Anterior gradient protein 2 promotes survival, migration and invasion of papillary thyroid carcinoma cells

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.

Downregulation of AGR2, p21, and cyclin D and alterations in p53 function were associated with tumor progression and chemotherapy resistance in epithelial ovarian carcinoma

“…The increase in AGR2 has been associated with phenotypes such as cell viability, invasion, and metastasis in various human cancers, [15][16][17] however, in our study, the expression of AGR2 evaluated by IHC was associated with better prognosis, suggesting a versatility in the function of this protein in cancer pathophysiology. Here, we observed that the lower levels of AGR2 protein in ovarian carcinoma were correlated with high-grade serous carcinoma and characteristics of malignancy, such as lymphatic vascular invasion, bilateral involvement, necrosis, ovarian surface involvement, lymph node metastasis, and relapse ( Table 2).…”

“…14 In tumorigenesis, AGR2 plays an important role by activating survival and metastasis pathways by interacting with cyclin D1, cathepsin B, D, Myc, p-Src, and EGFR and by blocking cell death inhibiting p53 function. The overexpression of AGR2 was observed in several tumor types, [15][16][17] which supports the hypothesis of AGR2 be an oncogene, but the downregulation of this gene also was observed in prostate tumors, 18 ovarian, 19 colorectal, 20 and pancreas. 21 Despite the existing knowledge that AGR2 may interact with p53, 7,22 little is known about its possible relation with cell cycles proteins and prognostic value in ovarian cancer context.…”

“…In tumorigenesis, AGR2 plays an important role by activating survival and metastasis pathways by interacting with cyclin D1, cathepsin B, D, Myc, p‐Src, and EGFR and by blocking cell death inhibiting p53 function. The overexpression of AGR2 was observed in several tumor types, which supports the hypothesis of AGR2 be an oncogene, but the downregulation of this gene also was observed in prostate tumors, ovarian, colorectal, and pancreas …”

Proteomics of thyroid tumours provides new insights into their molecular composition and changes associated with malignancy

“…Recent studies show that AGR2 acts as a thioredoxin in the endoplasmic reticulum (ER), interacting directly with EGFR for disulfide bond formation and protein folding and determining its presentation to the cell surface 47 . Functional EGFR overexpression has been found in thyroid cancer cells 48 and AGR2 upregulation in PTC has also been demonstrated 49 .…”

Paracrine signalling of AGR2 stimulates RhoA function in fibroblasts and modulates cell elongation and migration

“…The tumour-related function of intracellular and secretory AGR2 has been investigated intensively in promoting angiogenesis and fibroblasts modulation in TME formation [22][23][24][25]. In tumorigenesis, AGR2 plays an important role by interacting with cyclin D1, cathepsin B, D, Myc, p-Src, and EGFR [26][27][28]. Very few functions of extracellular AGR2 have been reported explaining the fibroblasts coordinated tumour cell invasion and promotion of angiogenesis [16].…”