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Prognostic Role of Aryl Hydrocarbon Receptor Interacting Protein (AIP) Immunohistochemical Expression in Patients with Resected Gastric Carcinomas

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Pathology & Oncology Research

Abstract

Aryl hydrocarbon receptor (AHR) interacting protein (AIP) is a chaperone which binds to inactive AHR in the cell cytoplasm. AHR is best known for mediating the toxicity of halogenated aromatics, but it has also been linked to carcinogenesis and tumor progression in several tumor types. Our aims are to assess the features of AIP immunohistochemical (IHC) staining and to evaluate its possible role as a prognostic marker in gastric cancer (GC). Retrospective study of 147 cases of resected GC. Clinicopathological features were collected, tissue microarrays were constructed for AIP IHC and statistical analysis were performed. AIP staining was observed in 50.3% of tumors. All AIP-positive cases exhibited cytoplasmic or membranous staining, variably associated with nuclear co-staining. 93.2% of AIP-positive tumors showed AIP immunoreactivity in 100% of cells. Staining intensity was mild, moderate and intense in 33.8%, 13.5% and 52.7% of cases. Tumors were stratified according to AIP staining intensity into low expression (no or mild AIP immunoreactivity) and high expression (moderate or intense AIP immunoreactivity). 36.6% of our cases showed high AIP expression. High AIP expression was significantly and independently correlated to tumor progression and cancer death. Tumors with high AIP expression showed lower survival and higher progression rates. AIP expression might be useful for determining GC prognosis. More studies are needed to clarify the role of AHR pathway in GC, AIP expression and its potential use as a surrogate marker for selecting patients for AHR modulation therapy.

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References

  1. Camargo MC, Figueiredo C, Machado JC (2019) Review: gastric malignancies: basic aspects. Helicobacter 24:e12642

    Article  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Article  Google Scholar 

  3. Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F (2014) Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomark Prev 23:700–713

    Article  Google Scholar 

  4. Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, MAciejewski R, Polkowski WP (2018) Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res 10:239

    Article  CAS  Google Scholar 

  5. Wittekind C (2015) The development of the TNM classification of gastric cancer. Pathol

  6. Li Y, Wang D, Zhao B, Wang W, Yuan S, Huang C et al (2012) Poor prognosis of gastric adenocarcinoma with decreased expression of AHRR. PLoS One 7:e43555

    Article  CAS  Google Scholar 

  7. Apicella M, Corso S, Giordano S (2017) Targeted therapies for gastric cancer: failures and hopes from clinical trials. Oncotarget 8:57654–57669

    Article  Google Scholar 

  8. Salati M, Orsi G, Smyth E, Beretta G, De Vita F, Di Bartolomeo M et al (2019) Gastric cancer: translating novels concepts into clinical practice. Cancer Treat Rev 79:101889

    Article  CAS  Google Scholar 

  9. Boyiadzis MM, Kirkwood JM, Marshall JL, Pritchard CC, Azad NS, Gulley JL (2018) Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J Immunother Cancer 6:35

    Article  Google Scholar 

  10. Yelamanchi SD, Solanki HS, Radhakrishnan A, Balakrishnan L, Advani J, Raja R et al (2016) Signaling network map of the aryl hydrocarbon receptor. J Cell Commun Signal 10:341

    Article  Google Scholar 

  11. Murray IA, Patterson AD, Perdew GH (2014) Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 14:801–814 h

    Article  CAS  Google Scholar 

  12. Safe S, Lee S-O, Jin U-H (2013) Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. Toxicol Sci 135:1–16

    Article  CAS  Google Scholar 

  13. Poland A, Glover E (1973) Studies on the mechanism of toxicity of the chlorinated dibenzo-p-dioxins. Environ Health Perspect 5:245–251

    Article  CAS  Google Scholar 

  14. Coumoul X, Fernandez-Salguero PM (2007) The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett 581:3608–3615

    Article  Google Scholar 

  15. Feng S, Cao Z, Wang X (2013) Role of aryl hydrocarbon receptor in cancer. Biochim Biophys Acta - Rev Cancer 1836:197–210

    Article  CAS  Google Scholar 

  16. Kolluri SK, Jin U-H, Safe S (2017) Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. Arch Toxicol 91:2497–2513

    Article  CAS  Google Scholar 

  17. Peng T-L, Chen J, Mao W, Liu X, Tao Y, Chen L-Z et al (2009) Potential therapeutic significance of increased expression of aryl hydrocarbon receptor in human gastric cancer. World J Gastroenterol 15:1719

    Article  CAS  Google Scholar 

  18. Zhu R, Gao C, Wang L, Zhang G, Zhang W, Zhang Z et al (2018) Involvement of aryl hydrocarbon receptor and aryl hydrocarbon receptor repressor in Helicobacter Pylori -related gastric pathogenesis. J Cancer 9:2757–2764

    Article  Google Scholar 

  19. Andersson P, McGuire J, Rubio C, Gradin K, Whitelaw ML, Pettersson S et al (2002) A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc Natl Acad Sci 99:9990–9995. https://doi.org/10.1073/pnas.152706299

    Article  CAS  PubMed  Google Scholar 

  20. Peng T-L, Chen J, Mao W, Song X, Chen M-H (2009) Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9. BMC Cell Biol 10:27

    Article  Google Scholar 

  21. Gasiewicz TA, Henry EC, Collins LL (2008) Expression and activity of aryl hydrocarbon receptors in development and Cancer. Crit Rev Eukaryot Gene Expr 18:279–321

    Article  CAS  Google Scholar 

  22. Richter CA, Tillitt DE, Hannink M (2001) Regulation of subcellular localization of the aryl hydrocarbon receptor (AhR). Arch Biochem Biophys 389:207–217

    Article  CAS  Google Scholar 

  23. Novikov O, Wang Z, Stanford EA, Parks AJ, Ramirez-Cardenas A, Landesman E et al (2016) An aryl hydrocarbon receptor-mediated amplification loop that enforces cell migration in ER − /PR − /Her2 − human breast cancer cells. Mol Pharmacol 90:674–688

    Article  CAS  Google Scholar 

  24. Ma J-X, Zhang K-L, Liu X, Ma Y-L, Pei L-N, Zhu Y-F et al (2006) Concurrent expression of aryl hydrocarbon receptor and CYP1A1 but not CYP1A1 MspI polymorphism is correlated with gastric cancers raised in Dalian, China. Cancer Lett 240:253–260

    Article  CAS  Google Scholar 

  25. Yin X-F, Chen J, Mao W, Wang Y-H, Chen M-H (2013) Downregulation of aryl hydrocarbon receptor expression decreases gastric cancer cell growth and invasion. Oncol Rep 30:364–370

    Article  CAS  Google Scholar 

  26. Wei Y, Zhao L, He W et al (2016) Benzo[a]pyrene promotes gastric cancer cell proliferation and metastasis likely through the aryl hydrocarbon receptor and ERK-dependent induction of MMP9 and c-myc. Int J Oncol 49:2055–2063

    Article  CAS  Google Scholar 

  27. Yin X-F, Chen J, Mao W, Wang Y-H, Chen M-H (2012) A selective aryl hydrocarbon receptor modulator 3,3′-Diindolylmethane inhibits gastric cancer cell growth. J Exp Clin Cancer Res 31:46

    Article  CAS  Google Scholar 

  28. Lai D-W, Liu S-H, Karlsson AI, Lee W-J, Wang K-B, Chen Y-C et al (2014) The novel aryl hydrocarbon receptor inhibitor biseugenol inhibits gastric tumor growth and peritoneal dissemination. Oncotarget 5. https://doi.org/10.18632/oncotarget.2307

  29. Tsay JJ, Tchou-Wong K-M, Greenberg AK, Pass H, Rom WN (2013) Aryl hydrocarbon receptor and lung Cancer. Anticancer Res 33:1247–1256

    PubMed  PubMed Central  Google Scholar 

  30. Jaffrain-Rea M-L, Angelini M, Gargano D, Tichomirowa MA, Daly AF, Vanbellinghen J-F et al (2009) Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications. Endocr Relat Cancer 16:1029–1043. https://doi.org/10.1677/ERC-09-0094

    Article  CAS  PubMed  Google Scholar 

  31. Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A et al (2015) Tissue-based map of the human proteome. Science 347:1260419–1260419

    Article  Google Scholar 

  32. Narasimhan S, Stanford Zulick E, Novikov O, Parks A, Schlezinger J, Wang Z et al (2018) Towards resolving the pro- and anti-tumor effects of the aryl hydrocarbon receptor. Int J Mol Sci 19:1388

    Article  Google Scholar 

  33. Ye M, Zhang Y, Gao H, Xu Y, Jing P, Wu J et al (2018) Activation of the aryl hydrocarbon receptor leads to resistance to EGFR TKIs in non–small cell lung Cancer by activating Src-mediated bypass signaling. Clin Cancer Res 24:1227–1239

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Complutense University of Madrid, Madrid, Spain

    Cristina Díaz del Arco, Luis Ortega Medina & Mª Jesús Fernández Aceñero

  2. Hospital Clínico San Carlos, Madrid, Spain

    Cristina Díaz del Arco, Luis Ortega Medina & Elena Molina Roldán

  3. Rey Juan Carlos University, Madrid, Spain

    Lourdes Estrada Muñoz & Soledad García Gómez de las Heras

  4. Carlos III Health Institute (ISCIII), Madrid, Spain

    Rodrigo Barderas Manchado & Guillermo Solís Fernández

  5. Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain

    Alberto Peláez García

  6. Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Mª Jesús Fernández Aceñero

Authors
  1. Cristina Díaz del Arco
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  2. Lourdes Estrada Muñoz
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  3. Rodrigo Barderas Manchado
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  4. Alberto Peláez García
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  5. Luis Ortega Medina
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  6. Elena Molina Roldán
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  7. Guillermo Solís Fernández
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  8. Soledad García Gómez de las Heras
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  9. Mª Jesús Fernández Aceñero
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Contributions

Díaz del Arco C. data acquisition, analysis, interpretation, manuscript draft, approval and agreement.

Estrada Muñoz L. data acquisition, analysis, interpretation, manuscript revision, approval and agreement.

Barderas Manchado R. data acquisition, manuscript revision, approval and agreement.

Peláez García A. data acquisition, manuscript revision approval and agreement.

Ortega Medina L. study design, data interpretation, manuscript revision, approval and agreement.

Molina Roldán E. data acquisition, manuscript revision, approval and agreement.

Solís Fernández G. data acquisition, manuscript revision, approval and agreement.

García Gómez de las Heras S. data interpretation, manuscript revision, approval and agreement.

Fernández Aceñero MJ. study design, data analysis and interpretation, manuscript draft, approval and agreement.

Corresponding author

Correspondence to Cristina Díaz del Arco.

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Research Involving Human Participants and/or Animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Retrospective study; for this type of study formal consent is not required.

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Díaz del Arco, C., Estrada Muñoz, L., Barderas Manchado, R. et al. Prognostic Role of Aryl Hydrocarbon Receptor Interacting Protein (AIP) Immunohistochemical Expression in Patients with Resected Gastric Carcinomas. Pathol. Oncol. Res. 26, 2641–2650 (2020). https://doi.org/10.1007/s12253-020-00863-7

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