AGR2

Gene Summary

Gene:AGR2; anterior gradient 2
Aliases: AG2, GOB-4, HAG-2, XAG-2, PDIA17, HEL-S-116
Location:7p21.3
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:anterior gradient protein 2 homolog
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
Show (6)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Breast Cancer
  • Neoplasm Metastasis
  • Colorectal Cancer
  • RTPCR
  • Cell Movement
  • Xenopus Proteins
  • Sequence Alignment
  • Gene Expression
  • Lymphatic Metastasis
  • Prostate Cancer
  • Messenger RNA
  • Gene Expression Profiling
  • Neoplasm Proteins
  • Proteins
  • Western Blotting
  • Oligonucleotide Array Sequence Analysis
  • Carcinoma
  • Immunohistochemistry
  • Drug Resistance
  • Transfection
  • Uroplakin II
  • siRNA
  • Base Sequence
  • Pancreatic Cancer
  • Carrier Proteins
  • Adenocarcinoma
  • Cell Proliferation
  • Estrogen Receptors
  • Signal Transduction
  • Staging
  • Cancer Gene Expression Regulation
  • Disease Progression
  • Amino Acid Sequence
  • Chromosome 7
  • Neoplasm Invasiveness
  • Antineoplastic Agents, Hormonal
  • Ductan Pancreatic Carcinoma
  • Molecular Sequence Data
  • Protein Disulfide-Isomerases
  • Multivariate Analysis
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AGR2 (cancer-related)

Souchek JJ, Baine MJ, Lin C, et al.
Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation.
Br J Cancer. 2014; 111(6):1139-49 [PubMed] Related Publications
BACKGROUND: Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance-associated pathways using global, unbiased techniques.
METHODS: Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model.
RESULTS: Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model.
CONCLUSIONS: Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser.

Huang J, Wang L, Jiang M, et al.
AGR2-mediated lung adenocarcinoma metastasis novel mechanism network through repression with interferon coupling cytoskeleton to steroid metabolism-dependent humoral immune response.
Cell Immunol. 2014; 290(1):102-6 [PubMed] Related Publications
7 anterior gradient homolog 2 (AGR2)-inhibited different molecular mutual positive correlation network was constructed in lung adenocarcinoma compared with human normal adjacent tissues by 17 overlapping molecules of 358 GRNInfer and 19 Pearson (AGR2 CC⩽-0.25). Based on GO, KEGG, GenMAPP, BioCarta and disease databases, we determined AGR2-mediated lung adenocarcinoma metastasis through repression with cytoskeleton of MAST1; steroid metabolism of SOAT2; humoral immune response of POU2AF1; interferon alpha-inducible of IFI6; immunoglobulin of IGKC_3, CTA_246H3.1. Thus we proposed AGR2-mediated lung adenocarcinoma metastasis novel mechanism network through repression with interferon coupling cytoskeleton to steroid metabolism-dependent humoral immune response.

Sung HY, Choi EN, Lyu D, et al.
Aberrant hypomethylation-mediated AGR2 overexpression induces an aggressive phenotype in ovarian cancer cells.
Oncol Rep. 2014; 32(2):815-20 [PubMed] Related Publications
The metastatic properties of cancer cells result from genetic and epigenetic alterations that lead to the abnormal expression of key genes regulating tumor phenotypes. Recent discoveries suggest that aberrant DNA methylation provides cancer cells with advanced metastatic properties; however, the precise regulatory mechanisms controlling metastasis-associated genes and their roles in metastatic transformation are largely unknown. We injected SK-OV-3 human ovarian cancer cells into the perineum of nude mice to generate a mouse model that mimics human ovarian cancer metastasis. We analyzed the mRNA expression and DNA methylation profiles in metastasized tumor tissues in the mice. The pro-oncogenic anterior gradient 2 (AGR2) gene showed increased mRNA expression and hypomethylation at CpG sites in its promoter region in the metastatic tumor tissues compared with the cultured SK-OV-3 cells. We identified crucial cytosine residues at CpG sites in the AGR2 promoter region. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine reduced the level of CpG methylation in the AGR2 promoter and increased the level of AGR2 expression. Next, we explored the functional role of AGR2 in the metastatic transformation of SK-OV-3 cells. SK-OV-3 cells overexpressing AGR2 showed increased migratory and invasive activity. Our results indicate that DNA methylation within the AGR2 promoter modulates more aggressive cancer cell phenotypes.

Chanda D, Lee JH, Sawant A, et al.
Anterior gradient protein-2 is a regulator of cellular adhesion in prostate cancer.
PLoS One. 2014; 9(2):e89940 [PubMed] Free Access to Full Article Related Publications
Anterior Gradient Protein (AGR-2) is reported to be over-expressed in many epithelial cancers and promotes metastasis. A clear-cut mechanism for its observed function(s) has not been previously identified. We found significant upregulation of AGR-2 expression in a bone metastatic prostate cancer cell line, PC3, following culturing in bone marrow-conditioned medium. Substantial AGR-2 expression was also confirmed in prostate cancer tissue specimens in patients with bone lesions. By developing stable clones of PC3 cells with varying levels of AGR-2 expression, we identified that abrogation of AGR-2 significantly reduced cellular attachment to fibronectin, collagen I, collagen IV, laminin I and fibrinogen. Loss of cellular adhesion was associated with sharp decrease in the expression of α4, α5, αV, β3 and β4 integrins. Failure to undergo apoptosis following detachment is a hallmark of epithelial cancer metastasis. The AGR-2-silenced PC3 cells showed higher resistance to Tumor necrosis factor-related apoptosis- inducing ligand (TRAIL) induced apoptosis in vitro. This observation was also supported by significantly reduced Caspase-3 expression in AGR-2-silenced PC3 cells, which is a key effector of both extrinsic and intrinsic death signaling pathways. These data suggest that AGR-2 influence prostate cancer metastasis by regulation of cellular adhesion and apoptosis.

Pentheroudakis G, Kotoula V, Fountzilas E, et al.
A study of gene expression markers for predictive significance for bevacizumab benefit in patients with metastatic colon cancer: a translational research study of the Hellenic Cooperative Oncology Group (HeCOG).
BMC Cancer. 2014; 14:111 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking.
METHODS: We profiled expession of 24526 genes by means of whole genome 24 K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab + chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS).
RESULTS: Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1 + TFF2 + MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p = 0.007), but not in the Control set (ORR 36.4%, p = 0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1 + TFF2 + MCM5) profile versus any other ALDH6A1 + TFF2 + MCM5 profile was 15 (p = 0.018) in the Bevacizumab qPCR set but only 0.72 (p = 0.63) in the Control set. The tumor expression profile of (KLF12-high + TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12 + TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p = 0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12 + TFF2 expression profile was 2.92 (p = 0.03) in the Validation and 1.29 (p = 0.39) in the Control set.
CONCLUSIONS: Our «three-stage» hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer.

Shishkin SS, Eremina LS, Kovalev LI, Kovaleva MA
AGR2, ERp57/GRP58, and some other human protein disulfide isomerases.
Biochemistry (Mosc). 2013; 78(13):1415-30 [PubMed] Related Publications
This review considers the major features of human proteins AGR2 and ERp57/GRP58 and of other members of the protein disulfide isomerase (PDI) family. The ability of both AGR2 and ERp57/GRP58 to catalyze the formation of disulfide bonds in proteins is the parameter most important for assigning them to a PDI family. Moreover, these proteins and also other members of the PDI family have specific structural features (thioredoxin-like domains, special C-terminal motifs characteristic for proteins localized in the endoplasmic reticulum, etc.) that are necessary for their assignment to a PDI family. Data demonstrating the role of these two proteins in carcinogenesis are analyzed. Special attention is given to data indicating the presence of biomarker features in AGR2 and ERp57/GRP58. It is now thought that there is sufficient reason for studies of AGR2 and ERp57/GRP58 for possible use of these proteins in diagnosis of tumors. There are also prospects for studies on AGR2 and ERp57/GRP58 leading to developments in chemotherapy. Thus, we suppose that further studies on different members of the PDI family using modern postgenomic technologies will broaden current concepts about functions of these proteins, and this will be helpful for solution of urgent biomedical problems.

Christgen M, Geffers R, Kreipe H, Lehmann U
IPH-926 lobular breast cancer cells are triple-negative but their microarray profile uncovers a luminal subtype.
Cancer Sci. 2013; 104(12):1726-30 [PubMed] Related Publications
Human primary breast cancers and breast cancer cell lines are classified by microarray-defined molecular subtypes, which reflect differentiation characteristics. Estrogen receptor (ER) expression is indicative of the luminal molecular subtype. We have previously established IPH-926, the first well-characterized cell line from infiltrating lobular breast cancer. IPH-926 displays an ER/PR/ErbB2 triple-negative immunophenotype, which is due to a loss of ER expression in its in vivo clonal ancestry. Loss of ER might indicate a fundamental change of cellular differentiation and it is unclear whether a luminal subtype is preserved beyond ER conversion. Using Affymetrix microarray analysis, seven different classifier gene lists (PAM305, DISC256, TN1288, PAM50, UNC1300, LAB704, INT500) and a background population of 50 common mammary carcinoma cell lines, we have now determined the molecular subtype of IPH-926. Strikingly, the IPH-926 expression profile is highly consistent with a luminal subtype. It is nearest to luminal/ER-positive breast cancer cell lines and far apart from basal breast cancer cell lines. Quantitative real-time RT-PCR confirmed enhanced expression of luminal marker genes (AGR2, CLU, CA12, EMP2, CLDN3) and low or absent expression of basal marker genes (KRT5, CD44, CAV1, VIM). Moreover, IPH-926 lacked androgen receptor (AR) expression, a transcription factor previously associated with luminal-like gene expression in a subset of triple-negative or molecular apocrine breast cancers. In conclusion, IPH-926 is triple-negative but belongs to the luminal subtype. Luminal differentiation characteristics can be preserved beyond ER conversion and might not require a compensatory expression of AR.

Hrstka R, Brychtova V, Fabian P, et al.
AGR2 predicts tamoxifen resistance in postmenopausal breast cancer patients.
Dis Markers. 2013; 35(4):207-12 [PubMed] Free Access to Full Article Related Publications
Endocrine resistance is a significant problem in breast cancer treatment. Thus identification and validation of novel resistance determinants is important to improve treatment efficacy and patient outcome. In our work, AGR2 expression was determined by qRT-PCR in Tru-Cut needle biopsies from tamoxifen-treated postmenopausal breast cancer patients. Our results showed inversed association of AGR2 mRNA levels with primary treatment response (P = 0.0011) and progression-free survival (P = 0.0366) in 61 ER-positive breast carcinomas. As shown by our experimental and clinical evaluations, elevated AGR2 expression predicts decreased efficacy of tamoxifen treatment. From this perspective, AGR2 is a potential predictive biomarker enabling selection of an optimal algorithm for adjuvant hormonal therapy in postmenopausal ER-positive breast cancer patients.

Chen YT, Ho CL, Chen PK, et al.
Anterior gradient 2: a novel sensitive tumor marker for metastatic oral cancer.
Cancer Lett. 2013; 339(2):270-8 [PubMed] Related Publications
The prevention of oral squamous cell carcinoma metastasis to improve overall patient survival has provided the rationale for biomarker development. We used the Transwell invasion assay to isolate a highly metastatic subpopulation, HSC-3-5 cells, with almost the same genetic background as HSC-3 cells but a higher metastatic capacity accompanied by cytoskeletal rearrangements and mesenchymal transformation. HSC-3-5 cells also showed tumorigenic and metastatic characteristics in vivo. In addition, Anterior gradient 2 (agr2), a pro-oncogenic signaling intermediate, was identified from gene expression profiling, and overexpression of AGR2 showed a positive correlation with oral tumor metastasis. Taken together, our data suggest that AGR2 may be a novel sensitive biomarker for metastatic oral cancer.

Hong XY, Wang J, Li Z
AGR2 expression is regulated by HIF-1 and contributes to growth and angiogenesis of glioblastoma.
Cell Biochem Biophys. 2013; 67(3):1487-95 [PubMed] Related Publications
Glioblastoma multiforme (GBM) tumors are the most common type of brain tumors characterized by extensive angiogenesis that is mostly orchestrated by tumor hypoxia. The hypoxia induced factor-1 (HIF-1) transcriptional complex is the "master control switch" for hypoxia. Dysregulation of anterior gradient protein 2 (AGR2) expression is associated with tumor growth and metastasis. Whether AGR2 is a hypoxia-responsive factor and affects tumor progression via angiogenesis remains unknown. Here, we show that GBM cell lines, U87 and LN18, exhibited enhanced hypoxic responses compared with control normal human astrocytes, and a corresponding HIF-1-dependent increase in AGR2 mRNA and protein. Recombinant AGR2 and conditioned medium from GBM cells induced human umbilical vein endothelial cell (HUVEC) migration and tube formation, which were abrogated by anti-AGR2 neutralizing antibodies. Expression of the HIF-1α oxygen-dependent degradation domain mutant in cells resulted in elevated AGR2 levels and an increased ability to induce HUVEC migration and tube formation in vitro and enhanced growth and vascularity of tumor xenografts in vivo, which were prevented by AGR2 knockdown. Taken together, these results indicate that AGR2 expression is regulated by HIF-1 and plays an important role in control of glioblastoma growth and vascularity. Our findings suggest that inhibiting AGR2 may represent a new therapeutic target for anti-angiogenic cancer treatment.

Bu H, Schweiger MR, Manke T, et al.
Anterior gradient 2 and 3--two prototype androgen-responsive genes transcriptionally upregulated by androgens and by oestrogens in prostate cancer cells.
FEBS J. 2013; 280(5):1249-66 [PubMed] Related Publications
Androgens and oestrogens have been implicated in prostatic carcinogenesis and tumour progression. Although the actions of androgens have been studied extensively, the mechanisms underlying oestrogen signalling in prostate cancer are not fully understood. In the present study, we analyzed the effect of androgens and oestrogens on the expression of anterior gradient 2 (AGR2) and anterior gradient 3 (AGR3), comprising two highly-related genes encoding secretory proteins that are expressed in prostate cancer and one of which (AGR2) has been associated with tumour metastasis. Quantitative reverse-transcriptase PCR and western blot analysis showed androgen induction of AGR2 and AGR3 in three androgen receptor positive cell lines, starting at concentrations of 0.1 nm. Both AGR genes were also transcriptionally activated by ≥ 5 nM oestradiol but not by isotype selective or nonselective oestrogen receptor agonists in DUCaP cells that harbour a high-level of wild-type androgen receptor. A functional androgen receptor but not oestrogen receptor turned out to be required for both androgen and oestrogen regulation. This pattern of androgen and oestrogen regulation was confirmed in VCaP cells and was also observed for FKBP5, a well-characterized androgen-regulated gene. Genome-wide chromatin-immunoprecipitation studies coupled with deep sequencing identified androgen receptor binding sites localized in the distal promoter and intron regions of the AGR2 and AGR3 genes, respectively. The androgen responsiveness of these enhancers was verified by luciferase reporter gene assays and site-directed mutagenesis analysis. Androgen treatment also induced p300 and RNA Pol II recruitment to androgen receptor enhancers of AGR2 and initiated local chromatin remodelling and the formation of RNA Pol II-containing androgen receptor transcription complexes.

Barry S, Chelala C, Lines K, et al.
S100P is a metastasis-associated gene that facilitates transendothelial migration of pancreatic cancer cells.
Clin Exp Metastasis. 2013; 30(3):251-64 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is the 5th most common cause of cancer death in the UK and the 4th in the US. The vast majority of deaths following pancreatic cancer are due to metastatic spread, hence understanding the metastatic process is vital for identification of critically needed novel therapeutic targets. An enriched set of 33 genes differentially expressed in common between primary PDAC and liver metastases, when compared to normal tissues, was obtained through global gene expression profiling. This metastasis-associated gene set comprises transcripts from both cancer (S100P, S100A6, AGR2, etc.) and adjacent stroma (collagens type I, III, and V, etc.), thus reinforcing the concept of a continuous crosstalk between the two compartments in both primary tumours and their metastases. The expression of S100P, SFN, VCAN and collagens was further validated in additional primary PDACs and matched liver metastatic lesions, while the functional significance of one of the most highly expressed genes, S100P, was studied in more detail. We show that this protein increases the transendothelial migration of PDAC cancer cells in vitro, which was also confirmed in vivo experiments using a zebrafish embryo model. Thus S100P facilitates cancer cell intravasation/extravasation, critical steps in the hematogenous dissemination of pancreatic cancer cells.

McKinney KQ, Lee JG, Sindram D, et al.
Identification of differentially expressed proteins from primary versus metastatic pancreatic cancer cells using subcellular proteomics.
Cancer Genomics Proteomics. 2012 Sep-Oct; 9(5):257-63 [PubMed] Related Publications
Pancreatic cancer is an aggressive disease with nearly equal yearly rates of diagnosis and death. Current therapies have failed to improve outcomes due to rapid disease progression and late stage at presentation. Recently, pathways involved in progression and metastasis have been elucidated; however, new knowledge has not generated more effective therapies. We report on the use of subcellular fractionation and liquid chromatography (LC)-mass spectrometry to identify 3,907 proteins in four pancreatic cancer cell lines, 540 of which are unique to primary cancer cells, and 487 unique to cells derived from metastatic sites. Statistical analysis identified 134 proteins significantly differentially expressed between the two populations. The subcellular localization of these proteins was determined and expression levels for four targets were validated using western blot techniques. These identified proteins can be further investigated to determine their roles in progression and metastasis and may serve as therapeutic targets in the development of more effective treatments for pancreatic cancer.

Chevet E, Fessart D, Delom F, et al.
Emerging roles for the pro-oncogenic anterior gradient-2 in cancer development.
Oncogene. 2013; 32(20):2499-509 [PubMed] Related Publications
Clinical studies have defined the core 'genetic blueprint' of a cancer cell, but this information does not necessarily predict the cancer phenotype. Signalling hubs that mediate such phenotype have been identified largely using OMICS platforms that measure dynamic molecular changes within the cancer cell landscape. The pro-oncogenic protein anterior gradient 2 (AGR2) is a case in point; AGR2 has been shown using a range of expression platforms to be involved in asthma, inflammatory bowel disease, cell transformation, cancer drug resistance and metastatic growth. AGR2 protein is also highly overexpressed in a diverse range of human cancers and can be secreted and detected in extracellular fluids, thus representing a compelling pro-oncogenic signalling intermediate in human cancer. AGR2 belongs to the protein disulphide isomerase family with all the key features of an endoplasmic reticulum-resident protein-this gives clues into how it might function as an oncoprotein through the regulation of protein folding, maturation and secretion that can drive metastatic cell growth. In this review, we will describe the known aspects of AGR2 molecular biology, including gene structure and regulation, emerging protein interaction networks and how its subcellular localization mediates its biological functions. We will finally review the cases of AGR2 expression in human cancers, the pathophysiological consequences of AGR2 overexpression, its potential role as a tumour biomarker that predicts the response to therapy and how the AGR2 pathway might form the basis for drug discovery programmes aimed at targeting protein folding/maturation pathways that mediate secretion and metastasis.

Norris AM, Gore A, Balboni A, et al.
AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia.
Oncogene. 2013; 32(33):3867-76 [PubMed] Free Access to Full Article Related Publications
The mechanisms controlling expression of the putative oncogene Anterior gradient 2 (AGR2) in pancreatic ductal adenocarcinoma (PDAC) are not well understood. We now show that AGR2 is a transforming growth factor-β (TGF-β)-responsive gene in human pancreatic cancer cells, whose downregulation is SMAD4 dependent. We also provide evidence supporting a role for AGR2 as an ER-chaperone for the cancer-associated mucin, MUC1. AGR2 is both sufficient and required for MUC1 expression in pancreatic cancer cells. Furthermore, AGR2 is coexpressed with MUC1 in mouse pancreatic intraepithelial neoplasia (mPanIN)-like lesions and in the cancer cells of four distinct genetically engineered mouse models of PDAC. We also show that Pdx1-Cre/LSL-Kras(G12D)/Smad4(lox/lox) mice heterozygous for Agr2 exhibit a delay in mPanIN initiation and progression to PDAC. It is proposed that loss of Smad4 may convert TGF-β from a tumor suppressor to a tumor promoter by causing the upregulation of AGR2, which then leads to increased MUC1 expression, at which point both AGR2 and MUC1 facilitate mPanIN initiation and progression to PDAC.

Yu H, Zhao J, Lin L, et al.
Proteomic study explores AGR2 as pro-metastatic protein in HCC.
Mol Biosyst. 2012; 8(10):2710-8 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors worldwide. The prognosis of patients with HCC still remains very dismal, mainly due to metastasis. We found that high-expression levels of AGR2 existed in metastatic HCC cell lines and patient samples. Overexpression of AGR2 was found to be correlated to the metastatic status of HCC cells, and inhibition of AGR2 by siRNA resulted in a dramatic decline in invasion abilities in metastatic cells in vitro. Overexpression of AGR2 increased the invasion of HCC cells in vitro and also in vivo with a nude mouse model. The tandem affinity purification (TAP) identified 18 AGR2-binding proteins and IPA analysis revealed that these proteins focus on MAPK and Caspase pathway. Therefore, we speculate that the overexpression of AGR2 can promote HCC metastasis, possibly by affecting MAPK and Caspase pathway through AGR2-interacting proteins.

Verma S, Salmans ML, Geyfman M, et al.
The estrogen-responsive Agr2 gene regulates mammary epithelial proliferation and facilitates lobuloalveolar development.
Dev Biol. 2012; 369(2):249-60 [PubMed] Free Access to Full Article Related Publications
Agr2 is a putative protein disulfide isomerase (PDI) initially identified as an estrogen-responsive gene in breast cancer cell lines. While Agr2 expression in breast cancer is positively correlated with estrogen receptor (ER) expression, it is upregulated in both hormone dependent and independent carcinomas. Several in vitro and xenograft studies have implicated Agr2 in different oncogenic features of breast cancer; however, the physiological role of Agr2 in normal mammary gland development remains to be defined. Agr2 expression is developmentally regulated in the mammary gland, with maximum expression during late pregnancy and lactation. Using a mammary gland specific knockout mouse model, we show that Agr2 facilitates normal lobuloalveolar development by regulating mammary epithelial cell proliferation; we found no effects on apoptosis in Agr2(-/-) mammary epithelial cells. Consequently, mammary glands of Agr2(-/-) females exhibit reduced expression of milk proteins, and by two weeks post-partum their pups are smaller in size. Utilizing a conditional mouse model, we show that Agr2 constitutive expression drives precocious lobuloalveolar development and increased milk protein expression in the virgin mammary gland. In vitro studies using knock down and overexpression strategies in estrogen receptor positive and negative mammary epithelial cell lines demonstrate a role for Agr2 in estradiol-induced cell proliferation. In conclusion, the estrogen-responsive Agr2, a candidate breast cancer oncogene, regulates epithelial cell proliferation and lobuloalveolar development in the mammary gland. The pro-proliferative effects of Agr2 may explain its actions in early tumorigenesis.

Pizzi M, Fassan M, Realdon S, et al.
Anterior gradient 2 profiling in Barrett columnar epithelia and adenocarcinoma.
Hum Pathol. 2012; 43(11):1839-44 [PubMed] Related Publications
Barrett esophagus is the precancerous lesion leading to Barrett adenocarcinoma. The natural history of Barrett metaplasia and its neoplastic progression are still controversial. Anterior gradient 2 is up-regulated in both Barrett intestinal metaplasia and Barrett adenocarcinoma, but no information is available on anterior gradient 2 expression in the spectrum of the phenotypic changes occurring in the natural history of Barrett adenocarcinoma (Barrett esophagus cardiac-type metaplasia, Barrett esophagus intestinal metaplasia, low-grade intraepithelial neoplasia [formerly called low-grade dysplasia], and high-grade intraepithelial neoplasia [formerly called high-grade dysplasia]). Applying immunohistochemistry and reverse transcription and quantitative real-time polymerase chain reaction, this study addressed the role of anterior gradient 2 in Barrett carcinogenesis. Anterior gradient 2 expression was assessed semiquantitatively in 125 consecutive biopsy samples in the adenocarcinoma spectrum arising in Barrett esophagus (Barrett esophagus cardiac-type metaplasia, 25; Barrett esophagus intestinal metaplasia, 25; low-grade intraepithelial neoplasia, 25; high-grade intraepithelial neoplasia, 25; Barrett adenocarcinoma, 25). Additional biopsy samples of esophageal squamous mucosa (n=25) served as controls. Anterior gradient 2 messenger RNA expression was also tested (reverse transcription and quantitative real-time polymerase chain reaction) in a different series of 40 samples (esophageal squamous mucosa, 10; Barrett esophagus cardiac-type metaplasia, 10; Barrett esophagus intestinal metaplasia, 10; Barrett adenocarcinoma, 10). Anterior gradient 2 was never expressed in squamous esophageal epithelium but consistently overexpressed (to much the same degree) in the whole spectrum of Barrett disease (Barrett esophagus cardiac-type metaplasia, Barrett esophagus intestinal metaplasia, low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, and Barrett adenocarcinoma). Anterior gradient 2 messenger RNA was expressed significantly more in Barrett esophagus cardiac-type metaplasia, Barrett esophagus intestinal metaplasia, and Barrett adenocarcinoma than in native squamous epithelium (P<.001), with no significant differences between the 3 groups. Anterior gradient 2 overexpression affects the whole spectrum of the metaplastic/neoplastic lesions involved in Barrett carcinogenesis. This study supports the biological similarity of the nonintestinal and intestinal types of Barrett metaplasia as precursors of Barrett adenocarcinoma.

Gray TA, MacLaine NJ, Michie CO, et al.
Anterior Gradient-3: a novel biomarker for ovarian cancer that mediates cisplatin resistance in xenograft models.
J Immunol Methods. 2012; 378(1-2):20-32 [PubMed] Related Publications
The Anterior Gradient (AGR) genes AGR2 and AGR3 are part of the Protein Disulfide Isomerase (PDI) family and harbour core thioredoxin folds (CxxS motifs) that have the potential to regulate protein folding and maturation. A number of proteomics and transcriptomics screens in the fields of limb regeneration, cancer cell metastasis, pro-oncogenic oestrogen-signalling, and p53 regulation have identified AGR2 as a novel component of these signalling pathways. Curiously, despite the fact that the AGR2 and AGR3 genes are contiguous on chromosome 7p21.1-3, the AGR3 protein has rarely been identified in such OMICs screens along with AGR2 protein. Therefore there is little information on how AGR3 protein is expressed in normal and diseased states. A panel of three monoclonal antibodies was generated towards AGR3 protein for identifying novel clinical models that can be used to define whether AGR3 protein could play a positive or negative role in human cancer development. One monoclonal antibody was AGR3-specific and bound a linear epitope that could be defined using both pep-scan and phage-peptide library screening. Using this monoclonal antibody, endogenous AGR3 protein expression was shown to be cytosolic in four human ovarian cancer subtypes; serous, endometrioid, clear cell, and mucinous. Mucinous ovarian cancers produced the highest number of AGR3 positive cells. AGR3 expression is coupled to AGR2 expression only in mucinous ovarian cancers, whereas AGR3 and AGR2 expressions are uncoupled in the other three types of ovarian cancer. AGR3 expression in ovarian cancer is independent of oestrogen-receptor expression, which is distinct from the oestrogen-receptor dependent expression of AGR3 in breast cancers. Isogenic cancer cell models were created that over-express AGR3 and these demonstrated that AGR3 mediates cisplatin-resistance in mouse xenografts. These data indicate that AGR3 is over-expressed by a hormone (oestrogen-receptor α)-independent mechanism and identify a novel protein-folding associated pathway that could mediate resistance to DNA-damaging agents in human cancers.

Lee HJ, Hong CY, Kim MH, et al.
In vitro induction of anterior gradient-2-specific cytotoxic T lymphocytes by dendritic cells transduced with recombinant adenoviruses as a potential therapy for colorectal cancer.
Exp Mol Med. 2012; 44(1):60-7 [PubMed] Free Access to Full Article Related Publications
Anterior gradient-2 (AGR2) promotes tumor growth, cell migration, and cellular transformation, and is one of the specific mRNA markers for circulating tumor cells in patients with gastrointestinal cancer. We investigated the feasibility of AGR2 as a potent antigen for tumor immunotherapy against colorectal cancer (CRC) cells using dendritic cells (DCs) transduced with a recombinant adenovirus harboring the AGR2 gene (AdAGR2). DCs transduced with a recombinant adenovirus encoding the AGR2 gene (AdAGR2/DCs) were characterized. These genetically-modified DCs expressed AGR2 mRNA as well as AGR2 protein at a multiplicity of infection of 1,000 without any significant alterations in DC viability and cytokine secretion (IL-10 and IL-12p70) compared with unmodified DCs as a control. In addition, AdAGR2 transduction did not impair DC maturation, but enhanced expression of HLA-DR, CD80, and CD86. AdAGR2/DCs augmented the number of IFN-γ-secreting T-cells and elicited potent AGR2-specific cytotoxic T lymphocytes capable of lysing AGR2-expressing CRC cell lines. These results suggest that AGR2 act as a potentially important antigen for immunotherapy against CRC in clinical applications.

Wayner EA, Quek SI, Ahmad R, et al.
Development of an ELISA to detect the secreted prostate cancer biomarker AGR2 in voided urine.
Prostate. 2012; 72(9):1023-34 [PubMed] Related Publications
BACKGROUND: Comparative transcriptomics between sorted cells identified AGR2 as one of the highest up-regulated genes in cancer. Overexpression in primary tumors was verified by tissue microarray analysis. AGR2 encodes a 19-kDa secreted protein that might be found in urine.
METHODS: Monoclonal antibodies were generated against AGR2. One antibody pair, P1G4 (IgG1) to capture and P3A5 (IgG2a) to detect, showed good performance characteristics in a sandwich ELISA. This assay could detect AGR2 at sub ng/ml quantities.
RESULTS: AGR2 was detected in tissue digestion media of tumor specimens and culture media of AGR2-secreting prostate cancer cell lines. Additional testings involved frozen section immunohistochemistry, immunoprecipitation, and Western blot analysis. Voided urine samples were collected from pre-operative cancer patients, and urinary protein was desalted and concentrated by filtration. The amount of AGR2 detected was scored as pg/100 µg total protein, and then converted to pg/ml urine. The developed ELISA detected AGR2 protein, ranging from 3.6 to 181 pg/ml, in an initial cohort of samples. AGR2 was not detected in the urine of non-cancer and a bladder cancer patient.
CONCLUSIONS: For prostate cancer, an AGR2 urine test could be used for diagnosis. The data, although derived from a small number of samples assayed, showed that developing such a test for clinical application is viable because AGR2 is specific to cancer cells, and apparently secreted into urine.

Marín-Aguilera M, Mengual L, Ribal MJ, et al.
Utility of urothelial mRNA markers in blood for staging and monitoring bladder cancer.
Urology. 2012; 79(1):240.e9-15 [PubMed] Related Publications
OBJECTIVE: To test the efficiency of 6 mRNA bladder markers in staging urothelial cell carcinoma (UCC) and monitoring UCC dissemination from blood samples.
METHODS: From 2002 to 2009, 347 blood samples were collected from 150 patients with UCC and 29 healthy controls. Sequential blood sampling was performed in patients undergoing cystectomy at surgery and 6, 12, 18, and 24 months postoperatively. The median follow-up was 33 months. The presence of KRT20, FXYD3, C10orf116, UPK2, AGR2, and KRT19 markers in blood was evaluated in all patients and controls by measuring the gene expression using preamplified cDNA and reverse transcriptase quantitative polymerase chain reaction. Gene expression data were correlated with the tumor risk, follow-up, and outcomes data.
RESULTS: Expression of C10orf116 and KRT19 genes differed between patients and controls (P<.001). KRT20, C10orf116, and AGR2 differentiated between low- and high-risk nonmuscle-invasive bladder cancer (P=.001, P=.011, and P=.001, respectively). FXYD3 differentiated between patients with high-risk nonmuscle-invasive bladder cancer and those with muscle-invasive bladder cancer (P=.009). In contrast, the 6 markers showed no differences in gene expression between metastatic and patients without metastases who had not undergone cystectomy (P=NS). None of the markers were significantly increased in the metastatic patients at 6, 12, 18, or 24 months after surgery.
CONCLUSION: The gene expression of bladder-specific mRNA markers in blood was different among the various tumor risk groups of patients with UCC. However, this gene expression analysis is not suitable for predicting metastases or monitoring UCC hematogenous dissemination in patients who have undergone cystectomy.

Nancarrow DJ, Clouston AD, Smithers BM, et al.
Whole genome expression array profiling highlights differences in mucosal defense genes in Barrett's esophagus and esophageal adenocarcinoma.
PLoS One. 2011; 6(7):e22513 [PubMed] Free Access to Full Article Related Publications
Esophageal adenocarcinoma (EAC) has become a major concern in Western countries due to rapid rises in incidence coupled with very poor survival rates. One of the key risk factors for the development of this cancer is the presence of Barrett's esophagus (BE), which is believed to form in response to repeated gastro-esophageal reflux. In this study we performed comparative, genome-wide expression profiling (using Illumina whole-genome Beadarrays) on total RNA extracted from esophageal biopsy tissues from individuals with EAC, BE (in the absence of EAC) and those with normal squamous epithelium. We combined these data with publically accessible raw data from three similar studies to investigate key gene and ontology differences between these three tissue states. The results support the deduction that BE is a tissue with enhanced glycoprotein synthesis machinery (DPP4, ATP2A3, AGR2) designed to provide strong mucosal defenses aimed at resisting gastro-esophageal reflux. EAC exhibits the enhanced extracellular matrix remodeling (collagens, IGFBP7, PLAU) effects expected in an aggressive form of cancer, as well as evidence of reduced expression of genes associated with mucosal (MUC6, CA2, TFF1) and xenobiotic (AKR1C2, AKR1B10) defenses. When our results are compared to previous whole-genome expression profiling studies keratin, mucin, annexin and trefoil factor gene groups are the most frequently represented differentially expressed gene families. Eleven genes identified here are also represented in at least 3 other profiling studies. We used these genes to discriminate between squamous epithelium, BE and EAC within the two largest cohorts using a support vector machine leave one out cross validation (LOOCV) analysis. While this method was satisfactory for discriminating squamous epithelium and BE, it demonstrates the need for more detailed investigations into profiling changes between BE and EAC.

Tveito S, Andersen K, Kåresen R, Fodstad Ø
Analysis of EpCAM positive cells isolated from sentinel lymph nodes of breast cancer patients identifies subpopulations of cells with distinct transcription profiles.
Breast Cancer Res. 2011; 13(4):R75 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: The presence of tumor cells in the axillary lymph nodes is the most important prognostic factor in early stage breast cancer. However, the optimal method for sentinel lymph node (SLN) examination is still sought and currently many different protocols are employed. To examine two approaches for tumor cell detection we performed, in sequence, immunomagnetic enrichment and RT-PCR analysis on SLN samples from early stage breast cancer patients. This allowed us to compare findings based on the expression of cell surface proteins with those based on detection of intracellular transcripts.
METHODS: Enrichment of EpCAM and Mucin 1 expressing cells from fresh SLN samples was achieved using magnetic beads coated with the appropriate antibodies. All resulting cell fractions were analyzed by RT-PCR using four chosen breast epithelial markers (hMAM, AGR2, SBEM, TFF1). Gene expression was further analyzed using RT-PCR arrays and markers for epithelial to mesenchymal transition (EMT).
RESULTS: Both EpCAM and Mucin 1 enriched for the epithelial-marker expressing cells. However, EpCAM-IMS identified epithelial cells in 71 SLNs, whereas only 35 samples were positive with RT-PCR targeting breast epithelial transcripts. Further analysis of EpCAM positive but RT-PCR negative cell fractions showed that they had increased expression of MMPs, repressors of E-cadherin, SPARC and vimentin, all transcripts associated with the process of epithelial to mesenchymal transition.
CONCLUSIONS: The EpCAM IMS-assay detected tumor cells with epithelial and mesenchymal-like characteristics, thus proving to be a more robust marker than pure epithelial derived biomarkers. This finding has clinical implications, as most methods for SLN analysis today rely on the detection of epithelial transcripts or proteins.

Pizzi M, Fassan M, Balistreri M, et al.
Anterior gradient 2 overexpression in lung adenocarcinoma.
Appl Immunohistochem Mol Morphol. 2012; 20(1):31-6 [PubMed] Related Publications
The histologic subtyping of the 2 major histotypes of nonsmall-cell lung cancer, that is, adenocarcinoma (AdC) and squamous cell carcinoma (SCC), is crucial to therapeutic decision making, but making this distinction can be a challenge. Querying the Oncomine database pinpointed anterior gradient 2 (AGR2) as being upregulated in lung AdC. On applying both quantitative real-time polymerase chain reaction and immunohistochemistry, this study tested the reliability of AGR2 status as a histotype-specific marker of lung AdC. AGR2 immunohistochemistry expression was semiquantitatively assessed in 120 cases of lung cancer (60 AdCs, 60 SCCs); 35 additional tissue samples from non-neoplastic lungs were considered as normal controls. To further support our findings, the expression of AGR2 mRNA was tested by quantitative real-time polymerase chain reaction in 30 of the considered cases (10 AdCs, 10 SCCs, and 10 normal lungs). AGR2 was consistently expressed in normal bronchial/bronchiolar columnar cells. Cases of AdC always expressed the protein (staining moderately in 30% and strongly in 70%), whereas none of the SCC cases strongly expressed AGR2 (staining was negative in 55%, weak in 33%, and moderate in 12%). AGR2 mRNA was significantly overexpressed in AdCs by comparison with SCCs (P=0.003) or normal lung tissue (P=0.002). AGR2 is upregulated in lung AdC (by comparison with either SCC or normal bronchial/bronchiolar columnar cells). AGR2 protein expression may support the histologic subtyping of nonsmall-cell lung cancer and be of clinical value in differentiating lung AdC from SCC.

Makawita S, Smith C, Batruch I, et al.
Integrated proteomic profiling of cell line conditioned media and pancreatic juice for the identification of pancreatic cancer biomarkers.
Mol Cell Proteomics. 2011; 10(10):M111.008599 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer is one of the leading causes of cancer-related deaths, for which serological biomarkers are urgently needed. Most discovery-phase studies focus on the use of one biological source for analysis. The present study details the combined mining of pancreatic cancer-related cell line conditioned media and pancreatic juice for identification of putative diagnostic leads. Using strong cation exchange chromatography, followed by LC-MS/MS on an LTQ-Orbitrap mass spectrometer, we extensively characterized the proteomes of conditioned media from six pancreatic cancer cell lines (BxPc3, MIA-PaCa2, PANC1, CAPAN1, CFPAC1, and SU.86.86), the normal human pancreatic ductal epithelial cell line HPDE, and two pools of six pancreatic juice samples from ductal adenocarcinoma patients. All samples were analyzed in triplicate. Between 1261 and 2171 proteins were identified with two or more peptides in each of the cell lines, and an average of 521 proteins were identified in the pancreatic juice pools. In total, 3479 nonredundant proteins were identified with high confidence, of which ∼ 40% were extracellular or cell membrane-bound based on Genome Ontology classifications. Three strategies were employed for identification of candidate biomarkers: (1) examination of differential protein expression between the cancer and normal cell lines using label-free protein quantification, (2) integrative analysis, focusing on the overlap of proteins among the multiple biological fluids, and (3) tissue specificity analysis through mining of publically available databases. Preliminary verification of anterior gradient homolog 2, syncollin, olfactomedin-4, polymeric immunoglobulin receptor, and collagen alpha-1(VI) chain in plasma samples from pancreatic cancer patients and healthy controls using ELISA, showed a significant increase (p < 0.01) of these proteins in plasma from pancreatic cancer patients. The combination of these five proteins showed an improved area under the receiver operating characteristic curve to CA19.9 alone. Further validation of these proteins is warranted, as is the investigation of the remaining group of candidates.

Dong A, Gupta A, Pai RK, et al.
The human adenocarcinoma-associated gene, AGR2, induces expression of amphiregulin through Hippo pathway co-activator YAP1 activation.
J Biol Chem. 2011; 286(20):18301-10 [PubMed] Free Access to Full Article Related Publications
Anterior Gradient Homolog 2 (AGR2) is expressed by the normal intestine and by most human adenocarcinomas, including those derived from the esophagus, pancreas, lung, breast, ovary, and prostate. Xenografts of human adenocarcinoma cell lines in nude mice previously demonstrated that AGR2 supports tumor growth. In addition, AGR2 is able to induce in vitro a transformed phenotype in fibroblast and epithelial cell lines. The mechanism underlying the growth promoting effects of AGR2 is unknown. The present study shows that AGR2 induces expression of amphiregulin (AREG), a growth promoting EGFR ligand. Induced AREG expression in adenocarcinoma cells is able to rescue the transformed phenotype that is lost when AGR2 expression is reduced. Additional experiments demonstrate that AGR2 induction of AREG is mediated by activation of the Hippo signaling pathway co-activator, YAP1. Thus AGR2 promotes growth by regulating the Hippo and EGF receptor signaling pathways.

Kim HS, Kang SH, Park CH, et al.
Genome-wide molecular characterization of mucinous colorectal adenocarcinoma using cDNA microarray analysis.
Oncol Rep. 2011; 25(3):717-27 [PubMed] Related Publications
Mucinous colorectal carcinoma exhibits distinct clinicopathological features compared to non-mucinous colorectal carcinoma. Previous studies have discovered several molecular genetic features in mucinous colorectal carcinomas, but have limitations as they are confined to a small number of molecules. To understand the mucinous colorectal carcinoma system, this study was designed to identify genes that are differentially expressed in mucinous colorectal carcinoma compared to non-mucinous colorectal carcinoma using cDNA microarrays. cDNA microarray experiments were performed using human cDNA 17k chips with 25 mucinous and 27 non-mucinous cancer tissues. Differentially expressed genes (DEGs) were determined by Welch's t-test and more accurate classifiers were selected from the DEGs using the prediction analysis for microarrays (PAM) software package. Array results were validated using quantitative real-time RT-PCR. The identified gene set was functionally investigated through in silico analysis. Sixty-two DEGs were identified and the 50 highest ranking genes could be used to accurately classify mucinous and non-mucinous colorectal carcinomas. The identified gene set included up-regulated TFF1 (4-fold), AGR2 (3.3-fold), FSCN1 (2.2-fold), CD44 (1.5-fold) and down-regulated SLC26A3 (0.2-fold) in MC. TFF1, AGR2 and SLC26A3 were validated by quantitative real-time RT-PCR. The functions of these DEGs were related to tumorigenesis (14 genes), cell cycle progression (6 genes), invasion (2 genes), anti-apoptosis (7 genes), cell adhesion and proliferation (5 genes) and carbohydrate metabolism (3 genes). We suggest that MC has distinct molecular characteristics from NMC and therefore, that the expression signatures of DEGs may improve the understanding of molecular pathogenesis and clinical behaviors in MC.

Park K, Chung YJ, So H, et al.
AGR2, a mucinous ovarian cancer marker, promotes cell proliferation and migration.
Exp Mol Med. 2011; 43(2):91-100 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer is a leading cause of death in women. Early detection of ovarian cancer is essential to decrease mortality. However, the early diagnosis of ovarian cancer is difficult due to a lack of clinical symptoms and suitable molecular diagnostic markers. Thus, identification of meaningful tumor biomarkers with potential clinical application is clearly needed. To search for a biomarker for the early detection of ovarian cancer, we identified human anterior gradient 2 (AGR2) from our systematic analysis of paired normal and ovarian tumor tissue cDNA microarray. We noted a marked overexpression of AGR2 mRNA and protein in early stage mucinous ovarian tumors compared to normal ovarian tissues and serous type ovarian tumors by Western blot analysis and immunohistochemistry. To further elucidate the role of AGR2 in ovarian tumorigenesis, stable 2774 human ovarian cancer cell lines overexpressing AGR2 were established. Forced expression of AGR2 in 2774 cells enhanced the growth and migration of ovarian cancer cells. AGR2 protein was detected in the serum of mucinous ovarian cancer patients by Western blot and ELISA analysis. Thus, AGR2 is a potential biomarker for the diagnosis of mucinous ovarian cancer and an ELISA assay may facilitate the early detection of mucinous ovarian cancer using patient serum.

Maresh EL, Mah V, Alavi M, et al.
Differential expression of anterior gradient gene AGR2 in prostate cancer.
BMC Cancer. 2010; 10:680 [PubMed] Free Access to Full Article Related Publications
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.

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