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Tumor Biology

, Volume 37, Issue 1, pp 1121–1129 | Cite as

Downregulated ECRG4 is associated with poor prognosis in renal cell cancer and is regulated by promoter DNA methylation

  • Liya Luo
  • Jianting Wu
  • Jun Xie
  • Lingling Xia
  • Xuemin Qian
  • Zhiming Cai
  • Zesong Li
Original Article

Abstract

Esophageal cancer-related gene 4 (ECRG4) has been proposed as a putative tumor suppressor gene in several tumors. However, the role and regulation of ECRG4 in the pathogenesis of human renal cancer remain largely unknown. Our current study revealed that expression of ECRG4 is downregulated in renal cell lines and renal cancer tissues. ECRG4 expression was significantly associated with histological grade of tumors (p < 0.001), primary tumor stage (p = 0.017), and distant metastasis (p = 0.017). Low expression of ECRG4 was an independent prognostic indicator for survival of renal cancer patients. Silencing of ECRG4 expression in renal cell lines was associated with its promoter methylation. Moreover, ectopic expression of ECRG4 markedly inhibited cell proliferation and invasion in renal cancer cell lines. These results indicated that ECRG4 is frequently silenced by the methylation of promoter in renal cell cancers. ECRG4 may be a tumor suppressor in renal cancer and serve as a prognostic marker.

Keywords

Renal cancer Prognosis ECRG4 Immunohistochemistry DNA methylation 

Notes

Acknowledgments

This work was supported by grants from the Young Scientists Fund of the National Natural Science Foundation of China (Grant No. 81201579), the National Key Scientific Program of China (Grant No. 2014CBA02005), and the National Natural Science Foundation of China (Grant No. 81272840, 81472584), Shenzhen Project of Science and Technology (Grant No. 20140416180149160, 201206133000192).

Conflicts of interest

None

Supplementary material

13277_2015_3913_MOESM1_ESM.doc (32 kb)
Supplementary Fig. 1 C2orf40 expression in Bittner renal cancer

References

  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Su T, Liu H, Lu S. Cloning and identification of cdna fragments related to human esophageal cancer. Zhonghua Zhong Liu Za Zhi. 1998;20:254–7.PubMedGoogle Scholar
  3. 3.
    Matsuzaki J, Torigoe T, Hirohashi Y, Kamiguchi K, Tamura Y, Tsukahara T, et al. Ecrg4 is a negative regulator of caspase-8-mediated apoptosis in human t-leukemia cells. Carcinogenesis. 2012;33:996–1003.CrossRefPubMedGoogle Scholar
  4. 4.
    Dang X, Podvin S, Coimbra R, Eliceiri B, Baird A. Cell-specific processing and release of the hormone-like precursor and candidate tumor suppressor gene product, ECRG4. Cell Tissue Res. 2012;348:505–14.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Yue CM, Deng DJ, Bi MX, Guo LP, Lu SH. Expression of ECRG4, a novel esophageal cancer-related gene, downregulated by CpG island hypermethylation in human esophageal squamous cell carcinoma. World J Gastroenterol. 2003;9:1174–8.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mori Y, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Kurehara H, et al. Expression of ECRG4 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma. Oncol Rep. 2007;18:981–5.PubMedGoogle Scholar
  7. 7.
    Li LW, Yu XY, Yang Y, Zhang CP, Guo LP, Lu SH. Expression of esophageal cancer related gene 4 (ECRG4), a novel tumor suppressor gene, in esophageal cancer and its inhibitory effect on the tumor growth in vitro and in vivo. Int J Cancer. 2009;125:1505–13.CrossRefPubMedGoogle Scholar
  8. 8.
    Li LW, Li YY, Li XY, Zhang CP, Zhou Y, Lu SH. A novel tumor suppressor gene ECRG4 interacts directly with TMPRSS11A (ECRG1) to inhibit cancer cell growth in esophageal carcinoma. BMC Cancer. 2011;11:52.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Matsuzaki J, Torigoe T, Hirohashi Y, Tamura Y, Asanuma H, Nakazawa E, et al. Expression of ECRG4 is associated with lower proliferative potential of esophageal cancer cells. Pathol Int. 2013;63:391–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Lee J, Dang X, Borboa A, Coimbra R, Baird A, Eliceiri BP. Thrombin-processed ECRG4 recruits myeloid cells and induces antitumorigenic inflammation. Neuro-Oncology. 2015;17:685–96.CrossRefPubMedGoogle Scholar
  11. 11.
    Vanaja DK, Ehrich M, Van den Boom D, Cheville JC, Karnes RJ, Tindall DJ, et al. Hypermethylation of genes for diagnosis and risk stratification of prostate cancer. Cancer Investig. 2009;27:549–60.CrossRefGoogle Scholar
  12. 12.
    Xu T, Xiao D, Zhang X. Ecrg4 inhibits growth and invasiveness of squamous cell carcinoma of the head and neck and. Oncol Lett. 2013;5:1921–6.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Gotze S, Feldhaus V, Traska T, Wolter M, Reifenberger G, Tannapfel A, et al. ECRG4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma. BMC Cancer. 2009;9:447.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Li W, Liu X, Zhang B, Qi D, Zhang L, Jin Y, et al. Overexpression of candidate tumor suppressor ECRG4 inhibits glioma proliferation and invasion. J Exp Clin Cancer Res. 2010;29:89.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wang YB, Ba CF. Promoter methylation of esophageal cancer-related gene 4 in gastric cancer tissue and its clinical significance. Hepato-Gastroenterology. 2012;59:1696–8.PubMedGoogle Scholar
  16. 16.
    You Y, Yang W, Qin X, Wang F, Li H, Lin C, et al. ECRG4 acts as a tumor suppressor and as a determinant of chemotherapy resistance in human nasopharyngeal carcinoma. Cell Oncol. 2015;38:205–14.CrossRefGoogle Scholar
  17. 17.
    Sabatier R, Finetti P, Adelaide J, Guille A, Borg JP, Chaffanet M, et al. Down-regulation of ECRG4, a candidate tumor suppressor gene, in human breast cancer. PLoS One. 2011;6:e27656.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Jiang CP, Wu BH, Wang BQ, Fu MY, Yang M, Zhou Y, et al. Overexpression of ECRG4 enhances chemosensitivity to 5-fluorouracil in the human gastric cancer sgc-7901 cell line. Tumour Biol. 2013;34:2269–73.CrossRefPubMedGoogle Scholar
  19. 19.
    Chen J, Liu C, Yin L, Zhang W. The tumor-promoting function of ECRG4 in papillary thyroid carcinoma and its related mechanism. Tumour Biol. 2015;36:1081–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Guo G, Gui Y, Gao S, Tang A, Hu X, Huang Y, et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet. 2011;44:17–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative pcr and the 2(−delta delta c(t)) method. Methods. 2001;25:402–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Li Z, Xie J, Wu J, Li W, Nie L, Sun X, et al. CMTM3 inhibits human testicular cancer cell growth through inducing cell-cycle arrest and apoptosis. PLoS One. 2014;9:e88965.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Li Z, Li W, Xie J, Wang Y, Tang A, Li X, et al. Epigenetic inactivation of pcdh10 in human prostate cancer cell lines. Cell Biol Int. 2011;35:671–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002;18:1427–31.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhou L, Chen J, Li Z, Li X, Hu X, Huang Y, et al. Integrated profiling of microRNAs and mRNAs: microRNAs located on Xq27.3 associate with clear cell renal cell carcinoma. PLoS One. 2010;5:e15224.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Yusenko MV, Kuiper RP, Boethe T, Ljungberg B, van Kessel AG, Kovacs G. High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas. BMC Cancer. 2009;9:152.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lenburg ME, Liou LS, Gerry NP, Frampton GM, Cohen HT, Christman MF. Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data. BMC Cancer. 2003;3:31.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007;9:166–80.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Liya Luo
    • 1
    • 2
  • Jianting Wu
    • 1
  • Jun Xie
    • 3
  • Lingling Xia
    • 1
    • 2
  • Xuemin Qian
    • 1
  • Zhiming Cai
    • 1
  • Zesong Li
    • 1
  1. 1.Shenzhen Key Laboratory of Genitourinary TumorShenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen UniversityShenzhenChina
  2. 2.Guangzhou Medical UniversityGuangzhouChina
  3. 3.Peking University Shenzhen HospitalShenzhenChina

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