Clinical implications of AGR2 in primary prostate cancer: Results from a large-scale study.
AGR2
TMA
androgen receptor
immunohistochemistry
prostate cancer
Journal
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica
ISSN: 1600-0463
Titre abrégé: APMIS
Pays: Denmark
ID NLM: 8803400
Informations de publication
Date de publication:
30 Jan 2024
30 Jan 2024
Historique:
received:
26
11
2023
accepted:
15
01
2024
medline:
30
1
2024
pubmed:
30
1
2024
entrez:
30
1
2024
Statut:
aheadofprint
Résumé
Human anterior gradient-2 (AGR2) has been implicated in carcinogenesis of various solid tumours, but the expression data in prostate cancer are contradictory regarding its prognostic value. The objective of this study is to evaluate the expression of AGR2 in a large prostate cancer cohort and to correlate it with clinicopathological data. AGR2 protein expression was analysed immunohistochemically in 1023 well-characterized prostate cancer samples with a validated antibody. AGR2 expression levels in carcinomas were compared with matched tissue samples of adjacent normal glands. AGR2 expression levels were dichotomized and tested for statistical significance. Increased AGR2 expression was found in 93.5% of prostate cancer cases. AGR2 levels were significantly higher in prostate cancer compared with normal prostate tissue. A gradual loss of AGR2 expression was associated with increasing tumour grade (ISUP), and AGR2 expression is inversely related to patient survival, however, multivariable significance is not achieved. AGR2 is clearly upregulated in the majority of prostate cancer cases, yet a true diagnostic value appears unlikely. In spite of the negative correlation of AGR2 expression with increasing tumour grade, no independent prognostic significance was found in this large-scale study.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.
Références
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209-249.
Smith-Palmer J, Takizawa C, Valentine W. Literature review of the burden of prostate cancer in Germany, France, the United Kingdom and Canada. BMC Urol. 2019;19:19.
Cucchiara V, Cooperberg MR, Dall'Era M, Lin DW, Montorsi F, Schalken JA, et al. Genomic markers in prostate cancer decision making. Eur Urol. 2018;73:572-582.
Maresh EL, Mah V, Alavi M, Horvath S, Bagryanova L, Liebeskind ES, et al. Differential expression of anterior gradient gene AGR2 in prostate cancer. BMC Cancer. 2010;10:680.
Zhang JS, Gong A, Cheville JC, Smith DI, Young CY. AGR2, an androgen-inducible secretory protein overexpressed in prostate cancer. Genes Chromosomes Cancer. 2005;43:249-259.
Bu H, Bormann S, Schäfer G, Horninger W, Massoner P, Neeb A, et al. The anterior gradient 2 (AGR2) gene is overexpressed in prostate cancer and may be useful as a urine sediment marker for prostate cancer detection. Prostate. 2011;71:575-587.
Kristiansen G, Pilarsky C, Wissmann C, Kaiser S, Bruemmendorf T, Roepcke S, et al. Expression profiling of microdissected matched prostate cancer samples reveals CD166/MEMD and CD24 as new prognostic markers for patient survival. J Pathol. 2005;205:359-376.
Zhang Y, Forootan SS, Liu D, Barraclough R, Foster CS, Rudland PS, et al. Increased expression of anterior gradient-2 is significantly associated with poor survival of prostate cancer patients. Prostate Cancer Prostatic Dis. 2007;10:293-300.
Zhang Y, Ali TZ, Zhou H, D'Souza DR, Lu Y, Jaffe J, et al. ErbB3 binding protein 1 represses metastasis-promoting gene anterior gradient protein 2 in prostate cancer. Cancer Res. 2010;70:240-248.
Chevet E, Fessart D, Delom F, Mulot A, Vojtesek B, Hrstka R, et al. Emerging roles for the pro-oncogenic anterior gradient-2 in cancer development. Oncogene. 2013;32:2499-2509.
Moidu NA, A Rahman NS, Syafruddin SE, Low TY, Mohtar MA. Secretion of pro-oncogenic AGR2 protein in cancer. Heliyon. 2020;6:e05000.
Wang Z, Hao Y, Lowe AW. The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer Res. 2008;68:492-497.
Higa A, Mulot A, Delom F, Bouchecareilh M, Nguyên DT, Boismenu D, et al. Role of pro-oncogenic protein disulfide isomerase (PDI) family member anterior gradient 2 (AGR2) in the control of endoplasmic reticulum homeostasis. J Biol Chem. 2011;286:44855-44868.
Tian SB, Tao KX, Hu J, Liu ZB, Ding XL, Chu YN, et al. The prognostic value of AGR2 expression in solid tumours: a systematic review and meta-analysis. Sci Rep. 2017;7:15500.
Fritzsche FR, Dahl E, Pahl S, Burkhardt M, Luo J, Mayordomo E, et al. Prognostic relevance of AGR2 expression in breast cancer. Clin Cancer Res. 2006;12:1728-1734.
Riener MO, Pilarsky C, Gerhardt J, Grützmann R, Fritzsche FR, Bahra M, et al. Prognostic significance of AGR2 in pancreatic ductal adenocarcinoma. Histol Histopathol. 2009;24:1121-1128.
Fritzsche FR, Dahl E, Dankof A, Burkhardt M, Pahl S, Petersen I, et al. Expression of AGR2 in non small cell lung cancer. Histol Histopathol. 2007;22:703-708.
Darb-Esfahani S, Fritzsche F, Kristiansen G, Weichert W, Sehouli J, Braicu I, et al. Anterior gradient protein 2 (AGR2) is an independent prognostic factor in ovarian high-grade serous carcinoma. Virchows Arch. 2012;461:109-116.
Ho ME, Quek SI, True LD, Seiler R, Fleischmann A, Bagryanova L, et al. Bladder cancer cells secrete while normal bladder cells express but do not secrete AGR2. Oncotarget. 2016;7:15747-15756.
Innes HE, Liu D, Barraclough R, Davies MP, O'Neill PA, Platt-Higgins A, et al. Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients. Br J Cancer. 2006;94:1057-1065.
Alavi M, Mah V, Maresh EL, Bagryanova L, Horvath S, Chia D, et al. High expression of AGR2 in lung cancer is predictive of poor survival. BMC Cancer. 2015;15:655.
Fessart D, Domblides C, Avril T, Eriksson LA, Begueret H, Pineau R, et al. Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties. Elife. 2016;5:e13887.
Hrstka R, Bouchalova P, Michalova E, Matoulkova E, Muller P, Coates PJ, et al. AGR2 oncoprotein inhibits p38 MAPK and p53 activation through a DUSP10-mediated regulatory pathway. Mol Oncol. 2016;10:652-662.
Lacambra MD, Tsang JY, Ni YB, Chan SK, Tan PH, Tse GM. Anterior gradient 2 is a poor outcome indicator in luminal breast cancer. Ann Surg Oncol. 2015;22:3489-3496.
Salmans ML, Zhao F, Andersen B. The estrogen-regulated anterior gradient 2 (AGR2) protein in breast cancer: a potential drug target and biomarker. Breast Cancer Res. 2013;15:204.
Zhang J, Jin Y, Xu S, Zheng J, Zhang QI, Wang Y, et al. AGR2 is associated with gastric cancer progression and poor survival. Oncol Lett. 2016;11:2075-2083.
Alves MR, E Melo NC, Barros-Filho MC, do Amaral NS, Silva FIB, Baiocchi Neto G, et al. Downregulation of AGR2, p21, and cyclin D and alterations in p53 function were associated with tumor progression and chemotherapy resistance in epithelial ovarian carcinoma. Cancer Med. 2018;7:3188-3199.
Hrstka R, Nenutil R, Fourtouna A, Maslon MM, Naughton C, Langdon S, et al. The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers. Oncogene. 2010;29:4838-4847.
Kani K, Malihi PD, Jiang Y, Wang H, Wang Y, Ruderman DL, et al. Anterior gradient 2 (AGR2): blood-based biomarker elevated in metastatic prostate cancer associated with the neuroendocrine phenotype. Prostate. 2013;73:306-315.
Rodríguez-Blanco G, Zeneyedpour L, Duijvesz D, Hoogland AM, Verhoef EI, Kweldam CF, et al. Tissue proteomics outlines AGR2 AND LOX5 as markers for biochemical recurrence of prostate cancer. Oncotarget. 2018;9:36444-36456.
Wayner EA, Quek SI, Ahmad R, Ho ME, Loprieno MA, Zhou Y, et al. Development of an ELISA to detect the secreted prostate cancer biomarker AGR2 in voided urine. Prostate. 2012;72:1023-1034.
Kristiansen G, Fritzsche FR, Wassermann K, Jäger C, Tölls A, Lein M, et al. GOLPH2 protein expression as a novel tissue biomarker for prostate cancer: implications for tissue-based diagnostics. Br J Cancer. 2008;99:939-948.
Huber F, Montani M, Sulser T, Jaggi R, Wild P, Moch H, et al. Comprehensive validation of published immunohistochemical prognostic biomarkers of prostate cancer -what has gone wrong? A blueprint for the way forward in biomarker studies. Br J Cancer. 2015;112:140-148.
Stein J, Majores M, Rohde M, Lim S, Schneider S, Krappe E, et al. KDM5C is overexpressed in prostate cancer and is a prognostic marker for prostate-specific antigen-relapse following radical prostatectomy. Am J Pathol. 2014;184:2430-2437.
Goldman MJ, Craft B, Hastie M, Repečka K, McDade F, Kamath A, et al. Visualizing and interpreting cancer genomics data via the Xena platform.[letter]. Nat Biotechnol. 2020;38(6):675-678.
Aberger F, Weidinger G, Grunz H, Richter K. Anterior specification of embryonic ectoderm: the role of the xenopus cement gland-specific gene XAG-2. Mech Dev. 1998;72:115-130.
Komiya T, Tanigawa Y, Hirohashi S. Cloning of the gene gob-4, which is expressed in intestinal goblet cells in mice. Biochim Biophys Acta. 1999;1444:434-438.
Petek E, Windpassinger C, Egger H, Kroisel PM, Wagner K. Localization of the human anterior gradient-2 gene (AGR2) to chromosome band 7p21.3 by radiation hybrid mapping and fluorescencein situ hybridisation. Cytogenet Cell Genet. 2000;89:141-142.
Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419.
Delom F, Mohtar MA, Hupp T, Fessart D. The anterior gradient-2 interactome. Am J Physiol Cell Physiol. 2020;318:C40-C47.
Al-Shaibi AA, Abdel-Motal UM, Hubrack SZ, Bullock AN, Al-Marri AA, Agrebi N, et al. Human AGR2 deficiency causes mucus barrier dysfunction and infantile inflammatory bowel disease. Cell Mol Gastroenterol Hepatol. 2021;12:1809-1830.
Maurel M, Obacz J, Avril T, Ding YP, Papadodima O, Treton X, et al. Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation. EMBO Mol Med. 2019;11:e10120.
Viladomiu M, Khounlotham M, Dogan B, Lima SF, Elsaadi A, Cardakli E, et al. Agr2-associated ER stress promotes adherent-invasive E. Coli dysbiosis and triggers CD103+ dendritic cell IL-23-dependent ileocolitis. Cell Rep. 2022;41:111637.
Maarouf A, Boissard A, Henry C, Leman G, Coqueret O, Guette C, et al. Anterior gradient protein 2 is a marker of tumor aggressiveness in breast cancer and favors chemotherapy-induced senescence escape. Int J Oncol. 2022;60:5.
Vivekanandan P, Micchelli ST, Torbenson M. Anterior gradient-2 is overexpressed by fibrolamellar carcinomas. Hum Pathol. 2009;40:293-299.
Yosudjai J, Inpad C, Chomwong S, Dana P, Sawanyawisuth K, Phimsen S, et al. An aberrantly spliced isoform of anterior gradient-2, AGR2vH promotes migration and invasion of cholangiocarcinoma cell. Biomed Pharmacother. 2018;107:109-116.
Neeb A, Hefele S, Bormann S, Parson W, Adams F, Wolf P, et al. Splice variant transcripts of the anterior gradient 2 gene as a marker of prostate cancer. Oncotarget. 2014;5:8681-8689.
Suwanmanee G, Yosudjai J, Phimsen S, Wongkham S, Jirawatnotai S, Kaewkong W. Upregulation of AGR2vH facilitates cholangiocarcinoma cell survival under endoplasmic reticulum stress via the activation of the unfolded protein response pathway. Int J Mol Med. 2020;45:669-677.
Yosudjai J, Inpad C, Pothipan P, Saisomboon S, Surangkul D, Phimsen S, et al. Overexpression of AGR2vH, an oncogenic AGR2 spliced transcript, potentiates tumorigenicity and proteomic alterations in cholangiocarcinoma cell. Biosci Biotechnol Biochem. 2021;85:2263-2273.