Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2014

Open Access 01-12-2014 | Research

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

Authors: Gennaro Di Maro, Paolo Salerno, Kristian Unger, Francesca Maria Orlandella, Mario Monaco, Gennaro Chiappetta, Gerry Thomas, Malgorzata Oczko-Wojciechowska, Mariorosario Masullo, Barbara Jarzab, Massimo Santoro, Giuliana Salvatore

Published in: Molecular Cancer | Issue 1/2014

Login to get access

Abstract

Background

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 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.

Methods

Expression 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.

Results

PTC 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.

Conclusions

AGR2 is a novel marker of PTC and plays a role in thyroid cancer cell survival, migration, invasion and protection from ER stress.
Appendix
Available only for authorised users
Literature
1.
2.
Kondo T, Ezzat S, Asa SL: Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006, 6: 292-306.CrossRefPubMed
3.
Nikiforov YE, Nikiforova MN: Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 2011, 7: 569-580.CrossRefPubMed
4.
5.
6.
Salvatore G, Nappi TC, Salerno P, Jiang Y, Garbi C, Ugolini C, Miccoli P, Basolo F, Castellone MD, Cirafici AM, Melillo RM, Fusco A, Bittner ML, Santoro M: A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma. Cancer Res. 2007, 67: 10148-10158.CrossRefPubMed
7.
Aberger F, Weidinger G, Grunz H, Richter K: Anterior specification of embryonic ectoderm: the role of the Xenopus cement gland-specific gene XAG-2. Mech Dev. 1998, 72: 115-130.CrossRefPubMed
8.
KomiyaT TY, Hirohashi S: Cloning of the gene gob-4, which is expressed in intestinal goblet cells in mice. Biochim Biophys Acta. 1999, 1444: 434-438.CrossRef
9.
Brychtova V, Vojtesek B, Hrstka R: Anterior gradient 2: a novel player in tumor cell biology. Cancer Lett. 2011, 304: 1-7.CrossRefPubMed
10.
Chevet E, Fessart D, Delom F, Mulot A, Vojtesek B, Hrstka R, Murray E, Gray T, Hupp T: Emerging roles for the pro-oncogenic anterior gradient-2 in cancer development. Oncogene. 2012, 6: 2499-2509.
11.
Fritzsche FR, Dahl E, Pahl S, Burkhardt M, Luo J, Mayordomo E, Gansukh T, Dankof A, Knuechel R, Denkert C, Winzer KJ, Dietel M, Kristiansen G: Prognostic relevance of AGR2 expression in breast cancer. Clin Cancer Res. 2006, 12: 1728-1734.CrossRefPubMed
12.
Ramachandran V, Arumugam T, Wang H, Logsdon CD: Anterior gradient 2 is expressed and secreted during the development of pancreatic cancer and promotes cancer cell survival. Cancer Res. 2008, 68: 7811-7818.PubMedCentralCrossRefPubMed
13.
Chen R, Pan S, Duan X, Nelson BH, Sahota RA, de Rham S, Kozarek RA, McIntosh M, Brentnall TA: Elevated level of anterior gradient-2 in pancreatic juice from patients with pre-malignant pancreatic neoplasia. Mol Cancer. 2010, 9: 149-PubMedCentralCrossRefPubMed
14.
Park K, Chung YJ, So H, Kim K, Park J, Oh M, Jo M, Choi K, Lee EJ, Choi YL, Song SY, Bae DS, Kim BG, Lee JH: AGR2, a mucinous ovarian cancer marker, promotes cell proliferation and migration. Exp Mol Med. 2011, 43: 91-100.PubMedCentralCrossRefPubMed
15.
Fritzsche FR, Dahl E, Dankof A, Burkhardt M, Pahl S, Petersen I, Dietel M, Kristiansen G: Expression of AGR2 in non small cell lung cancer. Histol Histopathol. 2007, 22: 703-708.PubMed
16.
Zhang JS, Gong A, Cheville JC, Smith DI, Young CY: AGR2, an androgen-inducible secretory protein over-expressed in prostate cancer. Genes Chromosomes Cancer. 2005, 43: 249-259.CrossRefPubMed
17.
Giordano TJ, Kuick R, Thomas DG, Misek DE, Vinco M, Sanders D, Zhu Z, Ciampi R, Roh M, Shedden K, Gauger P, Doherty G, Thompson NW, Hanash S, Koenig RJ, Nikiforov YE: Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene. 2005, 24: 6646-6656.CrossRefPubMed
18.
Hébrant A, Dom G, Dewaele M, Andry G, Trésallet C, Leteurtre E, Dumont JE, Maenhaut C: mRNA expression in papillary and anaplastic thyroid carcinoma: molecular anatomy of a killing switch. PLoS One. 2012, 7: e37807-PubMedCentralCrossRefPubMed
19.
Delys L, Detours V, Franc B, Thomas G, Bogdanova T, Tronko M, Libert F, Dumont JE, Maenhaut C: Gene expression and the biological phenotype of papillary thyroid carcinomas. Oncogene. 2007, 26: 7894-7903.CrossRefPubMed
20.
Jarzab B, Wiench M, Fujarewicz K, Simek K, Jarzab M, Oczko-Wojciechowska M, Wloch J, Czarniecka A, Chmielik E, Lange D, Pawlaczek A, Szpak S, Gubala E, Swierniak A: Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications. Cancer Res. 2005, 65: 1587-1597.CrossRefPubMed
21.
Huang Y, Prasad M, Lemon WJ, Hampel H, Wright FA, Kornacker K, LiVolsi V, Frankel W, Kloos RT, Eng C, Pellegata NS, de la Chapelle A: Gene expression in papillary thyroid carcinoma reveals highly consistent profiles. Proc Natl Acad Sci U S A. 2001, 98: 15044-15049.PubMedCentralCrossRefPubMed
22.
Persson S, Rosenquist M, Knoblach B, Khosravi-Far R, Sommarin M, Michalak M: Diversity of the protein disulfide isomerase family: identification of breast tumor induced Hag2 and Hag3 as novel members of the protein family. Mol Phylogenet Evol. 2005, 36: 734-740.CrossRefPubMed
23.
Benham AM: The protein disulfide isomerase family key players in health and disease. Antioxid Redox Signal. 2012, 16: 781-789.CrossRefPubMed
24.
Kozlov G, Määttänen P, Thomas DY, Gehring K: A structural overview of the PDI family of proteins. FEBS J. 2010, 277: 3924-3936.CrossRefPubMed
25.
Ma Y, Hendershot LM: The role of the unfolded protein response in tumour development: friend or foe?. Nat Rev Cancer. 2004, 4: 966-977.CrossRefPubMed
26.
Moenner M, Pluquet O, Bouchecareilh M, Chevet E: Integrated endoplasmic reticulum stress responses in cancer. Cancer Res. 2007, 67: 10631-10634.CrossRefPubMed
27.
Zhao F, Edwards R, Dizon D, Afrasiabi K, Mastroianni JR, Geyfman M, Ouellette AJ, Andersen B, Lipkin SM: Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress inAgr2−/−mice. DevBiol. 2010, 338: 270-272.
28.
Higa A, Mulot A, Delom F, Bouchecareilh M, Nguyên DT, Boismenu D, Wise MJ, Chevet E: Role of pro-oncogenic protein disulfide isomerase (PDI) family member anterior gradient 2 (AGR2) in the control of endoplasmic reticulum homeostasis. J Biol Chem. 2011, 286: 44855-44868.PubMedCentralCrossRefPubMed
29.
Ryu J, Park SG, Lee PY, Cho S, Lee do H, Kim GH, Kim JH, Park BC: Dimerization of pro-oncogenic protein Anterior Gradient 2 is required for the interaction with BiP/GRP78. Biochem Biophys Res Commun. 2013, 430: 610-615.CrossRefPubMed
30.
Patel P, Clarke C, Barraclough DL, Jowitt TA, Rudland PS, Barraclough R, Lian LY: Metastasis-promoting anterior gradient 2 protein has a dimeric thioredoxin fold structure and a role in cell adhesion. J Mol Biol. 2013, 425: 929-943.CrossRefPubMed
31.
Gray TA, Murray E, Nowicki MW, Remnant L, Scherl A, Muller P, Vojtesek B, Hupp TR: Development of a fluorescent monoclonal antibody-based assay to measure the allosteric effects of synthetic peptides on self-oligomerization of AGR2 protein. Protein Sci. 2013, 9: 1266-1278.CrossRef
32.
33.
Park SW, Zhen G, Verhaeghe C, Nakagami Y, Nguyenvu LT, Barczak AJ, Killeen N, Erle DJ: The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proc Natl Acad Sci U S A. 2009, 106: 6950-6955.PubMedCentralCrossRefPubMed
34.
Holmgren A: Thioredoxin catalyzes the reduction of insulin disulfides by dithiothreitol and dihydrolipoamide. J Biol Chem. 1979, 254: 9627-9632.PubMed
35.
Mujtaba T, Dou QP: Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discov Med. 2011, 12: 471-480.PubMedCentralPubMed
36.
Mitsiades CS, McMillin D, Kotoula V, Poulaki V, McMullan C, Negri J, Fanourakis G, Tseleni-Balafouta S, Ain KB, Mitsiades N: Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro. J Clin Endocrinol Metab. 2006, 91: 4013-4021.CrossRefPubMed
37.
Schönthal AH: Pharmacological targeting of endoplasmic reticulum stress signaling in cancer. Biochem Pharmacol. 2013, 85: 653-666.CrossRefPubMed
38.
Lee CY, Lee MG, Choi KC, Kang HM, Chang YS: Clinical significance of GADD153 expression in stage I non-small cell lung cancer. Oncol Lett. 2012, 4: 408-412.PubMedCentralPubMed
39.
40.
Luo B, Lee AS: The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene. 2013, 32: 805-818.CrossRefPubMed
41.
Lovat PE, Corazzari M, Armstrong JL, Martin S, Pagliarini V, Hill D, Brown AM, Piacentini M, Birch- Machin MA, Redfern CP: Increasing melanoma cell death using inhibitors of protein disulfide isomerases to abrogate survival responses to endoplasmic reticulum stress. Cancer Res. 2008, 68: 5363-5369.PubMedCentralCrossRefPubMed
42.
Goplen D, Wang J, Enger PØ, Tysnes BB, Terzis AJ, Laerum OD, Bjerkvig R: Protein disulfide isomerase expression is related to the invasive properties of malignant glioma. Cancer Res. 2006, 66: 9895-9902.CrossRefPubMed
43.
Thomas GA: The Chernobyl Tissue Bank: integrating research on radiation-induced thyroid cancer. J Radiol Prot. 2012, 32: 77-80.CrossRef
44.
Hedinger C, Williams ED, Sobin LH: The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer. 1989, 63: 908-911.CrossRefPubMed
Metadata
Title
Anterior gradient protein 2 promotes survival, migration and invasion of papillary thyroid carcinoma cells
Authors
Gennaro Di Maro
Paolo Salerno
Kristian Unger
Francesca Maria Orlandella
Mario Monaco
Gennaro Chiappetta
Gerry Thomas
Malgorzata Oczko-Wojciechowska
Mariorosario Masullo
Barbara Jarzab
Massimo Santoro
Giuliana Salvatore
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-160

Other articles of this Issue 1/2014

Molecular Cancer 1/2014 Go to the issue

Research

Metastasis of prostate cancer and melanoma cells in a preclinical in vivo mouse model is enhanced by L-plastin expression and phosphorylation

Research

IRF-1 regulates alternative mRNA splicing of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in breast epithelial cells generating an immunoreceptor tyrosine-based inhibition motif (ITIM) containing isoform

Research

Ambivalent role of pFAK-Y397 in serous ovarian cancer-a study of the OVCAD consortium

Research

Exemestane blocks mesothelioma growth through downregulation of cAMP, pCREB and CD44 implicating new treatment option in patients affected by this disease

Research

Differential chemosensitivity to antifolate drugs between RAS and BRAF melanoma cells

Research

Malignancy-associated metabolic profiling of human glioma cell lines using 1H NMR spectroscopy
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits