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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    https://doi.org/10.1007/s11684-019-0701-0
REVIEW
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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Abstract

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.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0701-0
http://academic.hep.com.cn/fmd/EN/Y2019/V13/I6/639
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].
In CVS
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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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
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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
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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
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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
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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
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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
https://doi.org/10.1080/2162402X.2016.1242547 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
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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
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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
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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
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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
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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
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[1] Xin Qin, Ping Zhang. ECRG4: a new potential target in precision medicine[J]. Front. Med., 2019, 13(5): 540-546.
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