Biology:AGR2

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Anterior gradient protein 2 homolog (AGR-2), also known as secreted cement gland protein XAG-2 homolog, is a protein that in humans is encoded by the AGR2 gene. Anterior gradient homolog 2 was originally discovered in Xenopus laevis.[1] In Xenopus AGR2 plays a role in cement gland differentiation,[2] but in human cancer cell lines high levels of AGR2 correlate with downregulation of the p53 response,[3] cell migration, and cell transformation.[4] However, there have been other observations that AGR2 can repress growth and proliferation.[5]

Discovery in Xenopus laevis

The Xenopus laevis anterior gradient genes - XAG-1, XAG-2, and XAG-3 - were discovered through dissection of different-aged embryos.[6] They become expressed in the anterior region of the dorsal ectoderm in late gastrula embryos.[6][7] XAG-2 expression gathers at the anterior region of the dorsal ectoderm, and this region corresponds to the cement gland anlage.[8] Many other homologous proteins have been discovered afterwards in Xenopus.

Tissue distribution

AGR2 is the human homolog of XAG-2. It is expressed strongly in tissues that secrete mucus or function as endocrine organs, including the lungs, stomach, colon, prostate and small intestine.[9][10] Its protein expression has been shown to be regulated by both androgens and estrogens.[5][11]

Structure and function

AGR2 is a protein disulfide isomerase, with a single CXXS active domain motif for oxidation and reduction reactions.[12][13] AGR2 forms mixed disulfides in substrates, such as intestinal mucin. AGR2 interacts with Mucin 2 through its thioredoxin-like domain forming a heterodisulfide bond with cysteine residues in MUC2.[14] AGR2 is suggested to play a role in protein folding, and it has a KTEL C-terminal motif similar to KDEL and KVEL endoplasmic reticulum retention sequences.[15]

Clinical significance

Agr2 is located on chromosome 7p21, a region that has frequent genetic alterations.[16] It was first identified in estrogen receptor-positive breast cancer cells.[10] Later studies showed elevated levels of AGR2 in adenocarcinomas of the esophagus, pancreas, and prostate. In Barrett's esophagus, Agr2 expression is elevated by over 70 times compared to normal esophageal epithelia.[17] Thus, this protein alone is enough to distinguish Barrett's esophagus, which is linked to esophageal adenocarcinoma, from a normal esophagus.[18]

Varying AGR2 levels exist in different cancers. In breast cancer, high AGR2 expression is correlated with low survival rate.[19] AGR2 levels are elevated in the preneoplastic tissue Barrett's oesophagus. AGR2 is also associated with prostate cancer, though lower levels are associated with higher Gleason grades.[20]

In contrast to upregulation of AGR2 in various cancers, downregulation of AGR2 is linked with inflammatory bowel disease and increases in the risk of Crohn's disease and ulcerative colitis. This implies the importance of AGR2 in maintaining epithelial barrier function, which is supported by FOXA1 and FOXA2 molecules (transcription factors for epithelial goblet cells) which can activate the AGR2 promoter.[21]

Breast cancer

In breast cancer, AGR2 and estrogen (ER) expression are positively correlated. Approximately 70% of breast cancer patients have breast cancer cells that heavily express ER and progesterone receptors (PgR). These patients are normally treated with endocrine therapy. Tamoxifen, which blocks the binding of estradiol to its receptor, is the standard treatment for ER-positive breast cancer. However, about one third of patients do not respond to this therapy,[22] and increased AGR2 may be one reason.

There is a positive correlation for a higher level of AGR2 expression with poor therapeutic results in ERα-positive breast cancer patients.[23][24] Agr2 mRNA expression is elevated in in vitro and in vivo studies responding to tamoxifen adjuvant therapy, so AGR2 is likely provides an agonistic effect on tamoxifen.[23][25] Therefore, AGR2 is a possible predictive biomarker when selecting patients with ER-positive breast cancer to participate this therapy.[26] Although Agr2 mRNA levels are correlated with the tamoxifen therapy response, AGR2 protein levels have yet to be statistically associated with the therapy. A combinatorial therapy using the anastrozole and fulvestrant has been shown to prevent binding of the ER to the Agr2 promoter, and there has been improved prognosis in the patients receiving it, possibly because AGR2 expression in the tumors have been reduced.[27][unreliable medical source]

What AGR2 does in cancers is poorly understood. In breast cancer, HSP90 is a molecular chaperone expressed in tumor cells when there exists an excess of unfolded protein, and its co-chaperone has been reported to induce expression of AGR2,[28][29] so AGR2 may be used by the endoplasmic reticulum to assist with protein folding to alleviate proteotoxic stress. AGR2 may help regulate the protein and mRNA levels in a cell overall as well. During late pregnancy and lactation, AGR2 levels peak when milk proteins are produced, and mammary-specific Agr2 knockout mice had downregulated milk protein mRNA expression.[30]

Prostate cancer

AGR2 is expressed in relatively high levels for prostate cancer patients. Urine sediment tests determined Agr2 transcript levels to be elevated.[5] AGR2 expression was increased in metastatic prostate cancer cells cultured in a bone marrow microenvironment, where intense levels of Agr2 mRNA were detected, suggesting AGR2 is required for bone metastasis of prostate cancer cells.[31] AGR2 transcript levels were lower in metastatic lesions compared to the primary tumor, however.[20] A greater chance of prostate cancer recurrence is linked to relatively lower levels of AGR2.[20]

AGR2 depletion through gene knockdown was shown to result in accumulation of prostate cancer cell lines at the G0/G1 phase of the cell cycle, while forced expression of AGR led to an increase in cell proliferation.[32] AGR2 was determined to be involved in cell adhesion. Agr2-silenced prostate cancer cells had a large decrease in association with fibronectin, lost expression of integrin, and reduced tumor cell migration.[31] In addition to these studies, AGR2 was among a set of genes consistently associated with prostate tumour visibility on MRI in a bioinformatic analysis, the analysis found that more visible tumours harboured more aggressive genetic characteristics.[33] The study also found genes involved with cell-ECM interactions to be altered in aggressive MRI-visible tumours,[33] potentially reflecting AGR2's association with cellular adhesion ans integrin signalling.[31]

Pancreatic cancer

AGR2 mRNA was discovered to be increased in precancerous lesions and neoplastic cells of pancreatic tumors and cancer cell lines.[34] Transient silencing of AGR2 by small interfering RNA and short hairpin RNA significantly reduces cell proliferation and invasion while increasing the effectiveness of gemcitabine treatment in pancreatic cancer cell lines in vitro,[34][35] indicating that AGR2 can help pancreatic cancer cells survive and protect tumors from chemotherapeutic treatments for pancreatic cancer. This is critical because pancreatic cancer is well recognized as being highly resistant to therapeutics, and five-year survival rates for pancreatic cancer are extremely low.

Protein interactions

AGR2 protein has been demonstrated to interact with C4.4A and DAG-1 proteins which are associated with metastasis formation since these transmembrane proteins are involved in cell and matrix interactions between cancer and normal cells.[36] AGR2 is able to suppress p53 activity by preventing phosphorylation after DNA damage.[3] AGR2 has been shown to bind to Reptin, a tumor repressor, in the nucleus.[37]

References

  1. ↑ "Entrez Gene: AGR2 anterior gradient homolog 2 (Xenopus laevis)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10551. 
  2. ↑ "Anterior specification of embryonic ectoderm: the role of the Xenopus cement gland-specific gene XAG-2". Mech. Dev. 72 (1–2): 115–30. March 1998. doi:10.1016/S0925-4773(98)00021-5. PMID 9533957. 
  3. ↑ 3.0 3.1 "The Barrett's antigen anterior gradient-2 silences the p53 transcriptional response to DNA damage". Mol. Cell. Proteomics 3 (6): 534–47. June 2004. doi:10.1074/mcp.M300089-MCP200. PMID 14967811. 
  4. ↑ "The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation". Cancer Res. 68 (2): 492–7. January 2008. doi:10.1158/0008-5472.CAN-07-2930. PMID 18199544. 
  5. ↑ 5.0 5.1 5.2 "The anterior gradient 2 (AGR2) gene is overexpressed in prostate cancer and may be useful as a urine sediment marker for prostate cancer detection". Prostate 71 (6): 575–87. May 2011. doi:10.1002/pros.21273. PMID 20945500. 
  6. ↑ 6.0 6.1 "Progressive determination during formation of the anteroposterior axis in Xenopus laevis". Cell 58 (1): 171–80. July 1989. doi:10.1016/0092-8674(89)90413-3. PMID 2752418. 
  7. ↑ "A sticky problem: the Xenopus cement gland as a paradigm for anteroposterior patterning". Dev. Dyn. 205 (3): 265–80. March 1996. doi:10.1002/(SICI)1097-0177(199603)205:3<265::AID-AJA7>3.0.CO;2-G. PMID 8850563. 
  8. ↑ "Anterior specification of embryonic ectoderm: the role of the Xenopus cement gland-specific gene XAG-2". Mech. Dev. 72 (1–2): 115–30. March 1998. doi:10.1016/S0925-4773(98)00021-5. PMID 9533957. 
  9. ↑ "Anterior gradient 2 homolog (Xenopus laevis)". Gene/Protein. The Human Protein Atlas. http://www.proteinatlas.org/ENSG00000106541/tissue. 
  10. ↑ 10.0 10.1 "hAG-2, the human homologue of the Xenopus laevis cement gland gene XAG-2, is coexpressed with estrogen receptor in breast cancer cell lines". Biochem. Biophys. Res. Commun. 251 (1): 111–6. October 1998. doi:10.1006/bbrc.1998.9440. PMID 9790916. 
  11. ↑ "Anterior gradient-2 plays a critical role in breast cancer cell growth and survival by modulating cyclin D1, estrogen receptor-alpha and survivin". Breast Cancer Res. 12 (3): R32. 2010. doi:10.1186/bcr2586. PMID 20525379. 
  12. ↑ "The human protein disulfide isomerase gene family". Human Genomics 6 (1): 6. July 2012. doi:10.1186/1479-7364-6-6. PMID 23245351. 
  13. ↑ "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. 36 (3): 734–40. September 2005. doi:10.1016/j.ympev.2005.04.002. PMID 15935701. 
  14. ↑ "The protein disulfide isomerase AGR2 is essential for production of intestinal mucus". Proc. Natl. Acad. Sci. U.S.A. 106 (17): 6950–5. April 2009. doi:10.1073/pnas.0808722106. PMID 19359471. Bibcode: 2009PNAS..106.6950P. 
  15. ↑ "AGR2 gene function requires a unique endoplasmic reticulum localization motif". J. Biol. Chem. 287 (7): 4773–82. 2012. doi:10.1074/jbc.M111.301531. PMID 22184114. 
  16. ↑ "Localization of the human anterior gradient-2 gene (AGR2) to chromosome band 7p21.3 by radiation hybrid mapping and fluorescencein situ hybridisation". Cytogenet. Cell Genet. 89 (3–4): 141–2. 2000. doi:10.1159/000015594. PMID 10965104. 
  17. ↑ "Gene expression profiling reveals stromal genes expressed in common between Barrett's esophagus and adenocarcinoma". Gastroenterology 131 (3): 925–33. September 2006. doi:10.1053/j.gastro.2006.04.026. PMID 16952561. 
  18. ↑ "Barrett's esophagus and its progression to adenocarcinoma". J Natl Compr Canc Netw 4 (4): 367–74. April 2006. doi:10.6004/jnccn.2006.0031. PMID 16569389. 
  19. ↑ "The metastasis-associated anterior gradient 2 protein is correlated with poor survival of breast cancer patients". Am. J. Pathol. 175 (5): 1848–57. November 2009. doi:10.2353/ajpath.2009.090246. PMID 19834055. 
  20. ↑ 20.0 20.1 20.2 "Differential expression of anterior gradient gene AGR2 in prostate cancer". BMC Cancer 10: 680. 2010. doi:10.1186/1471-2407-10-680. PMID 21144054. 
  21. ↑ "Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease". Genes Immun. 7 (1): 11–8. January 2006. doi:10.1038/sj.gene.6364263. PMID 16222343. 
  22. ↑ "Scientists Unravel Resistance to Breast Cancer Treatment". Artemis. http://www.hopkinsbreastcenter.org/artemis/201212/22.html. 
  23. ↑ 23.0 23.1 "The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers". Oncogene 29 (34): 4838–47. August 2010. doi:10.1038/onc.2010.228. PMID 20531310. 
  24. ↑ "Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients". Br. J. Cancer 94 (7): 1057–65. April 2006. doi:10.1038/sj.bjc.6603065. PMID 16598187. 
  25. ↑ "Data-independent proteomic screen identifies novel tamoxifen agonist that mediates drug resistance". J. Proteome Res. 10 (10): 4567–78. October 2011. doi:10.1021/pr2004117. PMID 21936522. 
  26. ↑ "AGR2 predicts tamoxifen resistance in postmenopausal breast cancer patients". Dis. Markers 35 (4): 207–12. 2013. doi:10.1155/2013/761537. PMID 24167368. 
  27. ↑ "Combination anastrozole and fulvestrant in metastatic breast cancer". N. Engl. J. Med. 367 (5): 435–44. 2012. doi:10.1056/NEJMoa1201622. PMID 22853014. 
  28. ↑ "HSP90 and the chaperoning of cancer". Nat. Rev. Cancer 5 (10): 761–72. 2005. doi:10.1038/nrc1716. PMID 16175177. http://dipbsf.uninsubria.it/monti/BFPN%202009/nrcHSP90.pdf. 
  29. ↑ "High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance". Cancer Res. 70 (21): 8446–56. 2010. doi:10.1158/0008-5472.CAN-10-1590. PMID 20847343. 
  30. ↑ "The estrogen-responsive Agr2 gene regulates mammary epithelial proliferation and facilitates lobuloalveolar development". Dev. Biol. 369 (2): 249–60. 2012. doi:10.1016/j.ydbio.2012.06.030. PMID 22819674. 
  31. ↑ 31.0 31.1 31.2 "Anterior gradient protein-2 is a regulator of cellular adhesion in prostate cancer". PLOS ONE 9 (2): e89940. 2014. doi:10.1371/journal.pone.0089940. PMID 24587138. Bibcode: 2014PLoSO...989940C. 
  32. ↑ "Knockdown of AGR2 induces cellular senescence in prostate cancer cells". Carcinogenesis 33 (6): 1178–86. 2012. doi:10.1093/carcin/bgs141. PMID 22467239. 
  33. ↑ 33.0 33.1 Norris, Joseph M.; Simpson, Benjamin S.; Parry, Marina A.; Allen, Clare; Ball, Rhys; Freeman, Alex; Kelly, Daniel; Kim, Hyung L. et al. (2020-07-01). "Genetic Landscape of Prostate Cancer Conspicuity on Multiparametric Magnetic Resonance Imaging: A Systematic Review and Bioinformatic Analysis" (in en). European Urology Open Science 20: 37–47. doi:10.1016/j.euros.2020.06.006. ISSN 2666-1683. PMID 33000006. 
  34. ↑ 34.0 34.1 "Anterior gradient 2 is expressed and secreted during the development of pancreatic cancer and promotes cancer cell survival". Cancer Res. 68 (19): 7811–8. October 2008. doi:10.1158/0008-5472.CAN-08-1320. PMID 18829536. 
  35. ↑ "Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies". Cancer Res. 63 (24): 8614–22. December 2003. PMID 14695172. 
  36. ↑ "hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan". Br. J. Cancer 88 (4): 579–85. February 2003. doi:10.1038/sj.bjc.6600740. PMID 12592373. 
  37. ↑ "A divergent substrate-binding loop within the pro-oncogenic protein anterior gradient-2 forms a docking site for Reptin". J. Mol. Biol. 404 (3): 418–38. 2010. doi:10.1016/j.jmb.2010.09.035. PMID 20888340. 

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