CoChat
Sign Up
Cited by 15Cardiac electrophysiology and arrhythmiasAtrial Fibrillation Management and OutcomesCardiac Arrhythmias and Treatments

A Potential Role of Esophageal Cancer Related Gene-4 for Atrial Fibrillation

Open access
Huang, Li, Yu, Hua, Fan, Xinrong, Li, Xue, Mao, Liang, Cheng, Jun, Zeng, Xiaorong, Dang, Xitong·2017·Scientific Reports
DOI 10.1038/s41598-017-02902-xPMC PMC5457405
Open this paper in CoChat — free accountOpen PDF

Abstract

Epidemiological studies have shown a strong correlation between tumor and AF. However, the molecular link between tumor and AF remains unknown. ECRG4, a tumor suppressor gene that is expressed in the A-V node and in sporadic ventricular myocytes, inhibits tumorigenesis and monitors tissue homeostasis by functioning as a 'sentinel' molecule gauging inflammatory and cell proliferative responses. To explore the potential physiological function of Ecrg4 in heart, we evaluated its distribution in heart, analyzed its expression in patients with persistent AF and in a canine AF model, and dissected the molecular events downstream of Ecrg4. The results showed that the level of Ecrg4 expression is homogenously high in atria and the conduction systems and in sporadic ventricular myocytes. Importantly, the expression of Ecrg4 was significantly decreased in atrial appendages of AF patients than patients with SR. Moreover, in rapid pacing canine AF models, the expression of ECRG4 in atria was significantly decreased compared to that of the controls. Mechanistically, knockdown ECRG4 in atrial myocytes significantly shortened the APDs, inhibited the expression of Gja1, and activated pro-inflammatory cascades and genes involved in cardiac remodeling. These results suggest that Ecrg4 may play a critical role in the pathogenesis of AF.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-017-02902-x

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • ECRG4 is expressed in a wide variety of tissues, including the heart and its conduction system, where its level has been inversely associated with inflammation, atrial fibrillation, and cardiac remodeling.

    “It is expressed in a wide variety of tissues, including the heart and its conduction system, where its level has been inversely associated with inflammation, atrial fibrillation, and cardiac remodeling.59,60”

    From Aortic valve-specific genes dysregulated in calcific aortic valve stenosis as potential biomarkers and therapeutic targets (2025) · cites this paper as [60]

    The Discussion reports ECRG4 expression in several tissues and in the heart’s conduction system, and lower atrial expression in patients with persistent atrial fibrillation. In the Results section on ECRG4 knockdown, reducing ECRG4 in neonatal atrial myocytes increased inflammatory and remodeling-related gene expression. The paper does not establish an inverse association between ECRG4 levels and inflammation or cardiac remodeling themselves; it presents the remodeling link as a possibility. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 44

  1. [1]Sankaranarayanan R Kirkwood G Dibb K Garratt CJ Comparison of Atrial Fibrillation in the Young versus That in the Elderly: A Review Cardiology research and practice 2013 2013 976976 16 10.1155/2013/976976 23401843 PMC3564268 · DOI
  2. [2]Lazzerini PE Capecchi PL Galeazzi M Laghi-Pasini F Biologic drugs and arrhythmic risk in chronic inflammatory arthritis: the good and the bad Immunologic research 2016 27423435
  3. [3]Lappegard KT Hovland A Pop GA Mollnes TE Atrial fibrillation: inflammation in disguise? Scandinavian journal of immunology 2013 78 112 119 10.1111/sji.12061 23672430 · DOI
  4. [4]Harada M Van Wagoner DR Nattel S Role of inflammation in atrial fibrillation pathophysiology and management Circulation journal: official journal of the Japanese Circulation Society 2015 79 495 502 10.1253/circj.CJ-15-0138 25746525 PMC4457364 · DOI
  5. [5]Tamariz L Hernandez F Bush A Palacio A Hare JM Association between serum uric acid and atrial fibrillation: a systematic review and meta-analysis Heart rhythm: the official journal of the Heart Rhythm Society 2014 11 1102 1108 10.1016/j.hrthm.2014.04.003 24709288 · DOI
  6. [6]Jiang Z Dai L Song Z Li H Shu M Association between C-reactive protein and atrial fibrillation recurrence after catheter ablation: a meta-analysis Clinical cardiology 2013 36 548 554 10.1002/clc.22157 23754787 PMC6649439 · DOI
  7. [7]Liu T Li G Li L Korantzopoulos P Association between C-reactive protein and recurrence of atrial fibrillation after successful electrical cardioversion: a meta-analysis Journal of the American College of Cardiology 2007 49 1642 1648 10.1016/j.jacc.2006.12.042 17433956 · DOI
  8. [8]Frustaci A Histological substrate of atrial biopsies in patients with lone atrial fibrillation Circulation 1997 96 1180 1184 10.1161/01.CIR.96.4.1180 9286947 · DOI
  9. [9]Guo Y Lip GY Apostolakis S Inflammation in atrial fibrillation Journal of the American College of Cardiology 2012 60 2263 2270 10.1016/j.jacc.2012.04.063 23194937 · DOI
  10. [10]Gedikli O Inflammatory markers according to types of atrial fibrillation International journal of cardiology 2007 120 193 197 10.1016/j.ijcard.2006.09.015 17240468 · DOI
  11. [11]Boos CJ Anderson RA Lip GY Is atrial fibrillation an inflammatory disorder? European heart journal 2006 27 136 149 10.1093/eurheartj/ehi645 16278230 · DOI
  12. [13]Levine MJ Schweitzer P Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers in atrial fibrillation Vnitrni lekarstvi 2010 56 1138 1141 21247007
  13. [14]Koyama T Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial Journal of the American College of Cardiology 2010 56 1463 1472 10.1016/j.jacc.2010.04.057 20951321 · DOI
  14. [15]Deftereos S Colchicine for prevention of early atrial fibrillation recurrence after pulmonary vein isolation: a randomized controlled study Journal of the American College of Cardiology 2012 60 1790 1796 10.1016/j.jacc.2012.07.031 23040570 · DOI
  15. [16]Mesubi OO Anderson ME Atrial remodelling in atrial fibrillation: CaMKII as a nodal proarrhythmic signal Cardiovascular research 2016 109 542 557 10.1093/cvr/cvw002 26762270 PMC4777912 · DOI
  16. [17]Hu YF Chen YJ Lin YJ Chen SA Inflammation and the pathogenesis of atrial fibrillation Nature reviews. Cardiology 2015 12 230 243 10.1038/nrcardio.2015.2 25622848 · DOI
  17. [18]Schotten U Verheule S Kirchhof P Goette A Pathophysiological mechanisms of atrial fibrillation: a translational appraisal Physiological reviews 2011 91 265 325 10.1152/physrev.00031.2009 21248168 · DOI · Paper page
  18. [19]Farmakis D Parissis J Filippatos G Insights into onco-cardiology: atrial fibrillation in cancer Journal of the American College of Cardiology 2014 63 945 953 10.1016/j.jacc.2013.11.026 24361314 · DOI
  19. [20]Erichsen R Colorectal cancer and risk of atrial fibrillation and flutter: a population-based case-control study Internal and emergency medicine 2012 7 431 438 10.1007/s11739-011-0701-9 21968511 · DOI
  20. [21]Ostenfeld EB Atrial fibrillation as a marker of occult cancer PloS one 2014 9 e102861 10.1371/journal.pone.0102861 25119880 PMC4138009 · DOI
  21. [22]Guzzetti S Costantino G Vernocchi A Sada S Fundaro C First diagnosis of colorectal or breast cancer and prevalence of atrial fibrillation Internal and emergency medicine 2008 3 227 231 10.1007/s11739-008-0124-4 18320149 · DOI
  22. [23]Su T Liu H Lu S Cloning and identification of cDNA fragments related to human esophageal cancer Zhonghua zhong liu za zhi [Chinese journal of oncology] 1998 20 254 257 10920976
  23. [24]Li LW 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 International journal of cancer 2009 125 1505 1513 10.1002/ijc.24513 19521989 · DOI
  24. [25]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 and tissue research 2012 348 505 514 10.1007/s00441-012-1396-6 22526622 PMC3367106 · DOI
  25. [26]Kurabi A Ecrg4 attenuates the inflammatory proliferative response of mucosal epithelial cells to infection PloS one 2013 8 e61394 10.1371/journal.pone.0061394 23626679 PMC3634077 · DOI
  26. [27]Matsuzaki J ECRG4 is a negative regulator of caspase-8-mediated apoptosis in human T-leukemia cells Carcinogenesis 2012 33 996 1003 10.1093/carcin/bgs118 22411956 · DOI
  27. [28]Baird A Cell surface localization and release of the candidate tumor suppressor Ecrg4 from polymorphonuclear cells and monocytes activate macrophages Journal of leukocyte biology 2012 91 773 781 10.1189/jlb.1011503 22396620 PMC3336773 · DOI
  28. [29]Podvin S 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 e24609 10.1371/journal.pone.0024609 21935431 PMC3173480 · DOI
  29. [30]Porzionato A ECRG4 expression in normal rat tissues: expression study and literature review European journal of histochemistry: EJH 2015 59 2458 10.4081/ejh.2015.2458 26150152 PMC4503965 · DOI
  30. [31]Mirabeau O Identification of novel peptide hormones in the human proteome by hidden Markov model screening Genome research 2007 17 320 327 10.1101/gr.5755407 17284679 PMC1800923 · DOI
  31. [32]Miyata A Zipes DP Hall S Rubart M Kb-R7943 prevents acute, atrial fibrillation-induced shortening of atrial refractoriness in anesthetized dogs Circulation 2002 106 1410 1419 10.1161/01.CIR.0000028587.85711.F6 12221061 · DOI
  32. [33]Gonzalez AM 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 and barriers of the CNS 2011 8 6 10.1186/2045-8118-8-6 21349154 PMC3042980 · DOI
  33. [34]Baird A Esophageal cancer-related gene 4 at the interface of injury, inflammation, infection, and malignancy Gastrointestinal cancer: targets and therapy 2014 2014 131 142 10.2147/GICTT.S49085 25580077 PMC4287990 · DOI
  34. [35]Kim NH Altered patterns of gene expression in response to chronic atrial fibrillation International heart journal 2005 46 383 395 10.1536/ihj.46.383 16043935 · DOI
  35. [38]Yamada K Miura Y Scheidl T Yoshida MC Tamaoki T Assignment of the human ATBF1 transcription factor gene to chromosome 16q22.3-q23.1 Genomics 1995 29 552 553 10.1006/geno.1995.9967 8666409 · DOI
  36. [39]Huang, Z. et al. Signal Transducer and Activator of Transcription 3/MicroRNA-21 Feedback Loop Contributes to Atrial Fibrillation by Promoting Atrial Fibrosis in a Rat Sterile Pericarditis Model. Circulation. Arrhythmia and electrophysiology9, doi:10.1161/CIRCEP.115.003396 (2016). PMC4956678 27406600 · DOI
  37. [40]Jiang Q Down-regulation of ATBF1 activates STAT3 signaling via PIAS3 in pacing-induced HL-1 atrial myocytes Biochemical and biophysical research communications 2014 449 278 283 10.1016/j.bbrc.2014.05.041 24857987 · DOI
  38. [41]Nojiri S ATBF1 enhances the suppression of STAT3 signaling by interaction with PIAS3 Biochemical and biophysical research communications 2004 314 97 103 10.1016/j.bbrc.2003.12.054 14715251 · DOI
  39. [42]Mabuchi M Tumor suppressor, AT motif binding factor 1 (ATBF1), translocates to the nucleus with runt domain transcription factor 3 (RUNX3) in response to TGF-beta signal transduction Biochemical and biophysical research communications 2010 398 321 325 10.1016/j.bbrc.2010.06.090 20599712 · DOI
  40. [43]Kraus C S100A1 in cardiovascular health and disease: closing the gap between basic science and clinical therapy Journal of molecular and cellular cardiology 2009 47 445 455 10.1016/j.yjmcc.2009.06.003 19538970 PMC2739260 · DOI
  41. [44]Yang Z Shen W Rottman JN Wikswo JP Murray KT Rapid stimulation causes electrical remodeling in cultured atrial myocytes Journal of molecular and cellular cardiology 2005 38 299 308 10.1016/j.yjmcc.2004.11.015 15698836 · DOI
  42. [45]Iwasaki YK Nishida K Kato T Nattel S Atrial fibrillation pathophysiology: implications for management Circulation 2011 124 2264 2274 10.1161/CIRCULATIONAHA.111.019893 22083148 · DOI
  43. [46]Kao YH ZFHX3 knockdown increases arrhythmogenesis and dysregulates calcium homeostasis in HL-1 atrial myocytes International journal of cardiology 2016 210 85 92 10.1016/j.ijcard.2016.02.091 26930642 · DOI
  44. [47]Colman MA Pro-arrhythmogenic effects of atrial fibrillation-induced electrical remodelling: insights from the three-dimensional virtual human atria The Journal of physiology 2013 591 4249 4272 10.1113/jphysiol.2013.254987 23732649 PMC3779115 · DOI

Cited by

Sorted by citations

Authors
Huang, L., Yu, H., Fan, X., Li, X., Mao, L., Cheng, J., Zeng, X., & Dang, X.
Affiliations
Southwest Medical University (CN)
Corresponding author
Dang, Xitong
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-06-02
Volume
7
Issue
1
Pages
2717-2717
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-02902-x
PMC
PMC5457405
OpenAlex
W2620061694
Cited by
15
References
3
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 1
FWCI
1.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81570277, 30870903)
  • Southwest Medical University
  • University of California, San Diego
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Arrhythmias and Treatments
Keywords
ECRG4, atrial fibrillation, tumor suppressor, atrial appendage, atrial myocytes, action potential duration, connexin 43, cardiac remodeling, inflammation, rapid pacing
MeSH terms
Action Potentials, Adult, Animals, Atrial Fibrillation, Dogs, Electrocardiography, Gene Expression Regulation, Heart Atria, Humans, Immunohistochemistry, Middle Aged, Neoplasm Proteins, Gene Expression, Genetic Predisposition to Disease, Atrial Appendage, Tumor Suppressor Proteins, Myocytes, Cardiac, Rats, Gene Knockdown Techniques, Atrial Remodeling

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review