional structure of the Stat3beta homodimer bound to DNA. Nature 394(6687):145–151

    Article  CAS  PubMed  Google Scholar 

  21. Brocklyn JR (2010) Regulation of cancer cell migration and invasion by sphingosine-1-phosphate. World J Biol Chem 1:307–312

    Article  PubMed Central  PubMed  Google Scholar 

  22. Eigentler TK, Figl A, Krex D et al (2011) Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma. Cancer 117:1697–1703

    Article  PubMed  Google Scholar 

  23. Lee SW, Jung KH, Jeong CH et al (2011) Inhibition of endothelial cell migration through the down-regulation of MMP-9 by A-kinase anchoring protein 12. Mol Med Rep 4:145–149

    CAS  PubMed  Google Scholar 

  24. Stearns D, Chaudhry A, Abel TW, Burger PC, Dang CV, Eberhart CG (2006) c-Myc overexpression causes anaplasia in medulloblastoma. Cancer Res 66:673–681

    Article  CAS  PubMed  Google Scholar 

  25. He G, Karin M (2011) NF-κB and STAT3—key players in liver inflammation and cancer. Cell Res 21:159–168

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Rosen DG, Mercado-Uribe I, Yang G et al (2006) The role of constitutively active signal transducer and activator of transcription 3 in ovarian tumorigenesis and prognosis. Cancer 107:2730–2740

    Article  CAS  PubMed  Google Scholar 

  27. Tsareva SA, Moriggl R, Corvinus FM et al (2007) Signal transducer and activator of transcription 3 activation promotes invasive growth of colon carcinomas through matrix metalloproteinase induction. Neoplasia 9:279–291

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Proietti CJ, Béguelin W, Flaqué MC et al (2011) Novel role of signal transducer and activator of transcription 3 as a progesterone receptor coactivator in breast cancer. Steroids 76:381–392

    Article  CAS  PubMed  Google Scholar 

  29. Monnien F, Zaki H, Borg C et al (2010) Prognostic value of phosphorylated STAT3 in advanced rectal cancer: a study from 104 French patients included in the EORTC 22921 trial. J Clin Pathol 63:873–878

    Article  PubMed  Google Scholar 

  30. Chang KC, Wu MH, Jones D, Chen FF, Tseng YL (2006) Activation of STAT3 in thymic epithelial tumors correlates with tumor type and clinical behavior. J Pathol 210:224–233

    Article  CAS  PubMed  Google Scholar 

  31. Kusaba T, Nakayama T, Yamazumi K et al (2005) Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors. J Clin Pathol 58:833–838

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Yang CH, Fan M, Slominski AT, Yue J, Pfeffer LM (2010) The role of constitutively activated STAT3 in B16 melanoma cells. Int J Infereron Cytokine Mediator Res 2:1–7

    CAS  Google Scholar 

  33. Ishdorj G, Johnston JB, Gibson SB (2010) Inhibition of constitutive activation of STAT3 by curcurbitacin-I (JSI-124) sensitized human B-leukemia cells to apoptosis. Mol Cancer Ther 9:3302–3314

    Article  CAS  PubMed  Google Scholar 

  34. Chen J, Wang J, Lin L et al (2012) Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer. Mol Cancer Ther 11:277–287

    Article  CAS  PubMed  Google Scholar 

  35. Wu ZS, Cheng XW, Wang XN, Song NJ (2011) Prognostic significance of phosphorylated signal transducer and activator of transcription 3 and suppressor of cytokine signaling 3 expression in human cutaneous melanoma. Melanoma Res 21:483–490

    Article  CAS  PubMed  Google Scholar 

  36. Qian WF, Guan WX, Gao Y et al (2011) Inhibition of STAT3 by RNA interference suppresses angiogenesis in colorectal carcinoma. Braz J Med Biol Res 44:1222–1230

    Article  CAS  PubMed  Google Scholar 

  37. Silver DL, Naora H, Liu J, Cheng W, Montell DJ (2004) Activated signal transducer and activator of transcription (STAT) 3: localization in focal adhesions and function in ovarian cancer cell motility. Cancer Res 64:3550–3558

    Article  CAS  PubMed  Google Scholar 

  38. Xie TX, Huang FJ, Aldape KD et al (2006) Activation of Stat3 in human melanoma promoter brain metastasis. Cancer Res 66:3188–3196

    Article  CAS  PubMed  Google Scholar 

  39. Scuto A, Krejci P, Popplewell L et al (2011) The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia 25:538–550

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Che Y, Hou S, Kang Z, Lin Q (2009) Serenoa repens induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of STAT 3 signaling. Oncol Rep 22:377–383

    CAS  PubMed  Google Scholar 

  41. Huang C, Yang G, Jiang T, Cao J, Huang KJ, Qiu ZJ (2011) Down-regulation of STAT3 expression by vector-based small interfering RNA inhibits pancreatic cancer growth. World J Gastroenterol 17:2992–3001

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM (2003) Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res 63:1270–1279

    CAS  PubMed  Google Scholar 

  43. Huang S, Chen M, Shen Y et al (2012) Inhibition of activated Stat3 reverses drug resistance to chemotherapeutic agents in gastric cancer cells. Cancer Lett 315:198–205

    Article  CAS  PubMed  Google Scholar 

  44. Glienke W, Maute L, Wicht J, Bergmann L (2010) Curcumin inhibits constitutive STAT3 phosphorylation in human pancreatic cancer cell lines and downregulation of survivin/BIRC5 gene expression. Cancer Invest 28:166–171

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors sincerely thank Dr. Guy Benian at Emory University in Atalanta, GA, USA and Dr. Junyi Lei at Jdxpath in Collegeville, PA, USA for their valuable comments and suggestions.

Funding

This research was supported with the Grant from National Natural Science Foundation of China (No. 81071970).

Conflict of interest

None.

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Author notes

  1. Xaioyan Xuan

    Present address: Department of Microbiology and Immunology, Zhengzhou University School of Medicine, Zhengzhou, Henan, China

Authors and Affiliations

  1. Department of Pathology, The First Affiliated Hospital and Key Laboratory of Tumor Pathology, Zhengzhou University School of Medicine, Zhengzhou, Henan, China

    Xaioyan Xuan, Shanshan Li, Xi Lou, Xianzhao Zheng, Yunyun Li, Feng Wang, Yuan Gao, Hongyan Zhang, Hongliu He & Qingru Zeng

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  1. Xaioyan Xuan
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Correspondence to Shanshan Li.

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Xuan, X., Li, S., Lou, X. et al. Stat3 promotes invasion of esophageal squamous cell carcinoma through up-regulation of MMP2. Mol Biol Rep 42, 907–915 (2015). https://doi.org/10.1007/s11033-014-3828-8

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