Increased plasma concentrations of anterior gradient 2 protein are positively associated with ovarian cancer

Edgell, Tracey A.; Barraclough, Dong L.; Rajic, Antonio; Dhulia, Janu; Lewis, Kate J.; Armes, Jane E.; Barraclough, Roger; Rudland, Philip S.; Rice, Gregory E.; Autelitano, Dominic J.

doi:10.1042/cs20090537

Cited by 42 publications

(31 citation statements)

References 17 publications

(29 reference statements)

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“…Agr2 has been shown to bind mucin proteins directly and by managing their conformation as they traffick through the endoplasmic reticulum (ER), Agr2 might increase their stability and expression (Zhao et al, 2010;Higa et al, 2011;Niederreiter and Kaser, 2011). Expression of Agr2 is also induced by ER stress and is highly enhanced in multiple carcinomas, leading to stimulation of proliferation (Liu et al, 2005;Zweitzig et al, 2007;Ramachandran et al, 2008;Barraclough et al, 2009;Edgell et al, 2010;Maresh et al, 2010;Bu et al, 2011). More relevant in light of our results are previous findings showing that Agr2 can alter cell fates by inducing ectopic cement gland differentiation and anterior neural fate in Xenopus laevis (Aberger et al, 1998).…”

Section: Discussionsupporting

confidence: 55%

Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2

Wang

Zhang

et al. 2012

Development

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SUMMARYThe molecular pathways regulating cell lineage determination and regeneration in epithelial tissues are poorly understood. The secretory epithelium of the lung is required for production of mucus to help protect the lung against environmental insults, including pathogens and pollution, that can lead to debilitating diseases such as asthma and chronic obstructive pulmonary disease. We show that the transcription factors Foxp1 and Foxp4 act cooperatively to regulate lung secretory epithelial cell fate and regeneration by directly restricting the goblet cell lineage program. Loss of Foxp1/4 in the developing lung and in postnatal secretory epithelium leads to ectopic activation of the goblet cell fate program, in part, through de-repression of the protein disulfide isomerase anterior gradient 2 (Agr2). Forced expression of Agr2 is sufficient to promote the goblet cell fate in the developing airway epithelium. Finally, in a model of lung secretory cell injury and regeneration, we show that loss of Foxp1/4 leads to catastrophic loss of airway epithelial regeneration due to default differentiation of secretory cells into the goblet cell lineage. These data demonstrate the importance of Foxp1/4 in restricting cell fate choices during development and regeneration, thereby providing the proper balance of functional epithelial lineages in the lung.

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Section: Discussionsupporting

confidence: 55%

Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2

Wang

Zhang

et al. 2012

Development

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“…In the clinical setting, AGR2 protein expression in the primary tumor is an independent prognostic indicator of poor outcome in patients with breast [29] and prostate adenocarcinomas [30], and one recent study showed that increased AGR2 protein in plasma is associated with ovarian cancer [31]. …”

Section: Resultsmentioning

confidence: 99%

Evaluation of the Adenocarcinoma-Associated Gene AGR2 and the Intestinal Stem Cell Marker LGR5 as Biomarkers in Colorectal Cancer

Valladares‐Ayerbes

Blanco-Calvo

Reboredo

et al. 2012

IJMS

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We aim to estimate the diagnostic performances of anterior gradient homolog-2 (AGR2) and Leucine-rich repeat-containing-G-protein-coupled receptor 5 (LGR5) in peripheral blood (PB) as mRNA biomarkers in colorectal cancer (CRC) and to explore their prognostic significance. Real-time PCR was used to analyze AGR2 and LGR5 in 54 stages I-IV CRC patients and 19 controls. Both mRNAs were significantly increased in PB from CRC patients compared to controls. The area under the receiver-operating characteristic curves were 0.722 (p = 0.006), 0.376 (p = 0.123) and 0.767 (p = 0.001) for AGR2, LGR5 and combined AGR2/LGR5, respectively. The AGR2/LGR5 assay resulted in 67.4% sensitivity and 94.7% specificity. AGR2 correlated with pT3–pT4 and high-grade tumors. LGR5 correlated with metastasis, R2 resections and high-grade. The progression-free survival (PFS) of patients with high AGR2 was reduced (p = 0.037; HR, 2.32), also in the stage I-III subgroup (p = 0.046). LGR5 indicated a poor prognosis regarding both PFS (p = 0.007; HR, 1.013) and overall survival (p = 0.045; HR, 1.01). High AGR2/LGR5 was associated with poor PFS (p = 0.014; HR, 2.8) by multivariate analysis. Our findings indicate that the assessment of AGR2 and LGR5 in PB might reflect the presence of circulating tumor cells (CTC) and stem cell like CTC in CRC. Increased AGR2 and LGR5 are associated with poor outcomes.

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“…7–9 AGR2 is a secreted, cancer-associated protein and upregulated in many types of epithelial cancer, 10,11 including breast, 12,13 lung, 14,15 colon, 16 ovarian, 17,18 esophageal, 19 and pancreatic 20,21 beside prostate. Compared with non-cancer, AGR2 is highly expressed in prostate cancer at both the mRNA and protein levels.…”

Section: Introductionmentioning

confidence: 99%

A Highly Sensitive Targeted Mass Spectrometric Assay for Quantification of AGR2 Protein in Human Urine and Serum

et al. 2013

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Anterior gradient 2 (AGR2) is a secreted, cancer-associated protein in many types of epithelial cancer cells. We developed a highly sensitive targeted mass spectrometric assay for quantification of AGR2 in urine and serum. Digested peptides from clinical samples were processed by PRISM (high pressure and high resolution separations coupled with intelligent selection and multiplexing), which incorporates high pH reversed-phase LC separations to fractionate and select target fractions for follow-on LC-SRM analyses. The PRISM-SRM assay for AGR2 showed a reproducibility of <10% CV and LOQ values of ~130 pg/mL in serum and ~10 pg per 100 μg total protein mass in urine, respectively. A good correlation (R2 = 0.91) was observed for the measurable AGR2 concentrations in urine between SRM and ELISA. Based on an initial cohort of 37 subjects, urinary AGR2/PSA concentration ratios showed a significant difference (P = 0.026) between non-cancer and cancer. Large clinical cohort studies are needed for the validation of AGR2 as a useful diagnostic biomarker for prostate cancer. Our work validated the approach of identifying candidate secreted protein biomarkers through genomics and measurement by targeted proteomics, especially for proteins where no immunoassays are available.

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Increased plasma concentrations of anterior gradient 2 protein are positively associated with ovarian cancer

Cited by 42 publications

References 17 publications

Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2

Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2

Evaluation of the Adenocarcinoma-Associated Gene AGR2 and the Intestinal Stem Cell Marker LGR5 as Biomarkers in Colorectal Cancer

A Highly Sensitive Targeted Mass Spectrometric Assay for Quantification of AGR2 Protein in Human Urine and Serum

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