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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2019, Vol. 13 Issue (6) : 639-645
Potential functions of esophageal cancer-related gene-4 in the cardiovascular system
Rui Zhou, Yuanshu Liu, Wenjun Huang, Xitong Dang()
The Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China
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Esophageal cancer-related gene-4 (Ecrg4) is cloned from the normal epithelium of the esophagus. It is constitutively expressed in quiescent epithelial cells and downregulated during tumorigenesis, and Ecrg4 expression levels are inversely correlated with the malignant phenotype of tumor cells, validating that Ecrg4 is a real tumor suppressor gene. Unlike other tumor suppressor genes that usually encode membrane or intracellular proteins, Ecrg4 encodes a 148-amino acid pre-pro-peptide that is tethered on the cell surface in epithelial cells, specialized epithelial cells, and human leukocytes, where it can be processed tissue dependently into several small peptides upon cell activation. Ecrg4 is expressed in a wide variety of other cells/tissues, including cardiomyocytes and conduction system of the heart,, the glomus cells of the carotid body, adrenal glands, choroid plexus, and leukocytes among others, where it exerts distinct functions, such as promoting/suppressing inflammation, inducing neuron senescence, stimulating the hypothalamus--pituitary--adrenal axis, maintaining the stemness of stem cells, participating in the rhythm and rate control of the heart, and possibly gauging the responsiveness of the cardiovascular system (CVS) to hypoxia, in addition to tumor suppression. Here, we briefly review the latest discoveries on Ecrg4 and its underlying molecular mechanisms as a tumor suppressor and focus on the emerging roles of Ecrg4 in the CVS.

Keywords tumor suppressor gene      esophageal cancer-related gene-4      cardiovascular disease, hypoxia     
Corresponding Authors: Xitong Dang   
Just Accepted Date: 28 June 2019   Online First Date: 30 August 2019    Issue Date: 16 December 2019
 Cite this article:   
Rui Zhou,Yuanshu Liu,Wenjun Huang, et al. Potential functions of esophageal cancer-related gene-4 in the cardiovascular system[J]. Front. Med., 2019, 13(6): 639-645.
Fig.1  Sentinel model of Ecrg4 in tissue homeostasis. Ecrg4 is covalently attached on the cell surface in quiescent state, and shed and/or proteolytically processed into various small peptides in 24 hours after insult. The loss of Ecrg4 and/or the processed Ecrg4 peptides activate injury responses including cell proliferation and inflammation, which lasts for 2−4 days. With the restoration of the cell surface Ecrg4, the inflammation dies down and wound resolves on 6−7 days post-injury (Dpi).
Cloning/functions/distribution References
Cloning of Ecrg4 Su, T., et al. Chin J Oncol. (Zhonghua Zhong Liu Za Zhi)1998; 20 (4): ?254–257 [3].
In organs/tissues other than CVS
As a tumor suppressor Yue, C. M., et al. World J Gastroenterol. 2003; 9(6): 1174–1178 [45].
Chondrocyte development/differentiation Huh, Y. H., et al. Gene. 2009; 448 (1): 7–15 [37].
Hypothalamus corticotrophin-releasing factor Tadross, J. A., et al. Br J Pharmacol. 2010;159 (8): 1663–1671 [30].
Alzheimer’s disease related Woo, J. M., et al. Int J Mol Med. 2010; 25(5): 667–675 [34].
Neurosenescence factor Kujuro, Y., et al. Proc Natl Acad Sci. 2010;107(18): 8259–8264 [29].
Brain homeostasis factor in wound healing Gonzalez, A. M., et al. Fluids Barriers CNS 2011; 8(1): 6 [27].
Epithelium Ecrg4 is surface tethered/secreted Dang, X., et al. Cell Tissue Res. 2012; 348 (3): 505–514 [10].
Apoptosis inhibitor Matsuzaki, J., et al. Carcinogenesis 2012; 33(5): 996–1003 [31].
Inhibition of neuronal stem cell proliferation Nakatani, Y., et al. Development 2019; 146 (4): dev168120 [38].
Ecrg4 in the carotid body (gene microarray) Balbir, A., et al. Am J Physiol Lung Cell Mol Physiol. 2007; 292 (3): ?L704–L715 [15].
Ecrg4 expression in the A-V node (in situ) Mirabeau, O., et al. Genome Res. 2007; 17(3): 320–327 [32].
Ecrg4 expression in cardiomyocytes of rat (IHC) Porzionato, A., et al. Eur J Histochem. 2015; 18; 59 (2): 2458 [7].
Distribution of Ecrg4 in rat heart (IHC and qPCR), in specimens ?of atria in patients with AFib. (IHC), and in canine model of ?AFib. (qPCR). Involved in AFib. Huang, L. et al. Sci Rep. 2017; 7(1): 2717 [5].
Tab.1  Representative articles showing Ecrg4 cloning/distinct functions and distribution
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2 A Baird, J Lee, S Podvin, A Kurabi, X Dang, R Coimbra, T Costantini, V Bansal, BP Eliceiri. Esophageal cancer-related gene 4 at the interface of injury, inflammation, infection, and malignancy. Gastrointest Cancer 2014; 2014(4): 131–142 pmid: 25580077
3 T Su, H Liu, S Lu. 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)
pmid: 10920976
4 R Sabatier, P Finetti, J Adelaide, A Guille, JP Borg, M Chaffanet, L Lane, D Birnbaum, F Bertucci. Down-regulation of Ecrg4, a candidate tumor suppressor gene, in human breast cancer. PLoS One 2011; 6(11): e27656 pmid: 22110708
5 L Huang, H Yu, X Fan, X Li, L Mao, J Cheng, X Zeng, X Dang. A potential role of esophageal cancer related gene-4 for atrial fibrillation. Sci Rep 2017; 7(1): 2717 pmid: 28578429
6 A Baird, R Coimbra, X Dang, N Lopez, J Lee, M Krzyzaniak, R Winfield, B Potenza, BP Eliceiri. 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 pmid: 22396620
7 A Porzionato, M Rucinski, V Macchi, G Sarasin, LK Malendowicz, R De Caro. Ecrg4 expression in normal rat tissues: expression study and literature review. Eur J Histochem 2015; 59(2): 2458 pmid: 26150152
8 S Podvin, AM Gonzalez, MC Miller, X Dang, H Botfield, JE Donahue, A Kurabi, M Boissaud-Cooke, R Rossi, WE Leadbeater, CE Johanson, R Coimbra, EG Stopa, BP Eliceiri, A Baird. 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 pmid: 21935431
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10 X Dang, S Podvin, R Coimbra, B Eliceiri, A Baird. 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 pmid: 22526622
11 A Kurabi, K Pak, X Dang, R Coimbra, BP Eliceiri, AF Ryan, A Baird. Ecrg4 attenuates the inflammatory proliferative response of mucosal epithelial cells to infection. PLoS One 2013; 8(4): e61394 pmid: 23626679
12 A Shaterian, S Kao, L Chen, LA DiPietro, R Coimbra, BP Eliceiri, A Baird. The candidate tumor suppressor gene Ecrg4 as a wound terminating factor in cutaneous injury. Arch Dermatol Res 2013; 305(2): 141–149 pmid: 22899245
13 MF McGrath, AJ de Bold. Transcriptional analysis of the mammalian heart with special reference to its endocrine function. BMC Genomics 2009; 10(1): 254 pmid: 19486520
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15 A Balbir, H Lee, M Okumura, S Biswal, RS Fitzgerald, M Shirahata. A search for genes that may confer divergent morphology and function in the carotid body between two strains of mice. Am J Physiol Lung Cell Mol Physiol 2007; 292(3): L704–L715 pmid: 17098806
16 J Matsuzaki, T Torigoe, Y Hirohashi, Y Tamura, H Asanuma, E Nakazawa, E Saka, K Yasuda, S Takahashi, N Sato. Expression of Ecrg4 is associated with lower proliferative potential of esophageal cancer cells. Pathol Int 2013; 63(8): 391–397 pmid: 23957914
17 J Lee, X Dang, A Borboa, R Coimbra, A Baird, BP Eliceiri. Thrombin-processed Ecrg4 recruits myeloid cells and induces antitumorigenic inflammation. Neuro-oncol 2015; 17(5): 685–696 pmid: 25378632
18 T Xu, D Xiao, X Zhang. 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 pmid: 23833667
19 W Li, X Liu, B Zhang, D Qi, L Zhang, Y Jin, H Yang. Overexpression of candidate tumor suppressor Ecrg4 inhibits glioma proliferation and invasion. J Exp Clin Cancer Res 2010; 29(1): 89 pmid: 20598162
20 LW Li, Y Yang, XY Li, LP Guo, Y Zhou, SX Lu. Tumor-suppressing function of human esophageal cancer related gene 4 in esophageal squamous cell carcinoma. Natl Med J China (Zhonghua Yi Xue Za Zhi) 2010; 90(38): 2713–2717 (in Chinese)
pmid: 21162904
21 LW Li, YY Li, XY Li, CP Zhang, Y Zhou, SH Lu. A novel tumor suppressor gene Ecrg4 interacts directly with TMPRSS11A (ECRG1) to inhibit cancer cell growth in esophageal carcinoma. BMC Cancer 2011; 11(1): 52 pmid: 21288367
22 J Jia, S Dai, X Sun, Y Sang, Z Xu, J Zhang, X Cui, J Song, X Guo. 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 pmid: 26165988
23 L Li, W Wang, X Li, T Gao. Association of Ecrg4 with PLK1, CDK4, PLOD1 and PLOD2 in esophageal squamous cell carcinoma. Am J Transl Res 2017; 9(8): 3741–3748
pmid: 28861165
24 T Moriguchi, S Kaneumi, S Takeda, K Enomoto, SK Mishra, T Miki, U Koshimizu, H Kitamura, T Kondo. Ecrg4 contributes to the anti-glioma immunosurveillance through type-I interferon signaling. OncoImmunology 2016; 5(12): e1242547 pmid: 28123880
25 T Moriguchi, S Takeda, S Iwashita, K Enomoto, T Sawamura, U Koshimizu, T Kondo. Ecrg4 peptide is the ligand of multiple scavenger receptors. Sci Rep 2018; 8(1): 4048 pmid: 29511297
26 CE Bryant, M Symmons, NJ Gay. Toll-like receptor signalling through macromolecular protein complexes. Mol Immunol 2015; 63(2): 162–165 pmid: 25081091
27 AM Gonzalez, S Podvin, SY Lin, MC Miller, H Botfield, WE Leadbeater, A Roberton, X Dang, SE Knowling, E Cardenas-Galindo, JE Donahue, EG Stopa, CE Johanson, R Coimbra, BP Eliceiri, A Baird. 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 pmid: 21349154
28 A Ozawa, AN Lick, I Lindberg. Processing of proaugurin is required to suppress proliferation of tumor cell lines. Mol Endocrinol 2011; 25(5): 776–784 pmid: 21436262
29 Y Kujuro, N Suzuki, T Kondo. 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 pmid: 20404145
30 JA Tadross, M Patterson, K Suzuki, KE Beale, CK Boughton, KL Smith, S Moore, MA Ghatei, SR Bloom. Augurin stimulates the hypothalamo-pituitary-adrenal axis via the release of corticotrophin-releasing factor in rats. Br J Pharmacol 2010; 159(8): 1663–1671 pmid: 20233222
31 J Matsuzaki, T Torigoe, Y Hirohashi, K Kamiguchi, Y Tamura, T Tsukahara, T Kubo, A Takahashi, E Nakazawa, E Saka, K Yasuda, S Takahashi, N Sato. Ecrg4 is a negative regulator of caspase-8-mediated apoptosis in human T-leukemia cells. Carcinogenesis 2012; 33(5): 996–1003 pmid: 22411956
32 O Mirabeau, E Perlas, C Severini, E Audero, O Gascuel, R Possenti, E Birney, N Rosenthal, C Gross. Identification of novel peptide hormones in the human proteome by hidden Markov model screening. Genome Res 2007; 17(3): 320–327 pmid: 17284679
33 S Podvin, MC Miller, R Rossi, J Chukwueke, JE Donahue, CE Johanson, A Baird, EG Stopa. The orphan C2orf40 gene is a neuroimmune factor in Alzheimer’s disease. JSM Alzheimers Dis Relat Dement 2016; 3(1): 1020
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36 TW Costantini, R Coimbra, NE Lopez, JG Lee, B Potenza, A Smith, A Baird, BP Eliceiri. Monitoring neutrophil-expressed cell surface esophageal cancer related gene-4 after severe burn injury. Surg Infect (Larchmt) 2015; 16(6): 669–674 pmid: 26460850
37 YH Huh, JH Ryu, S Shin, DU Lee, S Yang, KS Oh, CH Chun, JK Choi, WK Song, JS Chun. Esophageal cancer related gene 4 (Ecrg4) is a marker of articular chondrocyte differentiation and cartilage destruction. Gene 2009; 448(1): 7–15 pmid: 19735703
38 Y Nakatani, H Kiyonari, T Kondo. Ecrg4 deficiency extends the replicative capacity of neural stem cells in a Foxg1-dependent manner. Development 2019; 146(4): dev168120 pmid: 30745428
39 Y Mori, H Ishiguro, Y Kuwabara, M Kimura, A Mitsui, H Kurehara, R Mori, K Tomoda, R Ogawa, T Katada, K Harata, Y Fujii. Expression of Ecrg4 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma. Oncol Rep 2007; 18(4): 981–985 pmid: 17786363
40 S Götze, V Feldhaus, T Traska, M Wolter, G Reifenberger, A Tannapfel, C Kuhnen, D Martin, O Müller, S Sievers. Ecrg4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma. BMC Cancer 2009; 9(1): 447 pmid: 20017917
41 J Chen, C Liu, L Yin, W Zhang. The tumor-promoting function of Ecrg4 in papillary thyroid carcinoma and its related mechanism. Tumour Biol 2015; 36(2): 1081–1089 pmid: 25326809
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