Stanniocalcins, STC1 and STC2 are glycoprotein hormones. They were originally identified in fish, where they regulate calcium and phosphate homeostasis. Human STC2 is a 33.3 kDa protein, known to form disulfide-linked homodimers. The amino acid sequence of STC2 is only 30% identical to STC1, but the glycosylation sites and cysteine residues are conserved. STC2 is phosphorylated by Casein kinase 2. STC2 is widely expressed with most abundant protein expression in brain, adrenal gland, kidney, prostate and small intestine. 1

STC2 function in hormone signaling is indicated by reports showing inhibition of ovarian progesterone biosynthesis and transactivation of androgen receptor.2,3 STC2 exhibits anti-apoptotic functions in cells subjected to endoplasmic reticulum and hypoxic stress by a mechanism involving inhibition of plasma membrane store-operated calcium entry.4,5 STC2 overexpression mice exhibit growth restriction, while knockout mice are larger than wild-type littermates.1 STC2 function in growth regulation was demonstrated by its ability to interact with PAPP-A, potentially inhibiting its proteolytic activity towards IGFBP-4 and causing reduced IGF signaling. 6,7,8 STC2-mediated PAPP-A inhibition was also reported to reduce atherosclerosis in hypercholesterolemic mice. 9

In breast cancer STC2 is induced by estrogen and STC2 expression levels correlate with levels of estrogen receptor. STC2 function in different cancers may involve regulation of cell proliferation, neoplastic transformation and endothelial invasion. STC2 also plays a role in epithelial-mesenchymal transition by activation of MAPK/ERK signaling in hypoxic ovarian cancer cells. STC2 is upregulated in several cancers including, gastric cancer, lung cancer, renal cell carcinoma, colorectal cancer, castration-resistant prostate cancer and cervical cancer.1 Serum STC2 levels may serve as a valuable research tool for diagnosis and prognosis of several cancers and growth defects.

References:

1. Yeung BH, Law AY, Wong CK. 2012. Evolution and roles of stanniocalcin. Mol Cell Endocrinol. 26;349(2):272-80.
2. Shin J, Sohn YC. 2014. Identification of Ran-binding protein M as a stanniocalcin 2 interacting protein and implications for androgen receptor activity. BMB Rep. 47(11):643-8.
3. Luo, C.W., Pisarska, M.D., Hsueh, A.J., 2005. Identification of a stanniocalcin paralog, stanniocalcin-2, in fish and the paracrine actions of stanniocalcin-2 in the mammalian ovary. Endocrinology 146, 469–476.
4. Ito, D., Walker, J.R., Thompson, C.S., Moroz, I., Lin, W., Veselits, M.L., Hakim, A.M.,Fienberg, A.A., Thinakaran, G., 2004. Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties. Mol. Cell Biol. 24, 9456–9469.
5. Zeiger, W., Ito, D., Swetlik, C., Oh-hora, M., Villereal, M.L., Thinakaran, G., 2011. Stanniocalcin 2 is a negative modulator of store-operated calcium entry. Mol.Cell Biol. 31, 3710–3722.
6. Jepsen MR, Kløverpris S, Bøtkjær JA, Wissing ML, Andersen CY, Oxvig C. 2016.The proteolytic activity of pregnancy-associated plasma protein-A is potentially regulated by stanniocalcin-1 and -2 during human ovarian follicle development. Hum Reprod. 31(4):866-74
7. Monget P, Oxvig C. 2016. PAPP-A and the IGF system. Ann Endocrinol (Paris). 77(2):90-6
8. Jepsen MR, Kløverpris S, Mikkelsen JH, Pedersen JH, Füchtbauer EM, Laursen LS, Oxvig C. 2015. Stanniocalcin-2 inhibits mammalian growth by proteolytic inhibition of the insulin-like growth factor axis. J Biol Chem 6;290(6):3430-9
9. Steffensen LB, Conover CA, Bjørklund MM, Ledet T, Bentzon JF, Oxvig C.2016. Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice. Atherosclerosis, 248:36-43
10. HHS Publication, 5th ed., 2007. Biosafety in Microbiological and Biomedical Laboratories. Available http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5
11. DHHS (NIOSH) Publication No. 78–127, August 1976. Current Intelligence Bulletin 13 – Explosive Azide Hazard. Available http:// www.cdc.gov/niosh.
12. Approved Guideline – Procedures for the Handling and Processing of Blood Specimens, H18-A3. 2004. Clinical and Laboratory Standards Institute.
13. Kricka L. Interferences in immunoassays – still a threat. Clin Chem 2000; 46: 1037–1038.

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Cediel G, Rueda F, Oxvig C, Oliveras T, Labata C, de Diego O, Ferrer M, Aranda-Nevado MC, Serra-Gregori J, Núñez J, García C, Bayes-Genis A. Prognostic value of the Stanniocalcin-2/PAPP-A/IGFBP-4 axis in ST-segment elevation myocardial infarction. Cardiovasc Diabetol. 2018 Apr 30;17(1):63. doi: 10.1186/s12933-018-0710-3.

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Frystyk J, Teran E, Gude MF, Bjerre M, Hjortebjerg R. Pregnancy-associated plasma proteins and Stanniocalcin-2 – Novel players controlling IGF-I physiology. Growth Horm IGF Res. 2020 Aug-Oct;53-54:101330. doi: 10.1016/j.ghir.2020.101330. Epub 2020 Jul 4. PMID: 32693362.

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Hjortebjerg R, Høgdall C, Hansen KH, Høgdall E, Frystyk J. The IGF–PAPP-A–Stanniocalcin axis in serum and ascites associates with prognosis in patients with ovarian cancer. Int J Mol Sci. 2024;25(2014):1-16. doi:10.3390/ijms25042014.

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Hjortebjerg R, Pedersen DA, Mengel-From J, Jørgensen LH, Christensen K, Frystyk J. Heritability and circulating concentrations of pregnancy-associated plasma protein-A and stanniocalcin-2 in elderly monozygotic and dizygotic twins. Front Endocrinol (Lausanne). 2023;14:1193742. doi:10.3389/fendo.2023.1193742.

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Hjortebjerg R, Rasmussen LM, Gude MF, Irmukhamedov A, Riber LP, Frystyk J, De Mey JGR. Local IGF Bioactivity Associates with High PAPP-A Activity in the Pericardial Cavity of Cardiovascular Disease Patients. J Clin Endocrinol Metab. 2020 Nov 1;105(11):dgaa617. doi: 10.1210/clinem/dgaa617. PMID: 32875328.

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Hjortebjerg R, Thomsen KL, Agnholt J, Frystyk J. The IGF system in patients with inflammatory bowel disease treated with prednisolone or infliximab: potential role of the stanniocalcin-2 / PAPP-A / IGFBP-4 axis. BMC Gastroenterol. 2019 Jun 3;19(1):83. doi: 10.1186/s12876-019-1000-6. PMID: 31159802; PMCID: PMC6547608.

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Martín-Rivada Á, Guerra Cantera S, Campillo-Calatayud A, Andrés-Esteban EM, Sánchez Holgado M, Martos-Moreno GÁ, Pozo J, Güemes M, Soriano-Guillén L, Pellicer A, Oxvig C, Frystyk J, Chowen JA, Barrios V, Argente J. Pappalysins and Stanniocalcin and Their Relationship With the Peripheral IGF Axis in Newborns and During Development. J Clin Endocrinol Metab. 2022 Sep 28;107(10):2912-2924. doi: 10.1210/clinem/dgac453. PMID: 35902207.

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Panagiotou G, Ghaly W, Upadhyay J, Pazaitou-Panayiotou K, Mantzoros CS. Serum Follistatin Is Increased in Thyroid Cancer and Is Associated With Adverse Tumor Characteristics in Humans. J Clin Endocrinol Metab. 2021 Apr 23;106(5):e2137-e2150. doi: 10.1210/clinem/dgab041. PMID: 33493282.

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Rodríguez-Lorenzo S, Francisco DMF, Vos R, van het Hof B, Rijnsburger M, Schroten H, et al. Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis. Acta Neuropathol Commun. 2020;8(35):1-13. doi:10.1186/s40478-020-00903-y.

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Vicente Barrios, Álvaro Martín-Rivada, Gabriel Á Martos-Moreno, Sandra Canelles, Francisca Moreno-Macián, Carmen De Mingo-Alemany, Maurizio Delvecchio, Roberta Pajno, Danilo Fintini, Julie A Chowen, Jesús Argente, Increased IGFBP Proteolysis, IGF-I Bioavailability, and Pappalysin Levels in Children With Prader-Willi Syndrome, The Journal of Clinical Endocrinology & Metabolism, Volume 109, Issue 9, September 2024, Pages e1776–e1786, https://doi.org/10.1210/clinem/dgad754

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