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Prognostic Value of Raf Kinase Inhibitor Protein in Esophageal Squamous Cell Carcinoma

Abstract

Raf kinase inhibitory protein (RKIP, also PEBP1) is involved in regulation of multiple cellular signaling processes and suppressing metastasis in animal models. Downregulation of RKIP expression has been shown to promote tumor progression in a variety of human cancers. However, its role and clinical significance in resectable esophageal squamous cell carcinoma (ESCC) is still scanty. The purpose of this study was to investigate the prognostic significance of RKIP expression by immunohistochemistry in a group of patients with ESCC treated with surgical resection. RKIP expression in 233 surgically resected ESCC specimens and 49 cases of adjacent normal tissues was detected by using immunohistochemical staining. The clinical and prognostic significance of RKIP expression was statistically analyzed. Kaplan-Meier analysis was used to compare the postoperative survival between groups. Significant downregulation was noted for RKIP protein in ESCCs, compared to adjacent normal tissues (p < 0.001). A lower disease-free survival and overall survival of ESCC was found in patients whose tissues had low RKIP expression (both P < 0.001). In addition, RKIP expression could stratify the patient survival (disease-free survival/overall survival) in stage II (P = 0.01 and 0.02, repectively). The Cox proportionate hazard regression model also established that low expression of RKIP was significantly correlated with increased risk (RR = 3.572) of recurrence compared with high RKIP expression (P < 0.001). Furthermore, the results of multivariate analysis suggested that RKIP expression (P < 0.001) was an independent factor that affected overall survival. These findings suggest that the low expression of RKIP be associated with poor survival in resectable ESCC patients.

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References

  1. Landis SH, Murray T, Bolden S, Wingo PA (1999) Cancer statistics. CA Cancer J Clin 49:8–31

    PubMed  Article  CAS  Google Scholar 

  2. Yu WW, Guo YM, Zhu M, Cai XW, Zhu ZF, Zhao WX, Fu XL (2011) Clinicopathological and prognostic significance of EGFR over-expression in esophageal squamous cell carcinoma: a meta-analysis. Hepatogastroenterology 58:426–431

    PubMed  Article  CAS  Google Scholar 

  3. Liu J, Hu Y, Hu W, Xie X, Ela Bella A, Fu J, Rao D. (2011) Expression and prognostic relevance of p21(WAF1) in stage III esophageal squamous cell carcinoma. Dis Esophagus. In press.

  4. Keller ET, Fu Z, Brennan M (2004) The role of Raf kinase inhibitor protein (RKIP) in health and disease. Biochem Pharmacol 68:1049–1053

    PubMed  Article  CAS  Google Scholar 

  5. Keller ET (2004) Metastasis suppressor genes: a role for raf kinase inhibitor protein (RKIP). Anticancer Drugs 15:663–669

    PubMed  Article  CAS  Google Scholar 

  6. Trakul N, Rosner MR (2005) Modulation of the MAP kinase signaling cascade by Raf kinase inhibitory protein. Cell Res 15:19–23

    PubMed  Article  CAS  Google Scholar 

  7. Bernier I, Jolles P (1984) Purification and characterization of a basic 23 kDa cytosolic protein from bovine brain. Biochim Biophys Acta 790:174–181

    PubMed  Article  CAS  Google Scholar 

  8. Khamis ZI, Iczkowski KA, Sang QX. (2011) Metastasis suppressors in human benign prostate, intraepithelial neoplasia, and invasive cancer: their prospects as therapeutic agents. Med Res Rev. In press.

  9. Li HZ, Gao Y, Zhao XL, Liu YX, Sun BC, Yang J, Yao Z (2009) Effects of raf kinase inhibitor protein expression on metastasis and progression of human breast cancer. Mol Cancer Res 7:832–840

    PubMed  Article  CAS  Google Scholar 

  10. Xu YF, Yi Y, Qiu SJ, Gao Q, Li YW, Dai CX, Cai MY, Ju MJ, Zhou J, Zhang BH, Fan J (2010) PEBP1 downregulation is associated to poor prognosis in HCC related to hepatitis B infection. J Hepatol 53:872–879

    PubMed  Article  CAS  Google Scholar 

  11. Baritaki S, Katsman A, Chatterjee D, Yeung KC, Spandidos DA, Bonavida B (2007) Regulation of tumor cell sensitivity to TRAIL-induced apoptosis by the metastatic suppressor Raf kinase inhibitor protein via Yin Yang 1 inhibition and death receptor 5 up-regulation. J Immunol 179:5441–5453

    PubMed  CAS  Google Scholar 

  12. Rice TW, Blackstone EH, Rusch VW (2010) 7th edition of the AJCC Cancer Staging Manual: esophagus and esophagogastric junction. Ann Surg Oncol 17:1721–1724

    PubMed  Article  Google Scholar 

  13. Wang J, Yang YH, Wang AQ, Yao B, Xie G, Feng G, Zhang Y, Cheng ZS, Hui L, Dai TZ, Du XB, Wang D (2010) Immunohistochemical detection of the Raf kinase inhibitor protein in nonneoplastic gastric tissue and gastric cancer tissue. Med Oncol 27:219–223

    PubMed  Article  Google Scholar 

  14. Zaravinos A, Chatziioannou M, Lambrou GI, Boulalas I, Delakas D, Spandidos DA (2011) Implication of RAF and RKIP Genes in Urinary Bladder Cancer. Pathol Oncol Res 17:181–190

    PubMed  Article  CAS  Google Scholar 

  15. Baritaki S, Bonavida B (2010) Viral infection and cancer: the NF-kappaB/Snail/RKIP loop regulates target cell sensitivity to apoptosis by cytotoxic lymphocytes. Crit Rev Immunol 30:31–46

    PubMed  CAS  Google Scholar 

  16. Wu K, Bonavida B (2009) The activated NF-kappaB-Snail-RKIP circuitry in cancer regulates both the metastatic cascade and resistance to apoptosis by cytotoxic drugs. Crit Rev Immunol 29:241–254

    PubMed  CAS  Google Scholar 

  17. Fu Z, Smith PC, Zhang L, Rubin MA, Dunn RL, Yao Z, Keller ET (2003) Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J Natl Cancer Inst 95:878–889

    PubMed  Article  CAS  Google Scholar 

  18. Biewenga P, Buist MR, Moerland PD, Loren V, van Themaat E, van Kampen AH, ten Kate FJ, Baas F (2008) Gene expression in early stage cervical cancer. Gynecol Oncol 108:520–526

    PubMed  Article  CAS  Google Scholar 

  19. Ruan L, Wang GL, Yi H, Chen Y, Tang CE, Zhang PF, Li MY, Li C, Peng F, Li JL, Chen ZC, Xiao ZQ (2010) Raf kinase inhibitor protein correlates with sensitivity of nasopharyngeal carcinoma to radiotherapy. J Cell Biochem 110:975–981

    PubMed  Article  CAS  Google Scholar 

  20. Al-Mulla F, Hagan S, Al-Ali W et al (2008) Raf kinase inhibitor protein: mechanism of loss of expression and association with genomic instability. J Clin Pathol 61:524–529

    PubMed  Article  CAS  Google Scholar 

  21. Minoo P, Zlobec I, Baker K et al (2007) Loss of raf-1 kinase inhibitor protein expression is associated with tumor progression and metastasis in colorectal cancer. Am J Clin Pathol 127:820–827

    PubMed  Article  Google Scholar 

  22. Lee HC, Tian B, Sedivy JM, Wands JR, Kim M (2006) Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Gastroenterology 131:1208–1217

    PubMed  Article  CAS  Google Scholar 

  23. Hagan S, Al-Mulla F, Mallon E et al (2005) Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis. Clin Cancer Res 11:7392–7397

    PubMed  Article  CAS  Google Scholar 

  24. Park S, Yeung ML, Beach S, Shields JM, Yeung KC (2005) RKIP downregulates B-Raf kinase activity in melanoma cancer cells. Oncogene 24:3535–3540

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Chengcheng Ren.

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Gao, C., Pang, L., Ren, C. et al. Prognostic Value of Raf Kinase Inhibitor Protein in Esophageal Squamous Cell Carcinoma. Pathol. Oncol. Res. 18, 471–477 (2012). https://doi.org/10.1007/s12253-011-9470-z

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  • DOI: https://doi.org/10.1007/s12253-011-9470-z

Keywords

  • Esophageal squamous cell carcinoma
  • Raf kinase inhibitor protein
  • Prognosis