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The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 “interactome” and discuss the pathological and physiological role of such AGR2 interactions.

BCR-ABL1 independent mechanisms had been indicated to mediate drug resistance to tyrosine kinase inhibitors (TKIs) in patients with chronic myelogenous leukemia (CML). In this study, we observed increased level of pro-oncogenic anterior gradient 2 (AGR2) in TKIs-resistant CML cells. Silencing of AGR2 in dasatinib-resistant K562 (K562DR) cells led to restored sensitivity to dasatinib both in vitro and in vivo. Exposure to dasatinib induced up-regulation of AGR2 in K562 cells, which indicated a probable treatment related drug resistance. We further investigated the potential interaction between microRNA (miRNA) and AGR2 in K562DR cells, and found that down-regulation of miR-217 was associated with over-expression of AGR2 in K562DR cells. Luciferase reporter assay identified that miR-217 negatively regulated expression of AGR2 through binding 3'-untranslated region (3'-UTR) of AGR2. Forced expression of miR-217 led to decreased expression of AGR2 as well as compromised TKIs-resistant potential of K562DR cells. Similarly, over-expression of miR-217 re-sensitized K562DR cells to dasatinib-treatment in a murine xenograft transplantation model. Taken together, TKIs-treatment induced drug-resistance is correlated with decrease of miR-217 and up-regulation of AGR2. miR-217/AGR2 interaction might be a potential therapeutic target in treating CML patients with TKIs-resistant. Citation Format: Bin Pan, Xiangmin Wang, Kailin Xu, Takayuki Ikezoe. miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by targeting pro-oncogenic anterior gradient 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5892.

Ovarian cancer is often asymptomatic and is diagnosed at an advanced stage with poor survival rates, thus there is an urgent need to develop biomarkers for earlier detection of ovarian cancer. In the present study, we demonstrate for the first time that the previously reported metastasis-inducing protein AGR2 (anterior gradient protein 2) can be detected in the blood of ovarian cancer patients. Using a newly developed ELISA, we show significantly increased concentrations of AGR2 protein in plasma from cancer patients relative to normal controls. Plasma AGR2 concentrations were highest in stages II and III ovarian cancer patients and were similarly elevated in patients with both serous and non-serous tumours. The identification of elevated plasma concentrations of AGR2 may provide a useful biomarker to aid in the discrimination of normal and ovarian cancer patients particularly when used in combination with CA125.

Anterior Gradient 2 (AGR2), an ER stress-inducible protein, has been reported to be localized in endoplasmic reticulum (ER) and its level is elevated in numerous metastatic cancers. Recently, it has been demonstrated that AGR2 is involved in the control of ER homeostasis. However, the molecular mechanism how AGR2 regulates ER stress response remains unclear. Herein we show that AGR2 homo-dimerizes through an intermolecular disulfide bond. Moreover, dimerization of AGR2 attenuates ER stress-induced cell death through the association with BiP/GRP78. Thus, these results suggest that dimerization of AGR2 is crucial in mediating the ER stress signaling pathway.

Colorectal cancer is one of the leading causes of cancer-associated morbidity and mortality across the world. Every year many patients died from the advanced colorectal cancer. We had tried our best to stop the progress by the chemotherapy and radiotherapy, but the process has not stopped. And we just can use the target drug to extend the survival time of the patient who is in advanced stage. It is said that the circulating tumor cells, distributed in the peripheral blood, is the initial material leading to metastases formation. And Anterior gradient 2 is a biomarker of these cells. It shows an enormous role in the process of cancer's occurrence, development and metastasis. It may be a useful target for us to prevent colorectal cancer from progress. And it may be a new way to treat the colorectal cancer.

The aims of this study were: to characterise and compare plasma concentrations of midkine (MDK) in normal healthy women with concentrations observed in women with ovarian cancer; and to establish and compare the performance of MDK with that of anterior gradient 2 protein (AGR2) and CA125 in the development of multi-analyte classification algorithms for ovarian cancer. Median plasma concentrations of immunoreactive MDK, AGR2 and CA125 were significantly greater in the case cohort (909 pg/ml, 765 pg/ml and 502 U/ml, respectively n = 46) than in the control cohort (383 pg/ml, 188 pg/ml and 13 U/ml, respectively n = 61) (p < 0.001). The area under the receiver operator characteristic curve (AUC) for MDK and AGR2 was not significantly different (0.734 ± 0.046 and 0.784 ± 0.049, respectively, mean ± SE) but were both significantly less than the AUC for CA125 (0.934 ± 0.030, p < 0.003). When subjected to stochastic gradient boosted logistic regression modelling, the AUC of the multi-analyte panel (MDK, AGR2 and CA125, 0.988 ± 0.010) was significantly greater than that of CA125 alone (0.934 ± 0.030, p = 0.035). The sensitivity and specificity of the multi-analyte algorithm were 95.2 and 97.7%, respectively. Within the study cohort, CA125 displayed a sensitivity and specificity of 87.0 and 94.6%, respectively. The data obtained in this study confirm that both MDK and AGR2 individually display utility as biomarkers for ovarian cancer and that in a multi-analyte panel significantly improve the diagnostic utility of CA125 in symptomatic women.

Sea-farmed Atlantic salmon, Salmo salar L. , rainbow trout, Oncorhynchus mykiss , Chinook salmon, O. tshawytscha, coho salmon, O. kisutch and turbot, Psetta maxima (L.) are all susceptible to a condition known as amoebic gill disease

The method of the recovery of the potential on the module of its gradient under conditionof the similarity of the potential to that given as the limit of the succession of the solations of the boundary problems of Neumann for the Laplace equation that define the disturbing potential proposed in the first part is substantiated. The succession of the disturbing potential is generated by the succession of the solutions of linear integral equations of the second kind with compact operators having large cores. A correct solubility of the given kind of equations is established and the convergence of the succession of the solution of the Neumann's problems to the function unambiguously generating the desired potential is proven.

Objective Pulmonary artery banding is associated with a high morbidity and mortality. We describe a new technique of adjustable pulmonary artery banding to prevent these problems. Methods Between December 2003 and May 2005, 32 patients aged 18 days to 2 years (mean age, 2.5 ± 0.5 months) and weighing 2.1 to 6.3 kg (mean, 3.6 ± 1.3 kg) underwent adjustable pulmonary artery banding. Results All patients survived the operation. There were 2 deaths, one caused by meningitis and another caused by aspiration pneumonitis. Satisfactory band gradients were achieved between 3 and 10 days (7.2 ± 2.6 days) in 3 to 6 sittings. Mean follow-up was 7.5 ± 3.8 months (1-16 months). One patient required reoperation for unsatisfactory band gradient 2 weeks after discharge. There were no late deaths. Follow-up computed tomographic angiograms (n = 4) demonstrated proper band placement and ruled out distortion of the pulmonary arteries. Four patients underwent uneventful definitive operations after an interval of 7 to 13 months. Conclusion This technique of percutaneously adjustable pulmonary artery banding is simple and inexpensive and allows easy band adjustments without the need for multiple reoperations.