Abstract
BackgroundThrough a transcriptome microarray analysis, we have isolated Anterior gradient protein 2 (AGR2) as a gene up-regulated in papillary thyroid carcinoma (PTC). AGR2 is a disulfide isomerase over-expressed in several human carcinomas and recently linked to endoplasmic reticulum (ER) stress. Here, we analyzed the expression of AGR2 in PTC and its functional role.MethodsExpression of AGR2 was studied by immunohistochemistry and real time PCR in normal thyroids and in PTC samples. The function of AGR2 was studied by knockdown in PTC cells and by ectopic expression in non-transformed thyroid cells. The role of AGR2 in the ER stress was analyzed upon treatment of cells, expressing or not AGR2, with Bortezomib and analyzing by Western blot the expression levels of GADD153.ResultsPTC over-expressed AGR2 at mRNA and protein levels. Knockdown of AGR2 in PTC cells induced apoptosis and decreased migration and invasion. Ectopic expression of AGR2 in non-transformed human thyroid cells increased migration and invasion and protected cells from ER stress induced by Bortezomib.ConclusionsAGR2 is a novel marker of PTC and plays a role in thyroid cancer cell survival, migration, invasion and protection from ER stress.
Highlights
Through a transcriptome microarray analysis, we have isolated Anterior gradient protein 2 (AGR2) as a gene up-regulated in papillary thyroid carcinoma (PTC)
AGR2 is up-regulated in human PTC samples We measured AGR2 expression by immunohistochemistry with an anti-AGR2 monoclonal antibody in 64 samples including 25 normal thyroid (NT) samples and 39 PTC samples
By evaluating the aggregation of insulin as a result of reduction of disulfide bonds catalyzed by protein disulfide isomerase, we demonstrated that AGR2 over-expressing cells have an increased disulfide isomerase activity compared to control cells, an increased levels of Oxidized glutathione (GSSG) and Reduced glutathione (GSH) and a decreased level of H2O2
Summary
Through a transcriptome microarray analysis, we have isolated Anterior gradient protein 2 (AGR2) as a gene up-regulated in papillary thyroid carcinoma (PTC). We analyzed the expression of AGR2 in PTC and its functional role. PTC is a well-differentiated, slow growing and treatable tumor. The tumor is usually removed by surgery and treated by iodine 131-radiation therapy, a few PTC carriers develop recurrences and distant metastases [4,5]. To look for genes potentially involved in the neoplastic transformation of the thyroid gland, we conducted a transcriptome microarray screening [6]. Among the genes highly up-regulated in PTC, we focused on Anterior. AGR2 was found up-regulated in several published PTC microarrays [17,18,19,20,21]. Delys and colleagues produced a list of genes modulated in PTC, by comparing their data sets with two independent PTC microarray data sets, and AGR2 scored as one of the genes commonly up-regulated in PTC [19]
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