Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

Differential expression of anterior gradient gene AGR2 in prostate cancer

Authors: Erin L Maresh, Vei Mah, Mohammad Alavi, Steve Horvath, Lora Bagryanova, Emily S Liebeskind, Laura A Knutzen, Yong Zhou, David Chia, Alvin Y Liu, Lee Goodglick

Published in: BMC Cancer | Issue 1/2010

Login to get access

Abstract

Background

The protein AGR2 is a putative member of the protein disulfide isomerase family and was first identified as a homolog of the Xenopus laevis gene XAG-2. AGR2 has been implicated in a number of human cancers. In particular, AGR2 has previously been found to be one of several genes that encode secreted proteins showing increased expression in prostate cancer cells compared to normal prostatic epithelium.

Methods

Gene expression levels of AGR2 were examined in prostate cancer cells by microarray analysis. We further examined the relationship of AGR2 protein expression to histopathology and prostate cancer outcome on a population basis using tissue microarray technology.

Results

At the RNA and protein level, there was an increase in AGR2 expression in adenocarcinoma of the prostate compared to morphologically normal prostatic glandular epithelium. Using a tissue microarray, this enhanced AGR2 expression was seen as early as premalignant PIN lesions. Interestingly, within adenocarcinoma samples, there was a slight trend toward lower levels of AGR2 with increasing Gleason score. Consistent with this, relatively lower levels of AGR2 were highly predictive of disease recurrence in patients who had originally presented with high-stage primary prostate cancer (P = 0.009).

Conclusions

We have shown for the first time that despite an increase in AGR2 expression in prostate cancer compared to non-malignant cells, relatively lower levels of AGR2 are highly predictive of disease recurrence following radical prostatectomy.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA: a cancer journal for clinicians. 2010, 60 (5): 277-300. 10.3322/caac.20073.
2.
Pascal LE, Deutsch EW, Campbell DS, Korb M, True LD, Liu AY: The urologic epithelial stem cell database (UESC) - a web tool for cell type-specific gene expression and immunohistochemistry images of the prostate and bladder. BMC urology. 2007, 7: 19-10.1186/1471-2490-7-19.CrossRefPubMedPubMedCentral
3.
Nielsen H, Engelbrecht J, Brunak S, von Heijne G: A neural network method for identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Int J Neural Syst. 1997, 8 (5-6): 581-599. 10.1142/S0129065797000537.CrossRefPubMed
4.
Krogh A, Larsson B, von Heijne G, Sonnhammer EL: Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J Mol Biol. 2001, 305 (3): 567-580. 10.1006/jmbi.2000.4315.CrossRefPubMed
5.
Pascal LE, Vencio RZ, Page LS, Liebeskind ES, Shadle CP, Troisch P, Marzolf B, True LD, Hood LE, Liu AY: Gene expression relationship between prostate cancer cells of Gleason 3, 4 and normal epithelial cells as revealed by cell type-specific transcriptomes. BMC Cancer. 2009, 9: 452-10.1186/1471-2407-9-452.CrossRefPubMedPubMedCentral
6.
Thompson DA, Weigel RJ: hAG-2, the human homologue of the Xenopus laevis cement gland gene XAG-2, is coexpressed with estrogen receptor in breast cancer cell lines. Biochemical and biophysical research communications. 1998, 251 (1): 111-116. 10.1006/bbrc.1998.9440.CrossRefPubMed
7.
Persson S, Rosenquist M, Knoblach B, Khosravi-Far R, Sommarin M, Michalak M: Diversity of the protein disulfide isomerase family: identification of breast tumor induced Hag2 and Hag3 as novel members of the protein family. Molecular phylogenetics and evolution. 2005, 36 (3): 734-740. 10.1016/j.ympev.2005.04.002.CrossRefPubMed
8.
Zweitzig DR, Smirnov DA, Connelly MC, Terstappen LW, O'Hara SM, Moran E: Physiological stress induces the metastasis marker AGR2 in breast cancer cells. Molecular and cellular biochemistry. 2007, 306 (1-2): 255-260. 10.1007/s11010-007-9562-y.CrossRefPubMed
9.
Pohler E, Craig AL, Cotton J, Lawrie L, Dillon JF, Ross P, Kernohan N, Hupp TR: The Barrett's antigen anterior gradient-2 silences the p53 transcriptional response to DNA damage. Mol Cell Proteomics. 2004, 3 (6): 534-547. 10.1074/mcp.M300089-MCP200.CrossRefPubMed
10.
Ferraro A, Altieri F, Coppari S, Eufemi M, Chichiarelli S, Turano C: Binding of the protein disulfide isomerase isoform ERp60 to the nuclear matrix-associated regions of DNA. Journal of cellular biochemistry. 1999, 72 (4): 528-539. 10.1002/(SICI)1097-4644(19990315)72:4<528::AID-JCB8>3.0.CO;2-V.CrossRefPubMed
11.
Turano C, Coppari S, Altieri F, Ferraro A: Proteins of the PDI family: unpredicted non-ER locations and functions. Journal of cellular physiology. 2002, 193 (2): 154-163. 10.1002/jcp.10172.CrossRefPubMed
12.
Mandel R, Ryser HJ, Ghani F, Wu M, Peak D: Inhibition of a reductive function of the plasma membrane by bacitracin and antibodies against protein disulfide-isomerase. Proceedings of the National Academy of Sciences of the United States of America. 1993, 90 (9): 4112-4116. 10.1073/pnas.90.9.4112.CrossRefPubMedPubMedCentral
13.
Fritzsche FR, Dahl E, Pahl S, Burkhardt M, Luo J, Mayordomo E, Gansukh T, Dankof A, Knuechel R, Denkert C, et al: Prognostic relevance of AGR2 expression in breast cancer. Clin Cancer Res. 2006, 12 (6): 1728-1734. 10.1158/1078-0432.CCR-05-2057.CrossRefPubMed
14.
Innes HE, Liu D, Barraclough R, Davies MP, O'Neill PA, Platt-Higgins A, de Silva Rudland S, Sibson DR, Rudland PS: Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients. British journal of cancer. 2006, 94 (7): 1057-1065. 10.1038/sj.bjc.6603065.CrossRefPubMedPubMedCentral
15.
Liu D, Rudland PS, Sibson DR, Platt-Higgins A, Barraclough R: Human homologue of cement gland protein, a novel metastasis inducer associated with breast carcinomas. Cancer research. 2005, 65 (9): 3796-3805. 10.1158/0008-5472.CAN-04-3823.CrossRefPubMed
16.
Shen D, Chang HR, Chen Z, He J, Lonsberry V, Elshimali Y, Chia D, Seligson D, Goodglick L, Nelson SF, et al: Loss of annexin A1 expression in human breast cancer detected by multiple high-throughput analyses. Biochemical and biophysical research communications. 2005, 326 (1): 218-227. 10.1016/j.bbrc.2004.10.214.CrossRefPubMed
17.
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 (3): 249-259. 10.1002/gcc.20188.CrossRef
18.
Zhang Y, Ali TZ, Zhou H, D'Souza DR, Lu Y, Jaffe J, Liu Z, Passaniti A, Hamburger AW: ErbB3 binding protein 1 represses metastasis-promoting gene anterior gradient protein 2 in prostate cancer. Cancer research. 2010, 70 (1): 240-248. 10.1158/0008-5472.CAN-09-2904.CrossRefPubMedPubMedCentral
19.
Zhang Y, Forootan SS, Liu D, Barraclough R, Foster CS, Rudland PS, Ke Y: Increased expression of anterior gradient-2 is significantly associated with poor survival of prostate cancer patients. Prostate cancer and prostatic diseases. 2007, 10 (3): 293-300. 10.1038/sj.pcan.4500960.CrossRefPubMed
20.
Liu AY, Zhang H, Sorensen CM, Diamond DL: Analysis of prostate cancer by proteomics using tissue specimens. The Journal of urology. 2005, 173 (1): 73-78. 10.1097/01.ju.0000146543.33543.a3.CrossRefPubMed
21.
Bu H, Bormann S, Schafer G, Horninger W, Massoner P, Neeb A, Lakshmanan VK, Maddalo D, Nestl A, Sultmann H, 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. 2010
22.
Vivekanandan P, Micchelli ST, Torbenson M: Anterior gradient-2 is overexpressed by fibrolamellar carcinomas. Hum Pathol. 2009, 40 (3): 293-299. 10.1016/j.humpath.2008.08.003.CrossRefPubMed
23.
Riener MO, Pilarsky C, Gerhardt J, Grutzmann R, Fritzsche FR, Bahra M, Weichert W, Kristiansen G: Prognostic significance of AGR2 in pancreatic ductal adenocarcinoma. Histology and histopathology. 2009, 24 (9): 1121-1128.PubMed
24.
Lowe AW, Olsen M, Hao Y, Lee SP, Taek Lee K, Chen X, van de Rijn M, Brown PO: Gene expression patterns in pancreatic tumors, cells and tissues. PLoS One. 2007, 2 (3): e323-10.1371/journal.pone.0000323.CrossRefPubMedPubMedCentral
25.
Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, Walter K, Sato N, Parker A, Ashfaq R, et al: Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am J Pathol. 2003, 162 (4): 1151-1162.CrossRefPubMedPubMedCentral
26.
Lee S, Bang S, Song K, Lee I: Differential expression in normal-adenoma-carcinoma sequence suggests complex molecular carcinogenesis in colon. Oncol Rep. 2006, 16 (4): 747-754.PubMed
27.
Wang Z, Hao Y, Lowe AW: The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer research. 2008, 68 (2): 492-497. 10.1158/0008-5472.CAN-07-2930.CrossRefPubMed
28.
Wu ZS, Wu Q, Ding XD, Wang HQ, Shen YX, Fang SY: [Expression of a novel metastasis-inducing protein human anterior gradient-2 (AGR2) in breast cancer and its clinical and prognostic significance]. Zhonghua bing li xue za zhi Chinese journal of pathology. 2008, 37 (2): 109-113.PubMed
29.
Barraclough DL, Platt-Higgins A, de Silva Rudland S, Barraclough R, Winstanley J, West CR, Rudland PS: The metastasis-associated anterior gradient 2 protein is correlated with poor survival of breast cancer patients. Am J Pathol. 2009, 175 (5): 1848-1857. 10.2353/ajpath.2009.090246.CrossRefPubMedPubMedCentral
30.
Fritzsche FR, Dahl E, Dankof A, Burkhardt M, Pahl S, Petersen I, Dietel M, Kristiansen G: Expression of AGR2 in non small cell lung cancer. Histology and histopathology. 2007, 22 (7): 703-708.PubMed
31.
Yu YP, Landsittel D, Jing L, Nelson J, Ren B, Liu L, McDonald C, Thomas R, Dhir R, Finkelstein S, et al: Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol. 2004, 22 (14): 2790-2799. 10.1200/JCO.2004.05.158.CrossRefPubMed
32.
Lapointe J, Li C, Higgins JP, van de Rijn M, Bair E, Montgomery K, Ferrari M, Egevad L, Rayford W, Bergerheim U, et al: Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proceedings of the National Academy of Sciences of the United States of America. 2004, 101 (3): 811-816. 10.1073/pnas.0304146101.CrossRefPubMedPubMedCentral
33.
Seligson D, Horvath S, Huerta-Yepez S, Hanna S, Garban H, Roberts A, Shi T, Liu X, Chia D, Goodglick L, et al: Expression of transcription factor Yin Yang 1 in prostate cancer. International journal of oncology. 2005, 27 (1): 131-141.PubMed
34.
Seligson DB, Hongo F, Huerta-Yepez S, Mizutani Y, Miki T, Yu H, Horvath S, Chia D, Goodglick L, Bonavida B: Expression of X-linked inhibitor of apoptosis protein is a strong predictor of human prostate cancer recurrence. Clin Cancer Res. 2007, 13 (20): 6056-6063. 10.1158/1078-0432.CCR-07-0960.CrossRefPubMed
35.
Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani SK: Global histone modification patterns predict risk of prostate cancer recurrence. Nature. 2005, 435 (7046): 1262-1266. 10.1038/nature03672.CrossRefPubMed
36.
Yoon NK, Seligson DB, Chia D, Elshimali Y, Sulur G, Li A, Horvath S, Maresh E, Mah V, Bose S, et al: Higher expression levels of 14-3-3sigma in ductal carcinoma in situ of the breast predict poorer outcome. Cancer Biomark. 2009, 5 (4): 215-224.PubMedPubMedCentral
37.
Mah V, Seligson DB, Li A, Marquez DC, Wistuba , Elshimali Y, Fishbein MC, Chia D, Pietras RJ, Goodglick L: Aromatase expression predicts survival in women with early-stage non small cell lung cancer. Cancer research. 2007, 67 (21): 10484-10490. 10.1158/0008-5472.CAN-07-2607.CrossRefPubMedPubMedCentral
38.
Yoon NK, Maresh EL, Elshimali Y, Li A, Horvath S, Seligson DB, Chia D, Goodglick L: Elevated MED28 expression predicts poor outcome in women with breast cancer. BMC Cancer. 2010, 10: 335-10.1186/1471-2407-10-335.CrossRefPubMedPubMedCentral
39.
Tomlins SA, Mehra R, Rhodes DR, Cao X, Wang L, Dhanasekaran SM, Kalyana-Sundaram S, Wei JT, Rubin MA, Pienta KJ, et al: Integrative molecular concept modeling of prostate cancer progression. Nat Genet. 2007, 39 (1): 41-51. 10.1038/ng1935.CrossRefPubMed
40.
True L, Coleman I, Hawley S, Huang CY, Gifford D, Coleman R, Beer TM, Gelmann E, Datta M, Mostaghel E, et al: A molecular correlate to the Gleason grading system for prostate adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America. 2006, 103 (29): 10991-10996. 10.1073/pnas.0603678103.CrossRefPubMedPubMedCentral
41.
Aberger F, Weidinger G, Grunz H, Richter K: Anterior specification of embryonic ectoderm: the role of the Xenopus cement gland-specific gene XAG-2. Mechanisms of development. 1998, 72 (1-2): 115-130. 10.1016/S0925-4773(98)00021-5.CrossRefPubMed
42.
Kumar A, Godwin JW, Gates PB, Garza-Garcia AA, Brockes JP: Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science (New York, NY). 2007, 318 (5851): 772-777.CrossRef
43.
Uhlen M, Bjorling E, Agaton C, Szigyarto CA, Amini B, Andersen E, Andersson AC, Angelidou P, Asplund A, Asplund C, et al: A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics. 2005, 4 (12): 1920-1932. 10.1074/mcp.M500279-MCP200.CrossRefPubMed
44.
Park SW, Zhen G, Verhaeghe C, Nakagami Y, Nguyenvu LT, Barczak AJ, Killeen N, Erle DJ: The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proceedings of the National Academy of Sciences of the United States of America. 2009, 106 (17): 6950-6955. 10.1073/pnas.0808722106.CrossRefPubMedPubMedCentral
45.
Komiya T, Tanigawa Y, Hirohashi S: Cloning of the gene gob-4, which is expressed in intestinal goblet cells in mice. Biochimica et biophysica acta. 1999, 1444 (3): 434-438.CrossRefPubMed
46.
Fletcher GC, Patel S, Tyson K, Adam PJ, Schenker M, Loader JA, Daviet L, Legrain P, Parekh R, Harris AL, et al: hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan. British journal of cancer. 2003, 88 (4): 579-585. 10.1038/sj.bjc.6600740.CrossRefPubMedPubMedCentral
47.
Smirnov DA, Zweitzig DR, Foulk BW, Miller MC, Doyle GV, Pienta KJ, Meropol NJ, Weiner LM, Cohen SJ, Moreno JG, et al: Global gene expression profiling of circulating tumor cells. Cancer research. 2005, 65 (12): 4993-4997. 10.1158/0008-5472.CAN-04-4330.CrossRefPubMed
48.
Kovalev LI, Shishkin SS, Khasigov PZ, Dzeranov NK, Kazachenko AV, Toropygin I, Mamykina SV: [Identification of AGR2 protein, a novel potential cancer marker, using proteomics technologies]. Prikl Biokhim Mikrobiol. 2006, 42 (4): 480-484.PubMed
Metadata
Title
Differential expression of anterior gradient gene AGR2 in prostate cancer
Authors
Erin L Maresh
Vei Mah
Mohammad Alavi
Steve Horvath
Lora Bagryanova
Emily S Liebeskind
Laura A Knutzen
Yong Zhou
David Chia
Alvin Y Liu
Lee Goodglick
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-680

Other articles of this Issue 1/2010

BMC Cancer 1/2010 Go to the issue

Research article

Bone marrow transplantation in AML, and socioeconomic class: a UK population-based cohort study

Research article

Potent inhibition of rhabdoid tumor cells by combination of flavopiridol and 4OH-tamoxifen

Research article

Maternal consumption of canola oil suppressed mammary gland tumorigenesis in C3(1) TAg mice offspring

Correspondence

Eastern asian expert panel opinion: designing clinical trials of molecular targeted therapy for hepatocellular carcinoma

Research article

Relationships between hypoxia markers and the leptin system, estrogen receptors in human primary and metastatic breast cancer: effects of preoperative chemotherapy

Research article

LATS2 is De-methylated and Overexpressed in Nasopharyngeal Carcinoma and Predicts Poor Prognosis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits