Women with chronic follicular gastritis positive for Helicobacter pylori express lower levels of GKN1


In women, serum levels of CTSB, GKN2, LIPF, LIPFG, AZGP1, TOP2A and PGA4 are proposed as predictive markers of gastric cancer. It is unknown whether GKN1 expression varies with the sex of patients with chronic gastritis or gastric cancer. We studied 36 patients with histopathological diagnosis of chronic gastritis from the state of Guerrero, Mexico. PCR was performed for H. pylori detection and GKN1 expression was determined by RT-qPCR and western blot. GKN1 mRNA expression was significantly lower in patients with chronic follicular gastritis than in those with chronic chemical gastritis (p = 0.00071). The mRNA and protein level of expression of GKN1 were significantly lower in women with chronic follicular gastritis than in men with the same condition (p = 0.0279 and p = 0.0014, respectively); the lowest levels of GKN1 were detected in women with H. pylori-positive follicular gastritis (p = 0.0175 and p = 0.0111, respectively). Through a bioinformatic analysis, estrogen response elements were identified in the GKN1 promoter.

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  1. 1.

    Zhang Z, Li Z, Li Y, Zang A. MicroRNA and signaling pathways in gastric cancer. Cancer Gene Ther. 2014;21:305–16.

    Article  Google Scholar 

  2. 2.

    Yoon JH, Choi WS, Kim O, Park WS. The role of gastrokine 1 in gastric cancer. J Gastric Cancer. 2014;14:147–55.

    Article  Google Scholar 

  3. 3.

    Nardone G, Rippa E, Martin G, Rocco A, Siciliano RA, Fiengo A, et al. Gastrokine 1 expression in patients with and without Helicobacter pylori infection. Dig Liver Dis. 2007;39:122–9.

    CAS  Article  Google Scholar 

  4. 4.

    Moss SF, Lee JW, Sabo E, Rubin AK, Rommel J, Westley BR, et al. Decreased expression of gastrokine 1 and the trefoil factor interacting protein TFIZ1/GKN2 in gastric cancer: influence of tumor histology and relationship to prognosis. Clin Cancer Res. 2008;14:4161–7.

    CAS  Article  Google Scholar 

  5. 5.

    Guo XY, Dong L, Qin B, Jiang J, Shi AM. Decreased expression of gastrokine 1 in gastric mucosa of gastric cancer patients. World J Gastroenterol. 2014;20:16702–6.

    CAS  Article  Google Scholar 

  6. 6.

    Mao W, Chen J, Peng TL, Ying XF, Chen LZ, Chen MH. Downregulation of gastrokine-1 in gastric cancer tissues and restoration of its expression induced gastric cancer cells to apoptosis. J Exp Clin Cancer Res. 2012;1:49–58.

    Article  Google Scholar 

  7. 7.

    Yoon JH, Park YG, Nam SW, Park WS. The diagnostic value of serum gastrokine 1 (GKN1) protein in gastric cancer. Cancer Med. 2019;8:5507–14.

    CAS  Article  Google Scholar 

  8. 8.

    Mohammadi R, Mohammadi Z, Abedi R, Cireh F, Balali A, Mohamadynejad P, et al. Sexual dimorphism in the expression of GKN2 and FOXA2 genes in the human stomach. Mol Biol Rep. 2019;46:2355–62.

    CAS  Article  Google Scholar 

  9. 9.

    Kim HI, Lim H, Moon A. Sex differences in cancer: epidemiology, genetics and therapy. Biomol Ther. 2018;26:335–42.

    CAS  Article  Google Scholar 

  10. 10.

    Cui J, Chen Y, Chou WC, Sun L, Chen L, Suo J, et al. An integrated transcriptomic and computational analysis for biomarker identification in gastric cancer. Nucleic Acids Res. 2011;39:1197–11207.

    CAS  Article  Google Scholar 

  11. 11.

    Román-Román A, Martínez-Carrillo DN, Atrisco-Morales J, Azúcar-Heziquio JC, Cuevas-Caballero AS, Castañón-Sánchez CA, et al. Helicobacter pylori vacA s1m1 genotype but not cagA or babA2 increase the risk of ulcer and gastric cancer in patients from Southern Mexico. Gut Pathog. 2017;9:18.

    Article  Google Scholar 

  12. 12.

    Dreos R, Ambrosini G, Périer RC, Bucher P. The eukaryotic promoter database: expansion of EPDnew and new promoter analysis tools. Nucleic Acids Res. 2015;43:D92–96.

    CAS  Article  Google Scholar 

  13. 13.

    Nardone G, Martin G, Rocco A, Rippa E, La Monica G, Caruso F, et al. Molecular expression of Gastrokine 1 in normal mucosa and in Helicobacter pylori-related preneoplastic and neoplastic gastric lesions. Cancer Biol Ther. 2008;7:1890–5.

    CAS  Article  Google Scholar 

  14. 14.

    Yoon JH, Song JH, Zhang C, Jin M, Kang YH, Nam SW, et al. Inactivation of the gastrokine 1 gene in gastric adenomas and carcinomas. J Pathol. 2011;223:618–25.

    CAS  Article  Google Scholar 

  15. 15.

    Xiao JW, Chen JH, Ren MY, Tian XB, Wang CS. Relationship between expression of gastrokine 1 and clinicopathological characteristics in gastric cancer patients. Asian Pac J Cancer Prev. 2012;13:5897–901.

    Article  Google Scholar 

  16. 16.

    Guo Y, Zhang T, Shi Y, Zhang J, Li M, Lu F, et al. Helicobacter pylori inhibits GKN1 expression via the CagA/p-ERK/AUF1 pathway. Helicobacter. 2019;25:e12665.

    PubMed  Google Scholar 

  17. 17.

    di Stadio CS, Faraonio R, Federico A, Altieri F, Rippa E, Arcari P. GKN1 expression in gastric cancer cells is negatively regulated by miR-544a. Biochimie. 2019;8:42–8.

    Article  Google Scholar 

  18. 18.

    Yang M, Jiang N, Cao QW, Ma MQ, Sun Q. The E3 ligase UBR5 regulates gastric cancer cell growth by destabilizing the tumor suppressor GKN1. Biochem Biophys Res Commun. 2016;478:1624–9.

    CAS  Article  Google Scholar 

  19. 19.

    Alarcon-Millán J, Martínez-Carrillo DN, Peralta-Zaragoza O, Fernández-Tilapa G. Regulation of GKN1 expression in gastric carcinogensis: a problem to resolve (Review). Int J Oncol. 2019;55:555–69.

    PubMed  Google Scholar 

  20. 20.

    Chandanos E, Lagergren J. Oestrogen and the enigmatic male predominance of gastric cancer. Eur J Cancer. 2008;44:2397–23403.

    CAS  Article  Google Scholar 

  21. 21.

    Nie X, Xie R, Tuo B. Effects of estrogen on the gastrointestinal tract. Dig Dis Sci. 2018;63:583–96.

    CAS  Article  Google Scholar 

  22. 22.

    Kim SM, Min BH, Lee J, An JY, Lee JH, Sohn TS, et al. Protective effects of female reproductive factors on Lauren intestinal type gastric adenocarcinoma. Yonsei Med J. 2018;59:28–34.

    CAS  Article  Google Scholar 

  23. 23.

    Masiakowski P, Breathnach R, Bloch J, Gannon F, Krust A, Chambon P. Cloning of cDNA sequences of hormone-regulated genes from the MCF-7 human breast cancer cell lines. Nucleic Acids Res. 1982;10:7895–903.

    CAS  Article  Google Scholar 

  24. 24.

    Aihara E, Engevik KA, Montrose MH. Trefoil factor peptides and gastrointestinal function. Annu Rev Physiol. 2017;79:357–80.

    CAS  Article  Google Scholar 

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We express our sincere gratitude to all patients for their participation in the study, as well as to the nurses and staff of the Instituto Estatal de Cancerología who supported obtention of the biopsies. We thank. Josefina Atrisco Morales, MSc. and Ilce Valeria Román Fernández, PhD. for the support they provided in conducting this investigation.


The research was carried out with the funding granted by CONACYT to Project no. 258433, in the call for Basic Scientific Research 2015–01 and with the resources granted by the Program for Strengthening Educational Quality (PFCE-SEP-2017 and 2018), of the Ministry of Public Education, to the consolidated academic body Infectious Agents and Cancer (UAGro-CA-194). Judit Alarcón-Millán is a PhD student in biomedical sciences and she is receiving a doctoral fellowship from CONACYT, Mexico (Grant no. 296364). Sandra Ines Lorenzo-Nazario was a fellow of CONACYT while doing her masters in biomedical sciences (Grant no. 777741).

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All authors contributed to the study conception and design. Manuscript writing: JAM, DNMC and GFT. Data collection: JAM, SILN, GECV and EMCM. Data analyses: DNMC, JAM, JOO, MAMC, BIA and HJW. Patient management: SRN, MAJL, and CACS. Final manuscript approval: all authors.

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Correspondence to Dinorah Nashely Martínez-Carrillo.

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This study was approved by the Bioethics Committee of the Universidad Autónoma de Guerrero and by the Research Department of the Instituto Estatal de Cancerología.

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Informed consent was obtained from all the participants.

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Alarcón-Millán, J., Lorenzo-Nazario, S.I., Jiménez-Wences, H. et al. Women with chronic follicular gastritis positive for Helicobacter pylori express lower levels of GKN1. Gastric Cancer 23, 754–759 (2020). https://doi.org/10.1007/s10120-020-01049-5

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  • Gastrokine 1
  • Sex
  • Chronic gastritis
  • Helicobacter pylori