ECRG4: a new potential target in precision medicine

Abstract

Given the rapid development in precision medicine, tremendous efforts have been devoted to discovering new biomarkers for disease diagnosis and treatment. Esophageal cancer-related gene-4 (ECRG4), which is initially known as a new candidate tumor suppressor gene, is emerging as a sentinel molecule for gauging tissue homeostasis. ECRG4 is unique in its cytokine-like functional pattern and epigenetically-regulated gene expression pattern. The gene can be released from the cell membrane upon activation and detected in liquid biopsy, thus offering considerable potential in precision medicine. This review provides an updated summary on the biology of ECRG4, with emphasis on its important roles in cancer diagnosis and therapy. The future perspectives of ECRG4 as a potential molecular marker in precision medicine are also discussed in detail.

Keywords

ECRG4 / tumor suppressor gene / sentinel molecule / precision medicine / cell senescence / epithelium homeostasis

References

[1] Ghasemi M, Nabipour I, Omrani A, Alipour Z, Assadi M. Precision medicine and molecular imaging: new targeted approaches toward cancer therapeutic and diagnosis. Am J Nucl Med Mol Imaging 2016; 6(6): 310–327

[2] Su T, Liu H, Lu S, Zhou CX, Jin SQ. Cloning and identification of cDNA fragments related to human esophageal cancer. Chin J Oncol (Zhonghua Zhong Liu Za Zhi) 1998; 20(4): 254–257 (in Chinese)

[3] Mirabeau O, Perlas E, Severini C, Audero E, Gascuel O, Possenti R, Birney E, Rosenthal N, Gross C. Identification of novel peptide hormones in the human proteome by hidden Markov model screening. Genome Res 2007; 17(3): 320–327

[4] Jiang CP, Wu BH, Wang BQ, Fu MY, Yang M, Zhou Y, Liu F. Overexpression of ECRG4 enhances chemosensitivity to 5-fluorouracil in the human gastric cancer SGC-7901 cell line. Tumour Biol 2013; 34(4): 2269–2273

[5] 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(3): 505–514

[6] Gonzalez AMPS, Podvin S, Lin SY, Miller MC, Botfield H, Leadbeater WE, Roberton A, Dang X, Knowling SE, Cardenas-Galindo E, Donahue JE, Stopa EG, Johanson CE, Coimbra R, Eliceiri BP, Baird A. Ecrg4 expression and its product augurin in the choroid plexus: impact on fetal brain development, cerebrospinal fluid homeostasis and neuroprogenitor cell response to CNS injury. Fluids Barriers CNS 2011; 8(1): 6

[7] Costanza B, Umelo I, Bellier J, Castronovo V, Turtoi A. Stromal modulators of TGF-β in cancer. J Clin Med 2017; 6(1): 7

[8] Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 2016; 12(1): 49–62

[9] Huang L, Yu H, Fan X, Li X, Mao L, Cheng J, Zeng X, Dang X. A potential role of esophageal cancer related gene-4 for atrial fibrillation. Sci Rep 2017; 7(1): 2717–2729

[10] Carrasco-Garcia E, Moreno M, Moreno-Cugnon L, Matheu A. Increased Arf/p53 activity in stem cells, aging and cancer. Aging Cell 2017; 16(2): 219–225

[11] Dyson NJ. RB1: a prototype tumor suppressor and an enigma. Genes Dev 2016; 30(13): 1492–1502

[12] Kao S, Shaterian A, Cauvi DM, Dang X, Chun HB, De Maio A, Costantini TW, Coimbra R, Eliceiri BP, Baird A. Pulmonary preconditioning, injury, and inflammation modulate expression of the candidate tumor suppressor gene ECRG4 in lung. Exp Lung Res 2015; 41(3): 162–172

[13] Baird A, Coimbra R, Dang X, Lopez N, Lee J, Krzyzaniak M, Winfield R, Potenza B, Eliceiri BP. Cell surface localization and release of the candidate tumor suppressor Ecrg4 from polymorphonuclear cells and monocytes activate macrophages. J Leukoc Biol 2012; 91(5): 773–781

[14] Moriguchi T, Takeda S, Iwashita S, Enomoto K, Sawamura T, Koshimizu U, Kondo T. Ecrg4 peptide is the ligand of multiple scavenger receptors. Sci Rep 2018; 8(1):4048

[15] 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(7): 1505–1513

[16] Matsuzaki J, Torigoe T, Hirohashi Y, Tamura Y, Asanuma H, Nakazawa E, Saka E, Yasuda K, Takahashi S, Sato N. Expression of ECRG4 is associated with lower proliferative potential of esophageal cancer cells. Pathol Int 2013; 63(8): 391–397

[17] Porzionato A, Rucinski M, Macchi V, Sarasin G, Malendowicz LK, De Caro R. ECRG4 expression in normal rat tissues: expression study and literature review. Eur J Histochem 2015; 59(2): 2458

[18] Kujuro Y, Suzuki N, Kondo T. Esophageal cancer-related gene 4 is a secreted inducer of cell senescence expressed by aged CNS precursor cells. Proc Natl Acad Sci USA 2010; 107(18): 8259–8264

[19] Podvin S, Gonzalez AM, Miller MC, Dang X, Botfield H, Donahue JE, Kurabi A, Boissaud-Cooke M, Rossi R, Leadbeater WE, Johanson CE, Coimbra R, Stopa EG, Eliceiri BP, Baird A. Esophageal cancer related gene-4 is a choroid plexus-derived injury response gene: evidence for a biphasic response in early and late brain injury. PLoS One 2011; 6(9): e24609

[20] Kurabi A, Pak K, Dang X, Coimbra R, Eliceiri BP, Ryan AF, Baird A. Ecrg4 attenuates the inflammatory proliferative response of mucosal epithelial cells to infection. PLoS One 2013; 8(4): e61394

[21] Shaterian A, Kao S, Chen L, DiPietro LA, Coimbra R, Eliceiri BP, Baird A. The candidate tumor suppressor gene Ecrg4 as a wound terminating factor in cutaneous injury. Arch Dermatol Res 2013; 305(2): 141–149

[22] Costantini TWCR, Coimbra R, Lopez NE, Lee JG, Potenza B, Smith A, Baird A, Eliceiri BP. Monitoring neutrophil-expressed cell surface esophageal cancer related gene-4 after severe burn injury. Surg Infect (Larchmt) 2015; 16(6): 669–674

[23] Podvin S, Dang X, Meads M, Kurabi A, Costantini T, Eliceiri BP, Baird A, Coimbra R. Esophageal cancer-related gene-4 (ECRG4) interactions with the innate immunity receptor complex. Inflamm Res 2015; 64(2): 107–118

[24] Bi MX, Han WD, Lu SX. Using lab on-line to clone and identify the esophageal cancer related gene 4. Acta Bioch Bioph Sin (Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai)) 2001; 33(3): 257–261 (in Chinese)

[25] Götze S, Feldhaus V, Traska T, Wolter M, Reifenberger G, Tannapfel A, Kuhnen C, Martin D, Müller O, Sievers S. ECRG4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma. BMC Cancer 2009; 9: 447

[26] Cai Z, Liang P, Xuan J, Wan J, Guo H. ECRG4 as a novel tumor suppressor gene inhibits colorectal cancer cell growth in vitro and in vivo. Tumour Biol 2016; 37(7): 9111–9120

[27] Xu T, Xiao D, Zhang X. ECRG4 inhibits growth and invasiveness of squamous cell carcinoma of the head and neck in vitro and in vivo. Oncol Lett 2013; 5(6): 1921–1926

[28] Jia J, Dai S, Sun X, Sang Y, Xu Z, Zhang J, Cui X, Song J, Guo X. A preliminary study of the effect of ECRG4 overexpression on the proliferation and apoptosis of human laryngeal cancer cells and the underlying mechanisms. Mol Med Rep 2015; 12(4): 5058–5064

[29] Lu J, Wen M, Huang Y, He X, Wang Y, Wu Q, Li Z, Castellanos-Martin A, Abad M, Cruz-Hernandez JJ, Rodriguez CA, Pérez-Losada J, Mao JH, Wei G. C2ORF40 suppresses breast cancer cell proliferation and invasion through modulating expression of M phase cell cycle genes. Epigenetics 2013; 8(6): 571–583

[30] Li W, Liu X, Zhang B, Qi D, Zhang L, Jin Y, Yang H. Overexpression of candidate tumor suppressor ECRG4 inhibits glioma proliferation and invasion. J Exp Clin Cancer Res 2010; 29(1): 89

[31] Lee J, Dang X, Borboa A, Coimbra R, Baird A, Eliceiri BP. Thrombin-processed Ecrg4 recruits myeloid cells and induces antitumorigenic inflammation. Neuro-oncol 2015; 17(5): 685–696

[32] Moriguchi T, Kaneumi S, Takeda S, Enomoto K, Mishra SK, Miki T, Koshimizu U, Kitamura H, Kondo T. Ecrg4 contributes to the anti-glioma immunosurveillance through type-I interferon signaling. OncoImmunology 2016; 5(12): e1242547

[33] Wen Y, Hu X. Expression of esophageal carcinoma related gene 4 (ECRG4) and its clinical significance in prognosis of esophageal carcinoma. Int J Clin Exp Pathol 2015; 8(11): 14772–14778

[34] Sabatier R, Finetti P, Adelaide J, Guille A, Borg JP, Chaffanet M, Lane L, Birnbaum D, Bertucci F. Down-regulation of ECRG4, a candidate tumor suppressor gene, in human breast cancer. PLoS One 2011; 6(11): e27656

[35] You Y, Li H, Qin X, Ran Y, Wang F. Down-regulated ECRG4 expression in breast cancer and its correlation with tumor progression and poor prognosis—a short report. Cell Oncol (Dordr) 2016; 39(1): 89–95

[36] Vanaja DKEM, Ehrich M, Van den Boom D, Cheville JC, Karnes RJ, Tindall DJ, Cantor CR, Young CY. Hypermethylation of genes for diagnosis and risk stratification of prostate cancer. Cancer Invest 2009; 27(5): 549–560

[37] Wang YBBC, Ba CF. Promoter methylation of esophageal cancer-related gene 4 in gastric cancer tissue and its clinical significance. Hepatogastroenterology 2012; 59(118): 1696–1698

[38] Chen JY, Wu X, Hong CQ, Chen J, Wei XL, Zhou L, Zhang HX, Huang YT, Peng L. Downregulated ECRG4 is correlated with lymph node metastasis and predicts poor outcome for nasopharyngeal carcinoma patients. Clin Transl Oncol 2017; 19(1): 84–90

[39] Luo L, Wu J, Xie J, Xia L, Qian X, Cai Z, Li Z. Downregulated ECRG4 is associated with poor prognosis in renal cell cancer and is regulated by promoter DNA methylation. Tumour Biol 2016; 37(1): 1121–1129

[40] You Y, Yang W, Qin X, Wang F, Li H, Lin C, Li W, Gu C, Zhang Y, Ran Y. ECRG4 acts as a tumor suppressor and as a determinant of chemotherapy resistance in human nasopharyngeal carcinoma. Cell Oncol (Dordr) 2015; 38(3): 205–214

[41] Warton K, Mahon KL, Samimi G. Methylated circulating tumor DNA in blood: power in cancer prognosis and response. Endocr Relat Cancer 2016; 23(3): R157–R171

[42] Giannopoulou L, Chebouti I, Pavlakis K, Kasimir-Bauer S, Lianidou ES. RASSF1A promoter methylation in high-grade serous ovarian cancer: A direct comparison study in primary tumors, adjacent morphologically tumor cell-free tissues and paired circulating tumor DNA. Oncotarget 2017; 8(13): 21429–21443

[43] Linnekamp JF, Butter R, Spijker R, Medema JP, van Laarhoven HW. Clinical and biological effects of demethylating agents on solid tumours— a systematic review. Cancer Treat Rev 2017; 54: 10–23

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature