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Metadherin expression and lung relapse in patients with colorectal carcinoma

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Abstract

Colorectal cancer (CRC) is the third most common malignant disease in men and the second in women worldwide. CRC relapse occurs mostly in liver and lungs, decreasing the 5-year survival to 6 %. Metadherin (MTDH) is overexpressed in several types of cancer, has been implicated in proliferation, invasion, metastasis, angiogenesis, and chemoresistance, and is a factor of poor prognosis in CRC. In this work we addressed the prognostic significance of MTDH expression in CRC progression to the lungs. We found that MTDH gene was more frequently amplified (copy number >1.8) in patients with CRC and relapse to the lung, when compared to patients without lung metastases (17.4 vs 100 %; p < 0.001). We observed a correlation between MTDH gene copy number and MTDH expression by IHC (p = 0.0001). Next we also analyzed MTDH expression by IHC in samples from 85 patients diagnosed with CRC, stage II or III, M0, with at least 3 years of follow-up. Kaplan–Meier survival analysis showed that lung relapse-free survival (HR 5.29, 95 % CI 1.90–14.77, p = 0.0004), liver relapse-free survival (HR 8.59, 95 % CI 0.99–74.18, p = 0.003), relapse-free survival (HR 4.85, 95 % CI 1.88–12.45, p = 0.0003) and overall survival (HR 3.75, 95 % CI 1.15–12.18, p = 0.018) were significantly lower in the group with high MTDH expression. Multivariate analysis showed that high MTDH expression was an independent factor for all outcomes. This study demonstrates that high MTDH expression is a biomarker of relapse in CRC, including lung-specific relapse. Determination of MTDH expression in primary CRC may be useful in the earlier detection of lung metastases in patients with high expression and increased risk.

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References

  1. Ferlay J et al (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12):2893–2917

    CAS  PubMed  Google Scholar 

  2. Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17(6):1471–1474

    Article  PubMed  Google Scholar 

  3. Benson AB 3rd et al (2004) American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22(16):3408–3419

    Article  PubMed  Google Scholar 

  4. Liu Y et al (2013) Increased expression of metadherin protein predicts worse disease-free and overall survival in laryngeal squamous cell carcinoma. Int J Cancer 133(3):671–679

    CAS  PubMed  Google Scholar 

  5. Ke ZF et al (2013) Expression characteristics of astrocyte elevated gene-1 (AEG-1) in tongue carcinoma and its correlation with poor prognosis. Cancer Epidemiol 37(2):179–185

    Article  CAS  PubMed  Google Scholar 

  6. Ke ZF et al (2013) AEG-1 expression characteristics in human non-small cell lung cancer and its relationship with apoptosis. Med Oncol 30(1):383

    Article  PubMed  Google Scholar 

  7. Zhou J et al (2012) Metadherin is a novel prognostic marker for bladder cancer progression and overall patient survival. Asia Pac J Clin Oncol 8(3):e42–e48

    Article  PubMed  Google Scholar 

  8. Sun S et al (2012) Overexpression of astrocyte-elevated gene-1 is closely correlated with poor prognosis in human non-small cell lung cancer and mediates its metastasis through up-regulation of matrix metalloproteinase-9 expression. Hum Pathol 43(7):1051–1060

    Article  CAS  PubMed  Google Scholar 

  9. Gong Z et al (2012) Prognostic significance of metadherin overexpression in hepatitis B virus-related hepatocellular carcinoma. Oncol Rep 27(6):2073–2079

    CAS  PubMed  Google Scholar 

  10. Li C et al (2012) Elevated expression of astrocyte elevated gene-1 (AEG-1) is correlated with cisplatin-based chemoresistance and shortened outcome in patients with stages III–IV serous ovarian carcinoma. Histopathology 60(6):953–963

    Article  PubMed  Google Scholar 

  11. Baygi ME, Nikpour P (2012) Deregulation of MTDH gene expression in gastric cancer. Asian Pac J Cancer Prev 13(6):2833–2836

    Article  PubMed  Google Scholar 

  12. Liu HY et al (2012) AEG-1 is associated with clinical outcome in neuroblastoma patients. Cancer Biomark 11(2–3):115–121

    CAS  PubMed  Google Scholar 

  13. Hui AB et al (2011) Significance of dysregulated metadherin and microRNA-375 in head and neck cancer. Clin Cancer Res 17(24):7539–7550

    Article  CAS  PubMed  Google Scholar 

  14. Zhu K et al (2011) Metadherin promotes hepatocellular carcinoma metastasis through induction of epithelial–mesenchymal transition. Clin Cancer Res 17(23):7294–7302

    Article  CAS  PubMed  Google Scholar 

  15. Liao WT et al (2011) Astrocyte elevated gene-1 (AEG-1) is a marker for aggressive salivary gland carcinoma. J Transl Med 9:205

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Sun W et al (2011) Astrocyte elevated gene-1 overexpression in human primary gallbladder carcinomas: an unfavorable and independent prognostic factor. Oncol Rep 26(5):1133–1142

    CAS  PubMed  Google Scholar 

  17. Wang F et al (2011) Oncogenic roles of astrocyte elevated gene-1 (AEG-1) in osteosarcoma progression and prognosis. Cancer Biol Ther 12(6):539–548

    Article  CAS  PubMed  Google Scholar 

  18. Jian-bo X et al (2011) Astrocyte-elevated gene-1 overexpression is associated with poor prognosis in gastric cancer. Med Oncol 28(2):455–462

    Article  PubMed  Google Scholar 

  19. Li C et al (2011) AEG -1 overexpression: a novel indicator for peritoneal dissemination and lymph node metastasis in epithelial ovarian cancers. Int J Gynecol Cancer 21(4):602–608

    Article  PubMed  Google Scholar 

  20. Song H et al (2010) Expression of astrocyte elevated gene-1: a novel marker of the pathogenesis, progression, and poor prognosis for endometrial cancer. Int J Gynecol Cancer 20(7):1188–1196

    Article  PubMed  Google Scholar 

  21. Chen W et al (2010) Overexpression of AEG-1 in renal cell carcinoma and its correlation with tumor nuclear grade and progression. Neoplasma 57(6):522–529

    Article  CAS  PubMed  Google Scholar 

  22. Yu C et al (2009) Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis. Carcinogenesis 30(5):894–901

    Article  CAS  PubMed  Google Scholar 

  23. Yoo BK et al (2009) Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J Clin Invest 119(3):465–477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Hu G et al (2009) MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell 15(1):9–20

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Li J et al (2008) Astrocyte elevated gene-1 is a novel prognostic marker for breast cancer progression and overall patient survival. Clin Cancer Res 14(11):3319–3326

    Article  CAS  PubMed  Google Scholar 

  26. Brown DM, Ruoslahti E (2004) Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 5(4):365–374

    Article  CAS  PubMed  Google Scholar 

  27. Emdad L et al (2009) Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis. Proc Natl Acad Sci USA 106(50):21300–21305

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Lee SG et al (2008) Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling. Oncogene 27(8):1114–1121

    Article  CAS  PubMed  Google Scholar 

  29. van ‘t Veer LJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536

    Article  PubMed  Google Scholar 

  30. Britt DE et al (2004) Identification of a novel protein, LYRIC, localized to tight junctions of polarized epithelial cells. Exp Cell Res 300(1):134–148

    Article  CAS  PubMed  Google Scholar 

  31. Gnosa S et al (2012) Expression of AEG-1 mRNA and protein in colorectal cancer patients and colon cancer cell lines. J Transl Med 10:109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Song H et al (2010) Prognostic significance of AEG-1 expression in colorectal carcinoma. Int J Colorectal Dis 25(10):1201–1209

    PubMed  Google Scholar 

  33. Jiang T et al (2012) Clinical implications of AEG-1 in liver metastasis of colorectal cancer. Med Oncol 29(4):2858–2863

    Article  CAS  PubMed  Google Scholar 

  34. Wang N et al (2012) Prognostic impact of Metadherin-SND1 interaction in colon cancer. Mol Biol Rep 39(12):10497–10504

    Article  CAS  PubMed  Google Scholar 

  35. Yoo BK et al (2009) Identification of genes conferring resistance to 5-fluorouracil. Proc Natl Acad Sci USA 106(31):12938–12943

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Morales C et al (2009) Dihydrofolate reductase amplification and sensitization to methotrexate of methotrexate-resistant colon cancer cells. Mol Cancer Ther 8(2):424–432

    Article  CAS  PubMed  Google Scholar 

  37. Glockner S et al (2001) Amplification of growth regulatory genes in intraductal breast cancer is associated with higher nuclear grade but not with the progression to invasiveness. Lab Invest 81(4):565–571

    Article  CAS  PubMed  Google Scholar 

  38. Lehmann U et al (2000) Detection of gene amplification in archival breast cancer specimens by laser-assisted microdissection and quantitative real-time polymerase chain reaction. Am J Pathol 156(6):1855–1864

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Van Cutsem E et al (2010) Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol 21:v93–v97

    Article  PubMed  Google Scholar 

  40. Nozawa H et al (2012) Synchronous and metachronous lung metastases in patients with colorectal cancer: a 20-year monocentric experience. Exp Ther Med 3(3):449–456

    PubMed Central  PubMed  Google Scholar 

  41. Penna C, Nordlinger B (2002) Colorectal metastasis (liver and lung). Surg Clin N Am 82(5):1075–1090

    Article  PubMed  Google Scholar 

  42. Song HT et al (2010) Prognostic significance of AEG-1 expression in colorectal carcinoma. Int J Colorectal Dis 25(10):1201–1209

    PubMed  Google Scholar 

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Acknowledgments

Authors acknowledge the support of the IMM Histology Service and Mara Santos from the Pathology Division of Hospital de Santa Maria. This project was supported by a Grant from Fundação para a Ciência e Tecnologia (PIC/IC/82821/2007).S. Casimiro was supported by a Post-Doctoral Grant (SFRH/BPD/34801/2007) and J. Tato-Costa by a PhD Grant (SFRH/BD/45219/2008) from Fundação para a Ciência e Tecnologia.

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Correspondence to Sandra Casimiro.

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Casimiro, S., Fernandes, A., Oliveira, A.G. et al. Metadherin expression and lung relapse in patients with colorectal carcinoma. Clin Exp Metastasis 31, 689–696 (2014). https://doi.org/10.1007/s10585-014-9659-0

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  • DOI: https://doi.org/10.1007/s10585-014-9659-0

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