Skip to main content

Advertisement

Log in

Role of serum Metadherin mRNA expression in the diagnosis and prediction of survival in patients with colorectal cancer

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Early diagnosis and treatment of colorectal cancer (CRC) are important for improving patients’ survival. Metadherin is an oncogene that plays a pivotal role in carcinogenesis and can be suggested as a cancer biomarker. This study aimed to elucidate the efficacy of serum Metadherin mRNA expression as a potential non-invasive biomarker for early diagnosis of CRC in relation to other screening markers as carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA19.9) and Fecal occult blood (FOB) and also to assess its relationship with the tumor stage and survival rate. A convenience series of 86 CRC cases (group I) were recruited with 78 subjects as controls (group II). Serum Metadherin mRNA expression level was determined using reverse transcription polymerase chain reaction (RT-PCR). Serum Metadherin mRNA expression level was significantly elevated in CRC cases when compared with controls (P < 0.001). For CRC diagnosis; Receiver operator characteristic (ROC) analyses revealed that the diagnostic accuracy of serum Metadherin mRNA (AUC = 0.976) was significantly higher than other routine CRC screening markers as CEA, CA19.9 and FOB. The combined accuracy of these markers (AUC = 0.741) was increased when used with serum Metadherin mRNA (AUC = 0.820). High serum Metadherin mRNA expression was associated with poorly differentiated histological grade, advanced tumor stage and lower survival rate. AUC of Metadherin was 0.820 for differentiating advanced versus early tumor stages. Serum Metadherin mRNA expression is a useful non-invasive biomarker for CRC. It can be used for screening and early diagnosis of CRC and can increase the efficacy of other routine CRC screening markers when it is estimated in CRC patients with them. It is also associated with advanced tumor stage and a lower survival rate.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

CRC:

Colorectal cancer

CA19.9:

Carbohydrate antigen19.9

CEA:

Carcino-embryonic antigen

FOB:

Fecal occult blood

AEG-1:

Astrocyte elevated gene-1

PCR:

Polymerase chain reaction

AUC:

Area under curve

FIT:

Fecal immunochemical test

PI3K:

Phosphoinositol 3-kinase

NF-κB:

Nuclear factor kappa B

AJCC:

American Joint Committee on Cancer

EDTA:

Ethylene diamine tetra acetic acid

RT:

Reverse transcriptase

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

CT:

Cycle threshold

PPV:

Positive predictive value

NPV:

Negative predictive value

TNFα:

Tumor necrosis factor-alpha

References

  1. Siegel R, Desantis C, Jemal A (2014) Colorectal cancer statistics, 2014. CA Cancer J Clin 64(2):104–117

    Article  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

    Article  PubMed  Google Scholar 

  3. Abou-Zeid AA, Khafagy W, Marzouk DM, Alaa A, Mostafa I, Ela MA (2002) Colorectal cancer in Egypt. Dis Colon Rectum 45(9):1255–1260

    Article  PubMed  Google Scholar 

  4. Heiss JA, Brenner H (2017) Epigenome-wide discovery and evaluation of leukocyte DNA methylation markers for the detection of colorectal cancer in a screening setting. Clin Epigenet 9:24

    Article  CAS  Google Scholar 

  5. Vatandoost N, Ghanbari J, Mojaver M, Avan A, Ghayour-Mobarhan M, Nedaeinia R et al (2016) Early detection of colorectal cancer: from conventional methods to novel biomarkers. J Cancer Res Clin Oncol 142(2):341–351

    Article  CAS  PubMed  Google Scholar 

  6. Pellino G, Gallo G, Pallante P, Capasso R, De Stefano A, Maretto I et al (2018) Noninvasive biomarkers of colorectal cancer: role in diagnosis and personalised treatment perspectives. Gastroenterol Res Pract 2018:2397863

    Article  PubMed  PubMed Central  Google Scholar 

  7. van Rossum LG, van Rijn AF, Laheij RJ, van Oijen MG, Fockens P, van Krieken HH et al (2008) Random comparison of guaiac and immunochemical fecal occult blood tests for colorectal cancer in a screening population. Gastroenterology 135(1):82–90

    Article  PubMed  Google Scholar 

  8. Fraser CG, Matthew CM, Mowat NA, Wilson JA, Carey FA, Steele RJ (2006) Immunochemical testing of individuals positive for guaiac faecal occult blood test in a screening programme for colorectal cancer: an observational study. Lancet Oncol 7(2):127–131

    Article  PubMed  Google Scholar 

  9. Zhang SY, Lin M, Zhang HB (2015) Diagnostic value of carcinoembryonic antigen and carcinoma antigen 19 – 9 for colorectal carcinoma. Int J Clin Exp Pathol 8(8):9404–9409

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Hauptman N, Glavac D (2017) Colorectal cancer blood-based biomarkers. Gastroenterol Res Pract 2017:2195361

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F 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  PubMed Central  Google Scholar 

  12. Yu C, Chen K, Zheng H, Guo X, Jia W, Li M 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 

  13. Wang F, Ke ZF, Sun SJ, Chen WF, Yang SC, Li SH 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 

  14. Dong L, Qin S, Li Y, Zhao L, Dong S, Wang Y et al (2015) High expression of astrocyte elevated gene-1 is associated with clinical staging, metastasis, and unfavorable prognosis in gastric carcinoma. Tumour Biol 36(3):2169–2178

    Article  CAS  PubMed  Google Scholar 

  15. Hamilton SR, Bosman FT, Boffetta P, Ilyas M, Morreau H, Nakamura SI, Quirke P, Riboli E, Sobin (2010) L.H Carcinoma of the colon and rectum. In: Bosman T, Carneiro F, Hruban RH Theise N.D editor. IARC Press, WHO classification of tumors of the digestive system Lyon, pp 134–146

  16. 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 

  17. National Comprehensive Cancer Network (NCCN). [Available from: https://www.nccn.org/professionals/physician_gls/default.aspx

  18. Mei XL, Zheng QF (2019) Role of cellular biomolecules in screening, diagnosis and treatment of colorectal cancer. Curr Drug Metab 20(11):880–888

    Article  CAS  PubMed  Google Scholar 

  19. Xing H, Wang J, Wang Y, Tong M, Hu H, Huang C et al (2018) Diagnostic value of CA 19 – 9 and carcinoembryonic antigen for pancreatic cancer: a meta-analysis. Gastroenterol Res Pract 2018:8704751

    Article  PubMed  PubMed Central  Google Scholar 

  20. Vartak-Sharma N, Gelman BB, Joshi C, Borgamann K, Ghorpade A (2014) Astrocyte elevated gene-1 is a novel modulator of HIV-1-associated neuroinflammation via regulation of nuclear factor-kappaB signaling and excitatory amino acid transporter-2 repression. J Biol Chem 289(28):19599–19612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shi X, Wang X (2015) The role of MTDH/AEG-1 in the progression of cancer. Int J Clin Exp Med 8(4):4795–4807

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kang DC, Su ZZ, Sarkar D, Emdad L, Volsky DJ, Fisher PB (2005) Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. Gene 353(1):8–15

    Article  CAS  PubMed  Google Scholar 

  23. Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY, Mukhopadhyay ND et al (2009) Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J Clin Invest 119(3):465–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Emdad L, Sarkar D, Su ZZ, Randolph A, Boukerche H, Valerie K et al (2006) Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. Cancer Res 66(3):1509–1516

    Article  CAS  PubMed  Google Scholar 

  25. Thirkettle HJ, Girling J, Warren AY, Mills IG, Sahadevan K, Leung H et al (2009) LYRIC/AEG-1 is targeted to different subcellular compartments by ubiquitinylation and intrinsic nuclear localization signals. Clin Cancer Res 15(9):3003–3013

    Article  CAS  PubMed  Google Scholar 

  26. Huang Y, Li LP (2014) Progress of cancer research on astrocyte elevated gene-1/Metadherin (Review). Oncol Lett 8(2):493–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Meng X, Brachova P, Yang S, Xiong Z, Zhang Y, Thiel KW et al (2011) Knockdown of MTDH sensitizes endometrial cancer cells to cell death induction by death receptor ligand TRAIL and HDAC inhibitor LBH589 co-treatment. PLoS ONE 6(6):e20920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gnosa S, Shen YM, Wang CJ, Zhang H, Stratmann J, Arbman G 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  PubMed Central  Google Scholar 

  29. Emdad L, Das SK, Dasgupta S, Hu B, Sarkar D, Fisher PB (2013) AEG-1/MTDH/LYRIC: signaling pathways, downstream genes, interacting proteins, and regulation of tumor angiogenesis. Adv Cancer Res 120:75–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang Z, Cao CJ, Huang LL, Ke ZF, Luo CJ, Lin ZW et al (2015) EFEMP1 promotes the migration and invasion of osteosarcoma via MMP-2 with induction by AEG-1 via NF-kappaB signaling pathway. Oncotarget 6(16):14191–14208

    Article  PubMed  PubMed Central  Google Scholar 

  31. Yu HG, Yu LL, Yang Y, Luo HS, Yu JP, Meier JJ et al (2003) Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology 65(1):37–45

    Article  CAS  PubMed  Google Scholar 

  32. Wang Y, Jin X, Song H, Meng F (2016) AEG-1 as a predictor of sensitivity to neoadjuvant chemotherapy in advanced epithelial ovarian cancer. Onco Targets Ther 9:2385–2392

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Al-sheikh NM, El-Hefnway SM, Abuamer AM, Dala AG (2018) Metadherin mRNA expression in hepatocellular carcinoma. Egypt J Med Hum Genet 19:391–397

    Article  Google Scholar 

  34. Wang G, Yang J, Cao S, Li J, Liu B (2016) AEG-1 acts as a novel bio-marker in the diagnosis of patients with hepatocellular carcinoma. Int J Clin Exp Pathol 9(2):1940–1946

    CAS  Google Scholar 

  35. Lee SG, Su ZZ, Emdad L, Sarkar D, Fisher PB (2006) Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci USA 103(46):17390–17395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu H, Song X, Liu C, Xie L, Wei L, Sun R (2009) Knockdown of astrocyte elevated gene-1 inhibits proliferation and enhancing chemo-sensitivity to cisplatin or doxorubicin in neuroblastoma cells. J Exp Clin Cancer Res 28:19

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y et al (2007) Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene 26(55):7647–7655

    Article  CAS  PubMed  Google Scholar 

  38. Jian-bo X, Hui W, Yu-long H, Chang-hua Z, Long-juan Z, Shi-rong C et al (2011) Astrocyte-elevated gene-1 overexpression is associated with poor prognosis in gastric cancer. Med Oncol 28(2):455–462

    Article  PubMed  CAS  Google Scholar 

  39. Sun W, Fan YZ, Xi H, Lu XS, Ye C, Zhang JT (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 

  40. Chen W, Ke Z, Shi H, Yang S, Wang L (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 

  41. Li J, Zhang N, Song LB, Liao WT, Jiang LL, Gong LY 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 

  42. Song H, Li C, Li R, Geng J (2010) Prognostic significance of AEG-1 expression in colorectal carcinoma. Int J Colorectal Dis 25(10):1201–1209

    Article  PubMed  Google Scholar 

  43. 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 

  44. Zhu K, Dai Z, Pan Q, Wang Z, Yang GH, Yu L 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 

Download references

Acknowledgements

we would like to express our special appreciation for all patients participating in this study.

Funding

No funding was received.

Author information

Authors and Affiliations

Authors

Contributions

MTAG researched literature and conceived the study. FG, SA, RAE, and AE were involved in patient recruitment. MTAG and NAS performed laboratory and molecular investigations. DE and MAE have performed the histopathological examination. KHS, AAA, and MMA were responsible for data analysis. MTAG wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript

Corresponding author

Correspondence to Muhammad Tarek Abdel Ghafar.

Ethics declarations

Conflict of interest

The authors report no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abdel Ghafar, M.T., Gharib, F., Abdel-Salam, S. et al. Role of serum Metadherin mRNA expression in the diagnosis and prediction of survival in patients with colorectal cancer. Mol Biol Rep 47, 2509–2519 (2020). https://doi.org/10.1007/s11033-020-05334-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-05334-5

Keywords

Navigation