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Aydin AA, Yildirim S. Stanniocalcin-2 expression in glioblastoma - A novel prognostic biomarker: An observational study. Medicine (Baltimore) 2024; 103:e38913. [PMID: 38996177 PMCID: PMC11245224 DOI: 10.1097/md.0000000000038913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 06/21/2024] [Indexed: 07/14/2024] Open
Abstract
The objective of this study was to assess the prognostic relevance of Stanniocalcin-2 (STC2) expression, as determined via immunohistochemistry in tumor tissue, in a cohort of 83 patients diagnosed with glioblastoma who underwent maximal safe surgical resection followed by radiotherapy concurrent with adjuvant temozolomide. STC2 expression levels were categorized using a 3-tiered semiquantitative system: negative expression (level 0-), low expression (level 1+), and high expression (levels 2 + and 3+). Patients were categorized into 2 distinct groups according to their STC2 expression levels: negative STC2 (-/+) and positive STC2 (++/+++). The primary outcome measure was the relationship between STC2 expression and progression-free survival (PFS), with overall survival (OS) serving as the secondary endpoint. Kaplan-Meier survival analysis confirmed that patients exhibiting high STC2 expression had significantly shorter OS (8 vs 20 months, P < .001) and PFS (6 vs 18 months, P < .001) than those with low or negative STC2 expression. Multivariate analysis revealed that STC2 expression was an independent prognostic factor for both OS (hazard ratio: 0.4; 95% confidence interval: 0.2-0.8; P < .05) and PFS (hazard ratio: 0.3; 95% confidence interval: 0.2-0.4; P < .05) in patients with glioblastoma. Furthermore, elevated STC2 expression in GBM was correlated with several established aggressive clinicopathological characteristics, including advanced age (≥65 years), low ECOG PS (≥2), and isocitrate dehydrogenase mutation negativity. These findings underscore that heightened STC2 expression within the tumor tissue of GBM patients functions as an adverse prognostic marker, correlating with an elevated risk of progression and reduced OS. Therapeutic interventions targeting the AKT-mTOR, ERK1-2, and mitogen-activated protein kinase pathways as well as immune checkpoint inhibitors and vascular endothelial growth factor blockade, as well as potential forthcoming antibody-drug conjugates targeting the STC2 molecule, have the potential to broaden the scope of combined treatment strategies.
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Affiliation(s)
- Asim Armagan Aydin
- Department of Clinical Oncology, Health Science University Antalya Training and Research Hospital, Antalya, Turkey
| | - Senay Yildirim
- Department of Pathology, Health Science University Antalya Training and Research Hospital, Antalya, Turkey
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Li Y, Deng Y, He J. A novel prognostic index based on the analysis of glycolysis-related genes in idiopathic pulmonary fibrosis. Medicine (Baltimore) 2023; 102:e33330. [PMID: 36930085 PMCID: PMC10019186 DOI: 10.1097/md.0000000000033330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 01/20/2023] [Indexed: 03/18/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a lung disease that is both chronic and progressive and is characterized by glycolysis. However, glycolysis's function and its clinical significance in IPF are still not well understood. We accessed the Gene Expression Omnibus database to retrieve mRNA expression information for lung tissue and other samples. We identified genes associated with glycolysis that had differential expression levels between IPF and controls. In this work, we conducted a comprehensive bioinformatic analysis to systematically examine the glycolysis-associated genes with differential expression and subsequently investigated the possible prognostic significance of these genes. Additionally, the expression profiles of the associated prognostic genes were further investigated via quantitative real-time polymerase chain reaction in our cohort. In this investigation, we found that the expression of 16 genes involved in glycolysis was differentially expressed. Among them, 12 were upregulated and 4 were downregulated. We found that 3 glycolysis-related genes (stanniocalcin 2, transketolase like 1, artemin) might serve as hub genes for anticipating patient prognosis. The data from these genes were used to generate the prognostic models. The findings confirmed that high-risk IPF patients recorded a shorter overall survival relative to low-risk patients. This prognostic model yielded 1-, 2-, and 3-year survival rates of 0.666, 0.651, and 0.717, correspondingly, based on the area under the curve of the survival-dependent receiver operating characteristic. The GSE27957 and GSE70866 cohorts validated these findings, indicating the model has a good predictive performance. All 3 glycolysis-associated genes were validated to be expressed in our cohort. Finally, we used mRNA levels from 3 genes to produce a nomogram to quantitatively predict the prognosis of IPF individuals. As possible indicators for the prognosis of IPF, the glycolysis-related genes stanniocalcin 2, transketolase like 1, and artemin were shown to be promising candidate markers.
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Affiliation(s)
- Yu Li
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, PR China
| | - Yaju Deng
- Emergency Department, Guangxi District Maternal and Child Health Hospital, Nanning, Guangxi, PR China
| | - Jie He
- Clinical Medical College of Chengdu Medical College, Chengdu, Sichuan, PR China
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, PR China
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Liu YX, Ke Y, Qiu P, Gao J, Deng GP. LncRNA NEAT1 inhibits apoptosis and autophagy of ovarian granulosa cells through miR-654/STC2-mediated MAPK signaling pathway. Exp Cell Res 2023; 424:113473. [PMID: 36634743 DOI: 10.1016/j.yexcr.2023.113473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 01/03/2023] [Accepted: 01/08/2023] [Indexed: 01/11/2023]
Abstract
Long non-coding RNA (lncRNA) anomalies cause early ovarian failure. LncRNA nuclear enriched abundant transcript 1 (NEAT1) was down-regulated in premature ovarian failure (POF) mice and connected to the illness, however, the mechanism remained unclear. The levels of gene and protein were measured by using quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence. Follicle stimulating hormone (FSH), estradiol (E2), and luteinizing hormone (LH) levels were determined using enzyme-linked immunosorbent assay (ELISA). 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and flow cytometry were used to determine cell viability and apoptosis. The interaction of NEAT1, miR-654, and stanniocalcin-2 (STC2) was verified by dual-luciferase reporter assay or RNA binding protein immunoprecipitation (RIP) assays. The results showed NEAT1 and STC2 down-regulated, while miR-654 up-regulated in POF mice. Overexpression of NEAT1 reduced apoptosis and autophagy in cyclophosphamide (CTX)-treated ovarian granulosa cells (OGCs), and Bax, cleaved-caspase3, LC3B, LC3II/LC3I ratio were decreased and Bcl-2 and p62 were raised. NEAT1 suppressed miR-654 expression by directly targeting miR-654. The inhibition of NEAT1 overexpression on apoptosis and autophagy in OGCs was reversed by miR-654 mimics. STC2 was a target gene of miR-654, and miR-654 inhibitor reduced the apoptosis and autophagy by regulating the STC2/MAPK axis. To sum up, NEAT1 reduced miR-654 expression and modulated the STC2/MAPK pathway to decrease apoptosis and autophagy in POF, indicating a potential therapeutic target.
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Affiliation(s)
- Yu-Xi Liu
- Department of gynecology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510080, Guangdong Province, PR China; Guangzhou University of Chinese Medicine, Guangzhou 510080, Guangdong Province, PR China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, PR China; Department of Traditional Chinese Medicine and Gynecology, Shunde Women and Children's Hospital of Guangdong Medical University (Maternity & Child Healthcare Hospital of Shunde Foshan), Foshan 528000, Guangdong Province, PR China.
| | - Yan Ke
- Department of Gynecology, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen 518104, Guangdong Province, PR China
| | - Pin Qiu
- Department of gynecology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510080, Guangdong Province, PR China
| | - Jie Gao
- Department of gynecology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510080, Guangdong Province, PR China.
| | - Gao-Pi Deng
- Department of gynecology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510080, Guangdong Province, PR China.
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Karabulut Uzunçakmak S, Naldan ME, Dirican E, Kerget F, Halıcı Z. Preliminary investigation of gene expression levels of PAPP-A, STC-2, and HIF-1α in SARS-Cov-2 infected patients. Mol Biol Rep 2022; 49:8693-8699. [PMID: 35796937 PMCID: PMC9261127 DOI: 10.1007/s11033-022-07710-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 06/14/2022] [Indexed: 11/27/2022]
Abstract
Background Coronavirus-19 is still considered a pandemic that influences the world. Other molecular alterations should be clearer besides the increasing cytokine storm and pro-inflammatory molecules. Hypoxic conditions that induce HIF-1α lead to stimulate gene expression of STC-2 that targets PAPP-A expression. This study aimed to determine gene expression levels of PAPP-A, STC-2, and HIF-1α in COVID-19 infection. We also aimed to reveal the relationship of these genes with laboratory and clinical data of COVID-19 patients. Materials and Results We extracted RNA from peripheral blood samples of COVID-19(+) and COVID-19(−) individuals. The real-time PCR method was used to measure mRNA expression of PAPP-A, STC-2, and HIF-1α. Gene expression analysis was evaluated by the 2−ΔΔCt method. PAPP-A, STC-2, and HIF-1α mRNA expressions of severe patients were higher than healthy individuals (p = 0.0451, p = 0.4466, p < 0.0001, respectively). Correlation analysis of gene expression patterns of severe patients demonstrated a positive correlation between PAPP-A and STC-2 (p < 0.0001, r = 0.8638). Conclusion This is the first study that investigates the relation of PAPP-A, STC-2, and HIF-1α gene expression in patients with COVID-19 infection. Besides the routine laboratory findings, PAPP-A, STC-2, and HIF-1α mRNA expressions may be considered to patients’ prognosis as a sign of increased cytokines and pro-inflammatory molecules.
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Affiliation(s)
| | - Muhammet Emin Naldan
- Department of Anesthesia, Bilecik Seyh Edibali University, 11230, Bilecik, Turkey
| | - Ebubekir Dirican
- Health Services Vocational School, Bayburt University, 69000, Bayburt, Turkey
| | - Ferhan Kerget
- Department of Infectious and Clinical Microbiology Diseases, Erzurum Regional Education and Research Hospital, 25240, Erzurum, Turkey
| | - Zekai Halıcı
- Department of Pharmacology, Ataturk University, 25240, Erzurum, Turkey
- Clinical Research, Development and Design Application and Research Center, Ataturk University, 25240, Erzurum, Turkey
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Yun EJ, Kim D, Hsieh JT, Baek ST. Stanniocalcin 2 drives malignant transformation of human glioblastoma cells by targeting SNAI2 and Matrix Metalloproteinases. Cell Death Dis 2022; 8:308. [PMID: 35790735 PMCID: PMC9256701 DOI: 10.1038/s41420-022-01090-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/07/2022] [Accepted: 06/13/2022] [Indexed: 11/26/2022]
Abstract
Glioblastoma multiforme (GBM) is the most malignant brain tumor and is refractory to conventional therapies. Although previous studies have proposed that the interaction between gene mutations and the external environment leads to the occurrence of GBM, the pathogenesis of GBM is still unclear and much remains to be studied. Herein, we show an association between human glycoprotein stanniocalcin-2 (STC2) and aggressive GBM progression, and demonstrate the underlying mechanism. Elevated STC2 expression and secretion greatly increase GBM cell growth and invasive phenotypes. Mechanistically, both, conditioned media (CM) containing STC2 and recombinant STC2, can induce the transformation of GBM cells into more malignant phenotypes by upregulating the expression of the epithelial-mesenchymal transition transcription factor, snail family transcription repressor 2 (SNAI2) as well as matrix metalloproteinases (MMPs). Moreover, we further demonstrate that the oncogenic function of STC2 in GBM is mediated through the MAPK signaling pathway. Collectively, these results identify the mechanism of STC2 targeting SNAI2 and MMPs through the MAPK pathway in GBM, and provide insights into a potential therapeutic strategy for GBM.
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Ail D, Samardzija M, Chang ACM, Keck J, Reddel RR, Grimm C. Stanniocalcin2, but Not Stanniocalcin1, Responds to Hypoxia in a HIF1-Dependent Manner in the Retina. Front Neurosci 2022; 16:882559. [PMID: 35812222 PMCID: PMC9259883 DOI: 10.3389/fnins.2022.882559] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/02/2022] [Indexed: 11/17/2022] Open
Abstract
The quest for neuroprotective factors that can prevent or slow down the progression of retinal degeneration is still ongoing. Acute hypoxic stress has been shown to provide transient protection against subsequent damage in the retina. Stanniocalcins – STC1 and STC2 – are secreted glycoproteins that are hypoxia-regulated and were shown to be cytoprotective in various in vitro studies. Hence, we investigated the expression of stanniocalcins in the normal, degenerating and hypoxic retina. We show that the expression of Stc1 and Stc2 in the retina was detectable as early as postnatal day 10 and persisted during aging. Retinal expression of Stc2, but not Stc1, was induced in mice in an in vivo model of acute hypoxia and a genetic model of chronic hypoxia. Furthermore, we show that HIF1, not HIF2, is responsible for regulating Stc2 in cells with the molecular response to hypoxia activated due to the absence of von Hippel Lindau protein. Surprisingly, Stc2 was not normally expressed in photoreceptors but in the inner retina, as shown by laser capture microdissection and immunofluorescence data. The expression of both Stc1 and Stc2 remained unchanged in the degenerative retina with an almost complete loss of photoreceptors, confirming their expression in the inner retina. However, the absence of either Stc1 or Stc2 had no effect on retinal architecture, as was evident from retinal morphology of the respective knockout mice. Taken together our data provides evidence for the differential regulation of STC1 and STC2 in the retina and the prospect of investigating STC2 as a retinal neuroprotective factor.
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Affiliation(s)
- Divya Ail
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
- Lab for Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland
| | - Marijana Samardzija
- Lab for Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Andy C. M. Chang
- Faculty of Medicine and Health, Children’s Medical Research Institute, University of Sydney, Westmead, NSW, Australia
| | - Jadwiga Keck
- Lab for Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Roger R. Reddel
- Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland
| | - Christian Grimm
- Lab for Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
- *Correspondence: Christian Grimm,
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Stanniocalcin 2 (STC2): a universal tumour biomarker and a potential therapeutical target. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:161. [PMID: 35501821 PMCID: PMC9063168 DOI: 10.1186/s13046-022-02370-w] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/19/2022] [Indexed: 12/24/2022]
Abstract
Stanniocalcin 2 (STC2) is a glycoprotein which is expressed in a broad spectrum of tumour cells and tumour tissues derived from human breast, colorectum, stomach, esophagus, prostate, kidney, liver, bone, ovary, lung and so forth. The expression of STC2 is regulated at both transcriptional and post-transcriptional levels; particularly, STC2 is significantly stimulated under various stress conditions like ER stress, hypoxia and nutrient deprivation. Biologically, STC2 facilitates cells dealing with stress conditions and prevents apoptosis. Importantly, STC2 also promotes the development of acquired resistance to chemo- and radio- therapies. In addition, multiple groups have reported that STC2 overexpression promotes cell proliferation, migration and immune response. Therefore, the overexpression of STC2 is positively correlated with tumour growth, invasion, metastasis and patients' prognosis, highlighting its potential as a biomarker and a therapeutic target. This review focuses on discussing the regulation, biological functions and clinical importance of STC2 in human cancers. Future perspectives in this field will also be discussed.
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Li J, Zhang Z, Feng X, Shen Z, Sun J, Zhang X, Bu F, Xu M, Tan C, Wang Z. Stanniocalcin-2 promotes cell EMT and glycolysis via activating ITGB2/FAK/SOX6 signaling pathway in nasopharyngeal carcinoma. Cell Biol Toxicol 2022; 38:259-272. [PMID: 33797657 PMCID: PMC8986754 DOI: 10.1007/s10565-021-09600-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/03/2021] [Indexed: 12/18/2022]
Abstract
Stanniocalcin-2 (STC2) has been proved to regulate a variety of signaling pathways including cell growth, metastasis, and therapeutic resistance. However, the role of STC2 in the regulation of nasopharyngeal carcinoma (NPC) remains poorly understood. In this study, we investigated the regulatory function of STC2 on epithelial-mesenchymal transition (EMT) and glycolysis traits in NPC and revealed the underlying molecular mechanisms. We found that STC2 was highly expressed in primary nasopharyngeal carcinoma tissues and lymph node metastatic tissues. Silencing of STC2 inhibited cell proliferation, invasion, and glycolysis. Further analyses for the clinical samples demonstrated that STC2 expression was associated with the poor clinical progression. Moreover, we demonstrated the interaction of ITGB2 with STC2 and its involvement in STC2-mediated ITGB2/FAK/SOX6 axis. Collectively, our results provide new insights into understanding the regulatory mechanism of STC2 and suggest that the STC2/ITGB2/FAK/SOX6 signaling axis may be a potential therapeutic target for NPC.
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Affiliation(s)
- Jingquan Li
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
- Clinical Research Unit of Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Shanghai, 200071 China
| | - Zihao Zhang
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032 Anhui China
| | - Xu Feng
- Department of Pathology and Tissue Bank, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai, 200032 China
| | - Zhuqing Shen
- Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, 200031 China
| | - Ji Sun
- Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, 200031 China
| | - Xiuwen Zhang
- Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, 200031 China
| | - Fengjiao Bu
- Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, 200031 China
| | - Midie Xu
- Department of Pathology and Tissue Bank, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai, 200032 China
| | - Cong Tan
- Department of Pathology and Tissue Bank, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai, 200032 China
| | - Ziliang Wang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
- Clinical Research Unit of Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Shanghai, 200071 China
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Bishop A, Cartwright JE, Whitley GS. Stanniocalcin-1 in the female reproductive system and pregnancy. Hum Reprod Update 2021; 27:1098-1114. [PMID: 34432025 PMCID: PMC8542996 DOI: 10.1093/humupd/dmab028] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 06/15/2021] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Stanniocalcin-1 (STC-1) is a widely expressed glycoprotein hormone involved in a diverse spectrum of physiological and pathophysiological processes including angiogenesis, mineral homeostasis, cell proliferation, inflammation and apoptosis. Over the last 20 years, numerous studies have reported STC-1 expression within female reproductive tissues including the uterus, ovaries and placenta and implicated STC-1 in processes such as ovarian follicular development, blastocyst implantation, vascular remodelling in early pregnancy and placental development. Notably, dysregulation of STC-1 within reproductive tissues has been linked to the onset of severe reproductive disorders including endometriosis, polycystic ovary syndrome, poor trophoblast invasion and placental perfusion in early pregnancy. Furthermore, significant changes in tissue expression and in maternal systemic concentration take place throughout pregnancy and further substantiate the vital role of this protein in reproductive health and disease. OBJECTIVE AND RATIONALE Our aim is to provide a comprehensive overview of the existing literature, to summarise the expression profile and roles of STC-1 within the female reproductive system and its associated pathologies. We highlight the gaps in the current knowledge and suggest potential avenues for future research. SEARCH METHODS Relevant studies were identified through searching the PubMed database using the following search terms: ‘stanniocalcin-1’, ‘placenta’, ‘ovary’, ‘endometrium’, ‘pregnancy’, ‘reproduction’, ‘early gestation’. Only English language papers published between 1995 and 2020 were included. OUTCOMES This review provides compelling evidence of the vital function that STC-1 plays within the female reproductive system. The literature presented summarise the wide expression profile of STC-1 within female reproductive organs, as well as highlighting the putative roles of STC-1 in various functions in the reproductive system. Moreover, the observed link between altered STC-1 expression and the onset of various reproductive pathologies is presented, including those in pregnancy whose aetiology occurs in the first trimester. This summary emphasises the requirement for further studies on the mechanisms underlying the regulation of STC-1 expression and function. WIDER IMPLICATIONS STC-1 is a pleiotropic hormone involved in the regulation of a number of important biological functions needed to maintain female reproductive health. There is also growing evidence that dysregulation of STC-1 is implicated in common reproductive and obstetric disorders. Greater understanding of the physiology and biochemistry of STC-1 within the field may therefore identify possible targets for therapeutic intervention and/or diagnosis.
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Affiliation(s)
- Alexa Bishop
- Centre for Vascular Biology, Molecular and Clinical Sciences Research Institute, St George's, University of London, London, UK
| | - Judith E Cartwright
- Centre for Vascular Biology, Molecular and Clinical Sciences Research Institute, St George's, University of London, London, UK
| | - Guy S Whitley
- Centre for Vascular Biology, Molecular and Clinical Sciences Research Institute, St George's, University of London, London, UK
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Li S, Huang Q, Li D, Lv L, Li Y, Wu Z. The significance of Stanniocalcin 2 in malignancies and mechanisms. Bioengineered 2021; 12:7276-7285. [PMID: 34612765 PMCID: PMC8806499 DOI: 10.1080/21655979.2021.1977551] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Human stanniocalcin 2 (STC2) is an ortholog of fish stanniocalcins (STCs) and is widely expressed in various organs and tissues. The gene is localized on chromosome 5q33 or 5q35. STC2 has been implicated in glucose homeostasis and phosphorus metabolism. It is also reported to be implicated in various malignancies. STC2 was found to be implicated in breast cancer and gynecologic cancers, suggesting hormone-specific or -dependent activities in these malignancies. Moreover, it was reported to be involved in gastrointestinal tumors, including esophageal, gastric, colorectal, and liver cancers, and respiratory cancers, including laryngeal and lung cancers. It also influenced renal carcinoma and prostate cancer. Notably, as a secreted phosphoprotein, STC2 was detectable in serum and possessed promising predictive value in several malignancies. This review aims to improve the understanding of the role of STC2 in patient diagnosis and prognosis, and tumor development and progression, as well as the mechanisms involved.
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Affiliation(s)
- Shasha Li
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, China
| | - Qian Huang
- Department of Hepatobiliary Disease, Fuzong Clinical College, Fujian Medical University, Fuzhou, China
| | - Dongliang Li
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, China.,Department of Hepatobiliary Disease, Fuzong Clinical College, Fujian Medical University, Fuzhou, China
| | - Lizhi Lv
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, China.,Department of Hepatobiliary Disease, Fuzong Clinical College, Fujian Medical University, Fuzhou, China
| | - Yi Li
- Department of Oncology, 920th Hospital of Joint Logistics Support Force, Kunming, China
| | - Zhixian Wu
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, China.,Department of Hepatobiliary Disease, Fuzong Clinical College, Fujian Medical University, Fuzhou, China
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11
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Ni C, Yang S, Ji Y, Duan Y, Yang W, Yang X, Li M, Xie J, Zhang C, Lu Y, Lu H. Hsa_circ_0011385 knockdown represses cell proliferation in hepatocellular carcinoma. Cell Death Discov 2021; 7:270. [PMID: 34599150 PMCID: PMC8486831 DOI: 10.1038/s41420-021-00664-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 08/24/2021] [Accepted: 09/20/2021] [Indexed: 02/08/2023] Open
Abstract
Circular RNAs (circRNAs), continuous loops of single-stranded RNA, regulate gene expression during the development of various cancers. However, the function of circRNAs in hepatocellular carcinoma (HCC) is rarely discussed. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the mRNA levels of circ_0011385, miR-361-3p, and STC2 in 96 pairs of HCC tissues (tumor tissues and adjacent normal tissues), HCC cell lines, and L02 (human normal liver cell line) cells. The relationships between circ_0011385 expression and clinical features of HCC were evaluated. Functional experiments in vitro or in vivo were used to evaluate the biological function of circ_0011385. Bioinformatics analysis was performed to predict miRNAs and mRNAs sponged by circ_0011385. RNA immunoprecipitation (RIP) and dual-luciferase reporter gene assays were used to elucidate the interactions among circ_0011385, miR-361-3p, and STC2 (stanniocalcin 2). ChIP and dual-luciferase reporter gene assays were used to identify the upstream regulator of circ_0011385. High expression of circ_0011385 was observed in HCC tissues and cell lines and was significantly associated with tumor size, TNM stage, and prognosis. In addition, inhibition of circ_0011385 expression prevented the proliferation of HCC cells in vitro and in vivo. Circ_0011385 sponged miR-361-3p, thereby regulating the mRNA expression of STC2. In addition, the transcription of circ_0011385 was regulated by SP3. Circ_0011385 knockdown suppressed cell proliferation and tumor activity in HCC. Circ_0011385 may therefore serve as a new biomarker in the diagnosis and treatment of HCC.
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Affiliation(s)
- Chuangye Ni
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
| | - Shikun Yang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
| | - Yang Ji
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
| | - Yunfei Duan
- Department of Hepatobiliary Surgery, The First People's Hospital of Changzhou, The Third Hospital Affiliated to Soochow University, Changzhou, 213000, China
| | - Wenjie Yang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
| | - Xinchen Yang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
| | - Min Li
- Department of Hepatobiliary Surgery, The First People's Hospital of Changzhou, The Third Hospital Affiliated to Soochow University, Changzhou, 213000, China
| | - Jun Xie
- Department of Hepatobiliary Surgery, The First People's Hospital of Changzhou, The Third Hospital Affiliated to Soochow University, Changzhou, 213000, China
| | - Chuanyong Zhang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China.
| | - Yunjie Lu
- Department of Hepatobiliary Surgery, The First People's Hospital of Changzhou, The Third Hospital Affiliated to Soochow University, Changzhou, 213000, China.
| | - Hao Lu
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China.
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12
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Khal De Souza S, Sarapio E, Lopes Vogt E, Schein V, Bandeira Fabres R, Felipe Argenta Model J, Vieira Lima M, Santos Rocha D, Silveira Martins Da Silva R. Effects of stanniocalcin hormones on rat hepatic glucose homeostasis under fed and fasted conditions. Gen Comp Endocrinol 2021; 302:113661. [PMID: 33220302 DOI: 10.1016/j.ygcen.2020.113661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 10/16/2020] [Accepted: 11/12/2020] [Indexed: 10/22/2022]
Abstract
To test the hypothesis of conservation of stanniocalcin 1 and 2 (STC-1; STC-2) metabolic functions in vertebrates, we performed an in vitro study to determine if these hormones are implicated in regulation of the gluconeogenesis pathway, glycogen synthesis, and 14C-glucose conversion to 14CO2 in livers from fed and fasting rats (Rattus norvegicus). Stc1 and Stc2 gene expressions increased in the liver after fasting. STC-1 participated in the regulation of the hepatic gluconeogenesis pathway in rats when the precursor was 14C-lactate. STC-2 demonstrated variational signaling on rat hepatic gluconeogenesis activity and Pck1 gene expression, decreasing levels in the fed state when the substrate was 14C-alanine and increasing levels during fasting when the substrate was 14C-lactate. At the concentrations used in this study, STC-1 and STC-2 did not affect glycogen concentration and synthesis from 14C-glucose or 14C-glucose conversion to 14CO2 in the livers from fed or fasting rats. These findings highlight the role of stanniocalcins in the hepatic gluconeogenesis pathway in mammals and confirm the conservation of STC-1 and STC-2 metabolic functions in the vertebrates.
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Affiliation(s)
- Samir Khal De Souza
- Departament of Physiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
| | - Elaine Sarapio
- Departament of Physiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Everton Lopes Vogt
- Departament of Physiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Vanessa Schein
- Departament of Physiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Rafael Bandeira Fabres
- Departament of Physiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | | | - Matheus Vieira Lima
- Departament of Physiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Débora Santos Rocha
- Departament of Physiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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Li J, Yang Z, Huang S, Li D. BIRC7 and STC2 Expression Are Associated With Tumorigenesis and Poor Outcome in Extrahepatic Cholangiocarcinoma. Technol Cancer Res Treat 2020; 19:1533033820971676. [PMID: 33234031 PMCID: PMC7705185 DOI: 10.1177/1533033820971676] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background: Extrahepatic cholangiocarcinoma (EHCC) is a highly aggressive epithelial malignancy and has a poor prognosis for the insensitivity to therapies and difficulty in detection. Novel targets and biomarkers are urgently needed to develop for functional, diagnostic and prognostic application on EHCC. Methods: Immunohistochemical staining technique using the EnVision antibody complex was performed on the samples obtained from 100 EHCC, 30 peritumoral extrahepatic biliary tract (EHBT), 10 EHBT adenomas and 15 normal EHBT tissues. Results: The positive rates of BIRC7 and STC2 expression in tissues obtained from peritumoral EHBT, EHBT adenomas and normal EHBT were significantly lower than those in EHCC tissues. BIRC7 and STC2 proteins were expressed at significantly higher levels in patients with lymph node metastasis, invasion of adjacent tissues, and higher TNM stage (III and/or IV) and unable to undergo resection (biopsy only). Kaplan-Meier survival curves indicated that significantly decreased overall survival rate in patients with positive-BIRC7 or positive-STC2 expression compared with patients of negative-BIRC7 or negative-STC2 expression, respectively. Cox-proportional regression analysis demonstrated that positive-BIRC7 and positive-STC2 expression, along with poor differentiation of EHCC, tumor size >3 cm, lymph node metastasis, invasion of adjacent tissues and unable to undergo resection are independent prognostic factors of EHCC patients. Conclusions: The levels of BIRC7 and STC2 expression were correlated with clinicopathological characteristics of EHCC, and positive expression of BIRC7 and STC2 are associated with progression and poor clinical outcomes of EHCC. BIRC7 and STC2 might be a potential biomarker for EHCC in clinic.
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Affiliation(s)
- Jiequn Li
- Department of Liver Transplantation, 70566The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zhulin Yang
- Department of General Surgery, 70566The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shengfu Huang
- Department of General Surgery, 70566The Second Xiangya Hospital, Central South University, Changsha, China
| | - Daiqiang Li
- Department of Pathology, 70566The Second Xiangya Hospital, Central South University, Changsha, China
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14
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Wang T, Cao L, He S, Long K, Wang X, Yu H, Ma B, Xu X, Li W. Small RNA sequencing reveals a novel tsRNA-06018 playing an important role during adipogenic differentiation of hMSCs. J Cell Mol Med 2020; 24:12736-12749. [PMID: 32939933 PMCID: PMC7686998 DOI: 10.1111/jcmm.15858] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 07/28/2020] [Accepted: 08/21/2020] [Indexed: 12/17/2022] Open
Abstract
Transfer RNA-derived small RNAs (tsRNAs), a novel type of non-coding RNA derivative, are able to regulate a wide range of biological processes. What role these tsRNAs play in the regulation of human bone marrow mesenchymal stem cell (hMSCs) adipogenic differentiation remains uncertain. We induced the adipogenic differentiation of human bone marrow mesenchymal cells (hMSCs) and then performed small RNA transcriptomic sequencing, leading us to identify tsRNA-06018 as a target of interest based upon resultant the tsRNA expression profiles. When tsRNA-06018 was knocked down, this led to the inhibition of adipogenesis and a decrease in adipogenic marker expression. When STC2 was overexpressed, this impaired the adipogenic differentiation of these cells. We further used luciferase reporter assays to confirm that tsRNA-06018 directly binds the 3'-untranslated region (3'-UTR) of STC2. In addition, we determined that both knocking down tsRNA-06018 and overexpressing STC2 increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation within cells. We also assessed that the adipogenic differentiation of hMSCs in which tsRNA-06018 was knocked down was further enhanced upon the addition of the ERK1/2 inhibitor U0126 as compared tsRNA-06018 knockdown alone. Taken together, using small RNA sequencing we profiled tsRNAs in hMSCs during the process of adipogenesis, leading us to identify tsRNA-06018 as a novel regulator of this differentiation process. This tsRNA was able to regulate adipogenic differentiation by targeting STC2 via the ERK1/2 signalling pathway.
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Affiliation(s)
- Tao Wang
- Key Laboratory of System Bio‐medicine of Jiangxi ProvinceJiujiang UniversityJiujiangChina
| | - Lingling Cao
- Department of EndocrinologyJiujiang Hospital Affiliated to Nanchang UniversityJiujiangChina
| | - Shan He
- Key Laboratory of System Bio‐medicine of Jiangxi ProvinceJiujiang UniversityJiujiangChina
| | - Kai Long
- Key Laboratory of System Bio‐medicine of Jiangxi ProvinceJiujiang UniversityJiujiangChina
| | - Xinping Wang
- Key Laboratory of System Bio‐medicine of Jiangxi ProvinceJiujiang UniversityJiujiangChina
| | - Hui Yu
- Key Laboratory of System Bio‐medicine of Jiangxi ProvinceJiujiang UniversityJiujiangChina
| | - Baicheng Ma
- Key Laboratory of System Bio‐medicine of Jiangxi ProvinceJiujiang UniversityJiujiangChina
| | - Xiaoyuan Xu
- Key Laboratory of System Bio‐medicine of Jiangxi ProvinceJiujiang UniversityJiujiangChina
| | - Weidong Li
- Key Laboratory of System Bio‐medicine of Jiangxi ProvinceJiujiang UniversityJiujiangChina
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15
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Joshi AD. New Insights Into Physiological and Pathophysiological Functions of Stanniocalcin 2. Front Endocrinol (Lausanne) 2020; 11:172. [PMID: 32296395 PMCID: PMC7136389 DOI: 10.3389/fendo.2020.00172] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/10/2020] [Indexed: 12/14/2022] Open
Abstract
Stanniocalcin, a glycosylated peptide hormone, first discovered in a bony fish has originally been shown to play critical role in calcium and phosphate homeostasis. Two paralogs of stanniocalcin (STC1 and STC2) identified in mammals are widely expressed in variety of tissues. This review provides historical perspective on the discovery of fish and mammalian stanniocalcin, describes molecular regulation of STC2 gene, catalogs distribution as well as expression of STC2 in tissues, and provides key structural information known till date regarding mammalian STC2. Additionally, this mini review summarizes pivotal functions of STC2 in calcium and phosphate regulation, cytoprotection, cell development, and angiogenesis. Finally, STC2's role as a novel marker for human cancers has also been outlined. Reviewing these studies will provide an opportunity to understand STC2's structure, biological functions as well as key molecular pathways involving STC2, which will help us design innovative therapeutic interventions using this novel hormone.
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Affiliation(s)
- Aditya D. Joshi
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States
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16
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Hernandez Cordero AI, Gonzales NM, Parker CC, Sokolof G, Vandenbergh DJ, Cheng R, Abney M, Sko A, Douglas A, Palmer AA, Gregory JS, Lionikas A. Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2. Am J Hum Genet 2019; 105:1222-1236. [PMID: 31761296 PMCID: PMC6904802 DOI: 10.1016/j.ajhg.2019.10.014] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 10/28/2019] [Indexed: 12/11/2022] Open
Abstract
Muscle bulk in adult healthy humans is highly variable even after height, age, and sex are accounted for. Low muscle mass, due to fewer and/or smaller constituent muscle fibers, would exacerbate the impact of muscle loss occurring in aging or disease. Genetic variability substantially influences muscle mass differences, but causative genes remain largely unknown. In a genome-wide association study (GWAS) on appendicular lean mass (ALM) in a population of 85,750 middle-aged (aged 38-49 years) individuals from the UK Biobank (UKB), we found 182 loci associated with ALM (p < 5 × 10-8). We replicated associations for 78% of these loci (p < 5 × 10-8) with ALM in a population of 181,862 elderly (aged 60-74 years) individuals from UKB. We also conducted a GWAS on hindlimb skeletal muscle mass of 1,867 mice from an advanced intercross between two inbred strains (LG/J and SM/J); this GWAS identified 23 quantitative trait loci. Thirty-eight positional candidates distributed across five loci overlapped between the two species. In vitro studies of positional candidates confirmed CPNE1 and STC2 as modifiers of myogenesis. Collectively, these findings shed light on the genetics of muscle mass variability in humans and identify targets for the development of interventions for treatment of muscle loss. The overlapping results between humans and the mouse model GWAS point to shared genetic mechanisms across species.
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Affiliation(s)
- Ana I Hernandez Cordero
- School of Medicine, Medical Sciences, and Nutrition, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, UK AB24 3FX, UK
| | - Natalia M Gonzales
- Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
| | - Clarissa C Parker
- Department of Psychology, Middlebury College, Middlebury, VT 05753, USA; Program in Neuroscience, Middlebury College, Middlebury, VT, 05753, USA
| | - Greta Sokolof
- Department of Psychological and Brain Sciences, The University of Iowa, Iowa City, IA 52242, USA
| | - David J Vandenbergh
- Department of Biobehavioral Health, Penn State Institute for the Neurosciences, and Molecular, Cellular, and Integrative Sciences Program, Pennsylvania State University, University Park, PA 16802, USA
| | - Riyan Cheng
- Department of Health Sciences, University of California San Diego, La Jolla, CA 92093, USA
| | - Mark Abney
- Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
| | - Andrew Sko
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Alex Douglas
- Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 3FX, UK
| | - Abraham A Palmer
- Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Jennifer S Gregory
- School of Medicine, Medical Sciences, and Nutrition, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, UK AB24 3FX, UK
| | - Arimantas Lionikas
- School of Medicine, Medical Sciences, and Nutrition, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, UK AB24 3FX, UK.
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17
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Chen F, Zhang Z, Pu F. Role of stanniocalcin-1 in breast cancer. Oncol Lett 2019; 18:3946-3953. [PMID: 31579413 PMCID: PMC6757304 DOI: 10.3892/ol.2019.10777] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 07/16/2019] [Indexed: 12/28/2022] Open
Abstract
Breast cancer is a highly heterogeneous disease consisting of five disease subtypes with distinct histological characteristics, clinical behaviors and prognostic features. Stanniocalcin-1 (STC1) is a secreted glycoprotein hormone that has been demonstrated to regulate calcium and phosphate homeostasis. Mammalian STC1 is expressed in various tissues and is implicated in multiple physiological and pathophysiological processes. In addition, growing evidence has suggested that STC1 serves an oncogenic role in a number of different types of tumor. However, the role of STC1 in breast cancer is complex, considering that some studies have shown that it exerts an oncogenic role, whereas other studies have demonstrated the opposite. The aim of the present review article is to evaluate the currently available data on mammalian STC1 and discuss its potential roles in each subtype of breast cancer.
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Affiliation(s)
- Fengxia Chen
- Department of Medical Oncology, General Hospital of The Yangtze River Shipping, Wuhan, Hubei 430010, P.R. China.,Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Zhicai Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Feifei Pu
- Department of Orthopedics, Wuhan No. 1 Hospital, Wuhan Integrated Traditional Chinese Medicine and Western Medicine Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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STC2 Is a Potential Prognostic Biomarker for Pancreatic Cancer and Promotes Migration and Invasion by Inducing Epithelial-Mesenchymal Transition. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8042489. [PMID: 32258098 PMCID: PMC7099867 DOI: 10.1155/2019/8042489] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/11/2019] [Accepted: 06/20/2019] [Indexed: 01/20/2023]
Abstract
Aberrant expression of stanniocalcin 2 (STC2) is implicated in cancer development. STC2 acts as a tumor promoter to drive some cancers. However, its contribution to the development of pancreatic cancer remains unclear. This study showed that the expression of STC2 was significantly upregulated in pancreatic cancer tissues. Moreover, its expression was positively correlated with tumor size and lymph node metastasis and negatively correlated with 5-year survival rate of pancreatic cancer patients. Additionally, the expression levels of STC2 were a novel biomarker for predicting overall survival rate after surgery. Furthermore, overexpression of STC2 could promote the proliferation, migration, and invasion of pancreatic cancer cell lines, while knocking down of STC2 led to antiproliferation and antimetastasis activities. Further mechanistic investigations revealed that the expression of STC2 could significantly promote the epithelial-mesenchymal transition (EMT) in pancreatic cancer cells. These data indicated that the overexpression of STC2 in pancreatic cancer contributes to the metastasis through the promotion of EMT, suggesting that STC2 is a potential prognostic biomarker and therapeutic target for pancreatic cancer.
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19
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He H, Qie S, Guo Q, Chen S, Zou C, Lu T, Su Y, Zong J, Xu H, He D, Xu Y, Chen B, Pan J, Sang N, Lin S. Stanniocalcin 2 (STC2) expression promotes post-radiation survival, migration and invasion of nasopharyngeal carcinoma cells. Cancer Manag Res 2019; 11:6411-6424. [PMID: 31372045 PMCID: PMC6636319 DOI: 10.2147/cmar.s197607] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 06/06/2019] [Indexed: 12/26/2022] Open
Abstract
Background: Stanniocalcin 2 (STC2) expression is upregulated under multiple stress conditions including hypoxia, nutrient starvation and radiation. Overexpression of STC2 correlates with tumor progression and poor prognosis. Purpose: We previously demonstrated that overexpression of STC2 in nasopharyngeal carcinomas (NPC) positively correlates with radiation resistance and tumor metastasis, two major clinical obstacles to the improvement of NPC management. However, it remains elusive whether STC2 expression is a critical contributing factor for post-radiation survival and metastasis of NPC cells. Materials and methods: Using the radiation resistant CNE2 cell line as a model, we examined the importance of STC2 expression for post-radiation survival, migration and invasion. Here, we report the establishment of STC2 knockout lines (CNE2-STC2-KO) using the CRISPR/Cas9-based genome editing technique. Results: Compared with the parental line, STC2-KO cells showed similar proliferation and morphology in normal culture conditions, and loss of STC2 did not compromise the cell tumorigenicity in nude mice model. However, STC2-KO lines demonstrated increased sensitivity to X-radiation under either normoxic or hypoxic conditions. Particularly, upon X-radiation, parental CNE2 cells only slightly whereas STC2-KO cells remarkably decreased the migration and invasion ability. Cell cycle analysis revealed that loss of STC2 accumulated cells in G1 and G2/M phases but decreased S-population. Conclusion: These data indicate that the expression of STC2, which can be stimulated by metabolic or therapeutic stresses, is one important factor to promote survival and metastasis of post-radiation NPC cells. Therefore, targeting STC2 or relative downstream pathways may provide novel strategies to overcome radiation resistance and metastasis of NPC.
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Affiliation(s)
- Huocong He
- Department of Radiation Biology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People's Republic of China
| | - Shuo Qie
- Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA 19104, USA.,Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Qiaojuan Guo
- Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People's Republic of China
| | - Shuyang Chen
- Department of Biology, Drexel University College of Arts & Sciences, Philadelphia, PA 19104, USA.,Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Changyan Zou
- Department of Radiation Biology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People's Republic of China
| | - Tianzhu Lu
- Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People's Republic of China
| | - Ying Su
- Department of Radiation Biology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People's Republic of China
| | - Jingfeng Zong
- Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People's Republic of China
| | - Hanchuan Xu
- Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People's Republic of China
| | - Dan He
- Department of Biology, Drexel University College of Arts & Sciences, Philadelphia, PA 19104, USA
| | - Yun Xu
- Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People's Republic of China
| | - Bijuan Chen
- Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People's Republic of China
| | - Jianji Pan
- Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People's Republic of China
| | - Nianli Sang
- Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA 19104, USA.,Department of Biology, Drexel University College of Arts & Sciences, Philadelphia, PA 19104, USA
| | - Shaojun Lin
- Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People's Republic of China
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20
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Li JB, Liu ZX, Zhang R, Ma SP, Lin T, Li YX, Yang SH, Zhang WC, Wang YP. Sp1 contributes to overexpression of stanniocalcin 2 through regulation of promoter activity in colon adenocarcinoma. World J Gastroenterol 2019; 25:2776-2787. [PMID: 31236000 PMCID: PMC6580349 DOI: 10.3748/wjg.v25.i22.2776] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/22/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Aberrant expression of stanniocalcin 2 (STC2) is implicated in colon adenocarcinoma (COAD). A previous study identified that STC2 functions as a tumor promoter to drive development of some cancers, but the role of its overexpression in the development of COAD remains unclear. AIM To evaluate the regulation mechanism of STC2 overexpression in COAD. METHODS The expression of STC2 in COAD was assessed by TCGA COAD database and GEO (GSE50760). Methylation level of the STC2 promoter was evaluated with beta value in UALCAN platform, and the correlation between STC2 expression and survival rate was investigated with TCGA COAD. Transcription binding site prediction was conducted by TRANSFAC and LASAGNA, and a luciferase reporter system was used to identify STC2 promoter activity in several cell lines, including HEK293T, NCM460, HT29, SW480, and HCT116. Western blotting was performed to evaluate the role of Sp1 on the expression of STC2. RESULTS The central finding of this work is that STC2 is overexpressed in COAD tissues and positively correlated with poor prognosis. Importantly, the binding site of the transcription factor Sp1 is widely located in the promoter region of STC2. A luciferase reporter system was successfully constructed to analyze the transcription activity of STC2, and knocking down the expression of Sp1 significantly inhibited the transcription activity of STC2. Furthermore, inhibition of Sp1 remarkably decreased protein levels of STC2. CONCLUSION Our data provide evidence that the transcription factor Sp1 is essential for the overexpression of STC2 in COAD through activation of promoter activity. Taken together, our finding provides new insights into the mechanism of oncogenic function of COAD by STC2.
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Affiliation(s)
- Ji-Bin Li
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning Province, China
| | - Zhe-Xian Liu
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning Province, China
| | - Rui Zhang
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning Province, China
| | - Si-Ping Ma
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning Province, China
| | - Tao Lin
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning Province, China
| | - Yan-Xi Li
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning Province, China
| | - Shi-Hua Yang
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning Province, China
- China Medical University, Shenyang 110000, Liaoning Province, China
| | - Wan-Chuan Zhang
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning Province, China
- China Medical University, Shenyang 110000, Liaoning Province, China
| | - Yong-Peng Wang
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning Province, China
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21
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Coulson-Gilmer C, Humphries MP, Sundara Rajan S, Droop A, Jackson S, Condon A, Cserni G, Jordan LB, Jones LJ, Kanthan R, Di Benedetto A, Mottolese M, Provenzano E, Kulka J, Shaaban AM, Hanby AM, Speirs V. Stanniocalcin 2 expression is associated with a favourable outcome in male breast cancer. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2018; 4:241-249. [PMID: 29956502 PMCID: PMC6174618 DOI: 10.1002/cjp2.106] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/30/2018] [Accepted: 06/25/2018] [Indexed: 11/11/2022]
Abstract
Breast cancer can occur in either gender; however, it is rare in men, accounting for <1% of diagnosed cases. In a previous transcriptomic screen of male breast cancer (MBC) and female breast cancer (FBC) occurrences, we observed that Stanniocalcin 2 (STC2) was overexpressed in the former. The aim of this study was to confirm the expression of STC2 in MBC and to investigate whether this had an impact on patient prognosis. Following an earlier transcriptomic screen, STC2 gene expression was confirmed by RT‐qPCR in matched MBC and FBC samples as well as in tumour‐associated fibroblasts derived from each gender. Subsequently, STC2 protein expression was examined immunohistochemically in tissue microarrays containing 477 MBC cases. Cumulative survival probabilities were calculated using the Kaplan–Meier method and multivariate survival analysis was performed using the Cox hazard model. Gender‐specific STC2 gene expression showed a 5.6‐fold upregulation of STC2 transcripts in MBC, also supported by data deposited in Oncomine™. STC2 protein expression was a positive prognostic factor for disease‐free survival (DFS; Log‐rank; total p = 0.035, HR = 0.49; tumour cells p = 0.017, HR = 0.44; stroma p = 0.030, HR = 0.48) but had no significant impact on overall survival (Log‐rank; total p = 0.23, HR = 0.71; tumour cells p = 0.069, HR = 0.59; stroma p = 0.650, HR = 0.87). Importantly, multivariate analysis adjusted for patient age at diagnosis, node staging, tumour size, ER, and PR status revealed that total STC2 expression as well as expression in tumour cells was an independent prognostic factor for DFS (Cox regression; p = 0.018, HR = 0.983; p = 0.015, HR = 0.984, respectively). In conclusion, STC2 expression is abundant in MBC where it is an independent prognostic factor for DFS.
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Affiliation(s)
| | - Matthew P Humphries
- Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK
| | | | - Alastair Droop
- MRC Medical Bioinformatics Centre, University of Leeds, Leeds, UK
| | - Sharon Jackson
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - Alexandra Condon
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - Gabor Cserni
- Department of Pathology, Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary
| | | | | | - Rani Kanthan
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Canada
| | - Anna Di Benedetto
- Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy
| | | | - Elena Provenzano
- Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK
| | - Janina Kulka
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Abeer M Shaaban
- Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham and University of Birmingham, Birmingham, UK
| | - Andrew M Hanby
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - Valerie Speirs
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
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Jiao Y, Zhao J, Shi G, Liu X, Xiong X, Li X, Zhang H, Ma Q, Lu Y. Stanniocalcin2 acts as an anorectic factor through activation of STAT3 pathway. Oncotarget 2017; 8:91067-91075. [PMID: 29207625 PMCID: PMC5710906 DOI: 10.18632/oncotarget.19412] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 07/12/2017] [Indexed: 11/25/2022] Open
Abstract
The regulation of food intake and body weight has been hotly investigated. In the present study, we show that stanniocalcin2 (STC2), a cytokine ubiquitously expressed and especially upregulated in many types of human cancers, has a regulatory role in food intake and weight loss. Systemic treatment of C57BL/6 mice with recombinant STC2 protein resulted in decreased food intake and body weight, whereas energy expenditure was not affected. Similarly, STC2 treatment also induced anorexia in hyperphagic leptin-deficient mice, leading to a significant reduction in body weight and improvement of blood glucose levels. Furthermore, intracerebroventricular administration of STC2 to mice led to an acute decrease in food intake, which was mediated, at least in part, by activation of STAT3 pathway. Taken together, our results revealed the importance of STC2 in the regulation of feeding behavior as well as body weight.
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Affiliation(s)
- Yang Jiao
- Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jiejie Zhao
- Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Guojun Shi
- Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xing Liu
- Department of Endocrinology, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xuelian Xiong
- Department of Endocrinology, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiaoying Li
- Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.,Department of Endocrinology, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Huijie Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Qinyun Ma
- Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yan Lu
- Department of Endocrinology, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Zhou J, Li Y, Yang L, Wu Y, Zhou Y, Cui Y, Yang G, Hong Y. Stanniocalcin 2 improved osteoblast differentiation via phosphorylation of ERK. Mol Med Rep 2016; 14:5653-5659. [DOI: 10.3892/mmr.2016.5951] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 10/14/2016] [Indexed: 11/06/2022] Open
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Transcriptional regulation of 5′-flanking regions of stanniocalcin genes by estrogen receptor and estrogen receptor-related receptor. Genes Genomics 2016. [DOI: 10.1007/s13258-016-0386-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Wang Y, Gao Y, Cheng H, Yang G, Tan W. Stanniocalcin 2 promotes cell proliferation and cisplatin resistance in cervical cancer. Biochem Biophys Res Commun 2015; 466:362-8. [PMID: 26361149 DOI: 10.1016/j.bbrc.2015.09.029] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 09/05/2015] [Indexed: 12/14/2022]
Abstract
Cervical cancer is one of the most common carcinomas in the female reproductive system. Treatment of cervical cancer involves surgical removal and chemotherapy. Resistance to platinum-based chemotherapy drugs including cisplatin has increasingly become an important problem in the treatment of cervical cancer patients. We found in this study that stanniocalcin 2 (STC2) expression was upregulated in both cervical cancer tissues and cell lines. The levels of STC2 expression in cervical cancer cell lines were positively correlated with the rate of cell proliferation. Furthermore, in cisplatin resistant cervical cancer cells, the levels of STC2 expression were significantly elevated. Modulation of STC2 expression by siRNA or overexpression in cisplatin resistant cells resulted in altered cell survival, apoptosis, and cisplatin resistance. Finally, we found that there was significant difference in the activity of the MAPK signaling pathway between cisplatin sensitive and resistant cervical cancer cells, and that STC2 could regulate the activity of the MAPK signaling pathway.
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Affiliation(s)
- Yuxia Wang
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Ying Gao
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Hairong Cheng
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Guichun Yang
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China
| | - Wenhua Tan
- Department of Gynecology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150086, China.
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Kløverpris S, Mikkelsen JH, Pedersen JH, Jepsen MR, Laursen LS, Petersen SV, Oxvig C. Stanniocalcin-1 Potently Inhibits the Proteolytic Activity of the Metalloproteinase Pregnancy-associated Plasma Protein-A. J Biol Chem 2015. [PMID: 26195635 DOI: 10.1074/jbc.m115.650143] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Stanniocalcin-1 (STC1) is a disulfide-bound homodimeric glycoprotein, first identified as a hypocalcemic hormone important for maintaining calcium homeostasis in teleost fish. STC1 was later found to be widely expressed in mammals, although it is not believed to function in systemic calcium regulation in these species. Several physiological functions of STC1 have been reported, although many molecular details are still lacking. We here demonstrate that STC1 is an inhibitor of the metzincin metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A), which modulates insulin-like growth factor (IGF) signaling through proteolytic cleavage of IGF-binding proteins (IGFBPs). STC1 potently (Ki = 68 pm) inhibits PAPP-A cleavage of IGFBP-4, and we show in a cell-based assay that STC1 effectively antagonizes PAPP-A-mediated type 1 IGF receptor (IGF1R) phosphorylation. It has recently been found that the homologous STC2 inhibits PAPP-A proteolytic activity, and that this depends on the formation of a covalent complex between the inhibitor and the proteinase, mediated by Cys-120 of STC2. We find that STC1 is unable to bind covalently to PAPP-A, in agreement with the absence of a corresponding cysteine residue. It rather binds to PAPP-A with high affinity (KD = 75 pm). We further demonstrate that both STC1 and STC2 show inhibitory activity toward PAPP-A2, but not selected serine proteinases and metalloproteinases. We therefore conclude that the STCs are proteinase inhibitors, probably restricted in specificity to the pappalysin family of metzincin metalloproteinases. Our data are the first to identify STC1 as a proteinase inhibitor, suggesting a previously unrecognized function of STC1 in the IGF system.
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Affiliation(s)
| | | | | | | | | | - Steen V Petersen
- the Department of Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark
| | - Claus Oxvig
- From the Department of Molecular Biology and Genetics and
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Hayase S, Sasaki Y, Matsubara T, Seo D, Miyakoshi M, Murata T, Ozaki T, Kakudo K, Kumamoto K, Ylaya K, Cheng SY, Thorgeirsson SS, Hewitt SM, Ward JM, Kimura S. Expression of stanniocalcin 1 in thyroid side population cells and thyroid cancer cells. Thyroid 2015; 25:425-36. [PMID: 25647164 PMCID: PMC4390205 DOI: 10.1089/thy.2014.0464] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Mouse thyroid side population (SP) cells consist of a minor population of mouse thyroid cells that may have multipotent thyroid stem cell characteristics. However the nature of thyroid SP cells remains elusive, particularly in relation to thyroid cancer. Stanniocalcin (STC) 1 and 2 are secreted glycoproteins known to regulate serum calcium and phosphate homeostasis. In recent years, the relationship of STC1/2 expression to cancer has been described in various tissues. METHOD Microarray analysis was carried out to determine genes up- and down-regulated in thyroid SP cells as compared with non-SP cells. Among genes up-regulated, stanniocalcin 1 (STC1) was chosen for study because of its expression in various thyroid cells by Western blotting and immunohistochemistry. RESULTS Gene expression analysis revealed that genes known to be highly expressed in cancer cells and/or involved in cancer invasion/metastasis were markedly up-regulated in SP cells from both intact as well as partial thyroidectomized thyroids. Among these genes, expression of STC1 was found in five human thyroid carcinoma-derived cell lines as revealed by analysis of mRNA and protein, and its expression was inversely correlated with the differentiation status of the cells. Immunohistochemical analysis demonstrated higher expression of STC1 in the thyroid tumor cell line and thyroid tumor tissues from humans and mice. CONCLUSION These results suggest that SP cells contain a population of cells that express genes also highly expressed in cancer cells including Stc1, which warrants further study on the role of SP cells and/or STC1 expression in thyroid cancer.
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Affiliation(s)
- Suguru Hayase
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yoshihito Sasaki
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Kuwana East Medical Center, Kuwana, Mie, Japan
| | - Tsutomu Matsubara
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Daekwan Seo
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Bioinformatics Core, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Masaaki Miyakoshi
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Department of Oral Pathobiological Science, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Tsubasa Murata
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Dental and Oral Surgery, Tomakomai City Hospital, Tomakomai, Hokkaido, Japan
| | - Takashi Ozaki
- Department of Pathology, Wakayama Medical University, Wakayama City, Japan
| | - Kennichi Kakudo
- Department of Pathology, Nara Hospital Kinki University Faculty of Medicine, Ikoma, Japan
| | - Kensuke Kumamoto
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kris Ylaya
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sheue-yann Cheng
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Snorri S. Thorgeirsson
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stephen M. Hewitt
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | | | - Shioko Kimura
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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VandeVoort CA, Grimsrud KN, Midic U, Mtango N, Latham KE. Transgenerational effects of binge drinking in a primate model: implications for human health. Fertil Steril 2015; 103:560-9. [PMID: 25492684 PMCID: PMC4314404 DOI: 10.1016/j.fertnstert.2014.10.051] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 10/31/2014] [Accepted: 10/31/2014] [Indexed: 01/23/2023]
Abstract
OBJECTIVE To determine if binge ethanol consumption before ovulation affects oocyte quality, gene expression, and subsequent embryo development. DESIGN Binge levels of ethanol were given twice weekly for 6 months, followed by a standard in vitro fertilization cycle and subsequent natural mating. SETTING National primate research center. ANIMAL(S) Adult female rhesus monkeys. INTERVENTION(S) Binge levels of ethanol, given twice weekly for 6 months before a standard in vitro fertilization cycle with or without embryo culture. With in vivo development, ethanol treatment continued until pregnancy was identified. MAIN OUTCOME MEASURE(S) Oocyte and cumulus/granulosa cell gene expression, embryo development to blastocyst, and pregnancy rate. RESULT(S) Embryo development in vitro was reduced; changes were found in oocyte and cumulus cell gene expression; and spontaneous abortion during very early gestation increased. CONCLUSION(S) This study provides evidence that binge drinking can affect the developmental potential of oocytes even after alcohol consumption has ceased.
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Affiliation(s)
- Catherine A VandeVoort
- California National Primate Research Center, University of California, Davis, California; Department of Obstetrics and Gynecology, University of California, Davis, California.
| | - Kristin N Grimsrud
- California National Primate Research Center, University of California, Davis, California
| | - Uros Midic
- The Fels Institute for Cancer Research & Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania; Department of Animal Science, Michigan State University, East Lansing, Michigan
| | - Namdori Mtango
- The Fels Institute for Cancer Research & Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Keith E Latham
- The Fels Institute for Cancer Research & Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania; Department of Animal Science, Michigan State University, East Lansing, Michigan; Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania
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Clinical utility of measuring expression levels of Stanniocalcin 2 in patients with colorectal cancer. Med Oncol 2014; 31:237. [PMID: 25234931 DOI: 10.1007/s12032-014-0237-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Accepted: 09/04/2014] [Indexed: 12/11/2022]
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Abstract
Although most modern dog breeds are less than 200 years old, the symbiosis between man and dog is ancient. Since prehistoric times, repeated selection events have transformed the wolf into man's guardians, laborers, athletes, and companions. The rapid transformation from pack predator to loyal companion is a feat that is arguably unique among domesticated animals. How this transformation came to pass remained a biological mystery until recently: Within the past decade, the deployment of genomic approaches to study population structure, detect signatures of selection, and identify genetic variants that underlie canine phenotypes is ushering into focus novel biological mechanisms that make dogs remarkable. Ironically, the very practices responsible for breed formation also spurned morbidity; today, many diseases are correlated with breed identity. In this review, we discuss man's best friend in the context of a genetic model to understand paradigms of heritable phenotypes, both desirable and disadvantageous.
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Affiliation(s)
- Jeffrey J Schoenebeck
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland 20892;
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31
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Wang H, Wu K, Sun Y, Li Y, Wu M, Qiao Q, Wei Y, Han ZG, Cai B. STC2 is upregulated in hepatocellular carcinoma and promotes cell proliferation and migration in vitro. BMB Rep 2013. [PMID: 23187001 PMCID: PMC4133800 DOI: 10.5483/bmbrep.2012.45.11.086] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The human glycoprotein, stanniocalcin 2 (STC2) plays multiple roles in several tumor types, however, its function and clinical significance in hepatocellular carcinoma (HCC) remain unclear. In this study, we detected STC2 expression by quantitative real-time PCR and found STC2 was upregulated in HCC tissues, correlated with tumor size and multiplicity of HCC. Ectopic expression of STC2 markedly promoted HCC cell proliferation and colony formation, while silencing of endogenous STC2 resulted in a reduced cell growth by cell cycle delay in G0/G1 phase. Western blot analysis demonstrated that STC2 could regulate the expression of cyclin D1 and activate extracellular signal-regulated kinase 1/2 (ERK1/2) in a dominant-positive manner. Transwell chamber assay also indicated altered patterns of STC2 expression had an important effect on cell migration. Our findings suggest that STC2 functions as a potential oncoprotein in the development and progression of HCC as well as a promising molecular target for HCC therapy.
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Affiliation(s)
- Haixiao Wang
- Department of Hepatobiliary Surgery, Wuxi People's Hospital of Nanjing Medical University, Jiangsu, China
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Zaidi D, Turner JK, Durst MA, Wagner GF. Stanniocalcin-1 co-localizes with insulin in the pancreatic islets. ISRN ENDOCRINOLOGY 2012; 2012:834359. [PMID: 23119181 PMCID: PMC3479999 DOI: 10.5402/2012/834359] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Accepted: 09/09/2012] [Indexed: 12/18/2022]
Abstract
The polypeptide hormone stanniocalcin-1 (STC-1) is widely expressed in mammals and signals both locally and systemically. In many tissues STC-1 ligand is sequestered by target cell organelles (mitochondria, nuclei, and cholesterol lipid droplets) to exert diverse biological effects. Most notably, STC-1 serves as an uncoupler of oxidative phosphorylation in liver, muscle, and kidney mitochondria. The present paper describes the identification of STC-1 receptors in mouse pancreatic β cells and the discovery that the ligand co-localizes with insulin in pancreatic β cells. In situ hybridization (ISH) analysis subsequently revealed that pancreatic β cells were the source of the ligand. Intriguingly however, all ISH signal was localized over putative islet cell nuclei as opposed to the cell cytoplasm. Real-time qPCR and agarose gel electrophoresis revealed that the STC-1 amplicon generated from islet cell total RNA was the same size as that from kidney. However, relative levels of STC-1 gene expression were >100-fold lower in islets than those in kidney tissue. Collectively, these findings are indicative of a local STC-1 signalling pathway in pancreatic β cells. The role of STC-1 in this context remains to be established, but it could very well entail the regulation of β cell mitochondria membrane potential which is an integral aspect of regulated insulin release. Interestingly, STC-1 immunoreactivity was not evident in embryonic pancreatic islets, suggesting that ligand synthesis may only commence postnatally.
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Affiliation(s)
- Deenaz Zaidi
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada N6A 5C1
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Jiang J, Westberg JA, Andersson LC. Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein. Biochem Biophys Res Commun 2012; 421:274-9. [PMID: 22503972 DOI: 10.1016/j.bbrc.2012.03.151] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Accepted: 03/30/2012] [Indexed: 11/25/2022]
Abstract
Stanniocalcin 2 (STC2) is a homolog of stanniocalcin 1, a 56kD glycoprotein hormone that originally was found to confer calcitonin-like activity in fish. Human STC2 is expressed in various tissues such as kidney, spleen, heart, and pancreas. STC2 has been demonstrated to be induced by different kinds of stress and display cytoprotective activity, but the molecular mechanism is poorly understood. Heme oxygenase 1 (HO1) degrades heme to biliverdin, carbon monoxide and free iron, and is a stress-responsive protein. Using yeast two-hybrid screening we identified HO1 as a binding partner of STC2. The interaction was validated by in vivo co-immunoprecipitation and immunofluorescence. The binding site for HO1 was located to amino acids 181-200 of STC2. We also found that STC2 binds hemin via a consensus heme regulatory motif. Moreover, STC2 expression was induced by heat shock in HEK293 cells. Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme.
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Affiliation(s)
- Ji Jiang
- Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, PO Box 21, Haartmaninkatu 3, FI-00014 Helsinki, Finland.
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Takei Y, Yamamoto H, Sato T, Otani A, Kozai M, Masuda M, Taketani Y, Muto-Sato K, Lanske B, Takeda E. Stanniocalcin 2 is associated with ectopic calcification in α-klotho mutant mice and inhibits hyperphosphatemia-induced calcification in aortic vascular smooth muscle cells. Bone 2012; 50:998-1005. [PMID: 22285620 DOI: 10.1016/j.bone.2012.01.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2011] [Revised: 01/04/2012] [Accepted: 01/11/2012] [Indexed: 10/14/2022]
Abstract
Ectopic calcification of soft tissues can have severe clinical consequences especially when localized to vital organs such as heart, arteries and kidneys. Mammalian stanniocalcin (STC) 1 and 2 are glycoprotein hormones identified as calcium/phosphate-regulating hormones. The mRNA of STCs is upregulated in the kidney of α-klotho mutant (kl/kl) mice, which have hypercalcemia, hyperphosphatemia and hypervitaminosis D and exhibit a short life span, osteopenia and ectopic calcification. In the present study, we investigated the distribution and localization of STCs in kl/kl mice. Quantitative RT-PCR revealed that renal mRNA expression of STC2 was increased in both kl/kl mice and fibroblast growth factor 23 (Fgf23)-null mice compared with wild type mice. Interestingly, STC2 protein was focally localized with the calcified lesions of renal arterioles, renal tubular cells, heart and aorta in kl/kl mice. In vitro analysis of rat aortic vascular smooth muscle (A-10) cells showed that inorganic phosphate (Pi) stimulation significantly increased STC2 mRNA levels as well as that of osteocalcin, osteopontin and the type III sodium-dependent phosphate co-transporter (PiT-1), and induced STC2 secretion. Interestingly, the knockdown with a small interfering RNA or the over-expression of STC2 showed acceleration and inhibition of Pi-induced calcification in A-10 cells, respectively. These results suggest that the up-regulation of STC2 gene expression resulting from abnormal α-klotho-Fgf23 signaling may contribute to limitation of ectopic calcification and thus STC2 represents a novel target gene for cardio-renal syndrome.
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Affiliation(s)
- Yuichiro Takei
- Department of Clinical Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto-cho 3, Tokushima 770-8503, Japan
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Yeung BHY, Law AYS, Wong CKC. Evolution and roles of stanniocalcin. Mol Cell Endocrinol 2012; 349:272-80. [PMID: 22115958 DOI: 10.1016/j.mce.2011.11.007] [Citation(s) in RCA: 157] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Accepted: 11/07/2011] [Indexed: 12/11/2022]
Abstract
In fish, stanniocalcin-1 (STC1) is a key endocrine factor that acts on gill, intestine and kidney to regulate serum calcium and phosphate homeostasis. The recent identification and study of mammalian STCs (STC1 and STC2) revealed that the hormones are made in virtually all tissues and they act primarily as paracrine/autocrine factors to regulate various biological functions. Based on their ubiquitous expression patterns and generally undetectable levels in blood serum, it is unlikely that the mammalian STCs play important roles in serum Ca(2+)/P(i) homeostasis. However current evidences still support the local action of STCs in Ca(2+) and P(i) transport, probably via their action on Ca(2+)-channels and Na(+)/P(i) co-transporter. At present, information about the sequence, expression and distribution of the STC receptor(s) is lacking. However, recent emerging evidence hints the involvement of STC1 and STC2 in the sub-cellular functions of mitochondria and endoplasmic reticulum respectively, particularly responding to oxidative stress and unfolded protein response. With increasing evidence that demonstrates the local actions of STCs, the focus of the research has been moved to cellular inflammation and carcinogenesis. This review integrates the information available on STCs in fish and mammals, focusing mainly on their embryonic origin, tissue distribution, their potential regulatory mechanisms and the modes of action, and their physiological and pathophysiological functions, particularly in cancer biology.
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Affiliation(s)
- B H Y Yeung
- Department of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong
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Schein V, Cardoso JCR, Pinto PIS, Anjos L, Silva N, Power DM, Canário AVM. Four stanniocalcin genes in teleost fish: structure, phylogenetic analysis, tissue distribution and expression during hypercalcemic challenge. Gen Comp Endocrinol 2012; 175:344-56. [PMID: 22154646 DOI: 10.1016/j.ygcen.2011.11.033] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Revised: 11/20/2011] [Accepted: 11/21/2011] [Indexed: 10/14/2022]
Abstract
Stanniocalcin (STC), first isolated from the corpuscles of Stannius (CS) of teleost fishes and a systemic regulator of mineral metabolism, is present in all vertebrates as two isoforms, STC1 and STC2, encoded by separate genes. Here we show that the genome of Tetraodon nigroviridis, and other teleosts, possess duplicate genes for each STC isoform, designated stc1-a and -b, and stc2-a and -b. Stc1-a was cloned from CS, stc2-a from muscle and the two novel cDNAs, stc1-b and stc2-b, from brain. However, stc2-b was isolated as a conjoined (read-through) transcript with bod1 (bi-orientation defective 1, or FAM44B), and two additional alternative conjoined transcripts were also isolated. The predicted STC products shared the typical vertebrate 10 conserved cysteine residues and N-linked glycosylation motifs, in addition to specific features. Gene structure was generally conserved with four exons and three introns with the exception of stc1-a which gained an extra intron in exon three, originating one extra exon. Gene order and synteny is also maintained across vertebrates and the cpeb4 gene identified in the homologue region of the chordate Ciona was linked to vertebrate stc2 but not stc1. Immunohistochemistry in different species revealed that STC1-A was found only in CS and in a few cells in kidney. STC1-B had a restricted expression and was more prominent in the gills. STC2-A was detected in a variety of tissues, including pituitary, with most abundant immunoreaction in kidney cells and gill rakers and the CS was negative. Expression of stc1-a in CS of Tetraodon was 15-fold (p<0.05) up-regulated 2 h after transfer from 2.9 mM Ca(2+) to 10 mM Ca(2+) water and down-regulated after 12 hours to 11-fold lower than 2.9 mM Ca(2+) fish (p<0.05). With the exception of stc1-a in CS, low expression levels and high individual variation were generally found for the expression of stc transcripts in kidney and gills, with no statistically significant changes in response to the hypercalcemic shock. In conclusion, both stc1 and stc2 genes are represented by paralogues in teleosts genomes and the analysis performed suggests that only stc1-a in the CS is involved in extracellular calcium regulation. The widespread distribution of stcs in fish tissues supports pleiotropic roles.
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Affiliation(s)
- Vanessa Schein
- Centre of Marine Sciences, CCMAR-CIMAR Associate Laboratory, University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
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Hung NT, Yamamoto H, Takei Y, Masuda M, Otani A, Kozai M, Ikeda S, Nakahashi O, Tanaka S, Taketani Y, Takeda E. Up-regulation of stanniocalcin 1 expression by 1,25-dihydroxy vitamin D(3) and parathyroid hormone in renal proximal tubular cells. J Clin Biochem Nutr 2011; 50:227-33. [PMID: 22573926 PMCID: PMC3334377 DOI: 10.3164/jcbn.11-99] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Accepted: 08/05/2011] [Indexed: 11/22/2022] Open
Abstract
Stanniocalcin 1 and stanniocalcin 2 are two glycoprotein hormones, which act as calcium phosphate-regulating factor on intestine and kidney. We have previously reported that stanniocalcin 2 expression is positively and negatively controlled by 1,25(OH)2D3 and parathyroid hormone in renal proximal tubular cells. However, it has been unclear whether they regulate the stanniocalcin 1 gene expression. In this study, we identified the opossum stanniocalcin 1 cDNA sequence. The opossum stanniocalcin 1 amino acid sequence had 83% homology with human stanniocalcin 1, and has a conserved putative N-linked glycosylation site. Real-time PCR analysis using opossum kidney proximal tubular (OK-P) cells revealed that the mRNA levels of stanniocalcin 1 gene is up-regulated by both 1,25(OH)2D3 and parathyroid hormone in dose-dependent and time-dependent manners. We also demonstrated that the stanniocalcin 1 expression was increased in parathyroid hormone injected rat kidney. Furthermore, the mRNA expression of stanniocalcin 1 and stanniocalcin 2 were oppositely regulated by phorbol 12,13-myristic acetate, a specific PKC activator. Interestingly, the up-regulation of stanniocalcin 1 gene by 1,25(OH)2D3 and phorbol 12,13-myristic acetate were not prevented in the presence of actinomycin D, an RNA synthesis inhibitor. These results suggest that the stanniocalcin 1 gene expression is up-regulated by 1,25(OH)2D3 and parathyroid hormone through mRNA stabilization in renal proximal tubular cells.
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Affiliation(s)
- Nguyen Trong Hung
- Department of Clinical Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto-Cho 3-18-15, Tokushima 770-8503, Japan
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Abstract
Vertebrates have a large glycoprotein hormone, stanniocalcin, which originally was shown to inhibit calcium uptake from the environment in teleost fish gills. Later, humans, other mammals, and teleost fish were shown to have two forms of stanniocalcin (STC1 and STC2) that were widely distributed in many tissues. STC1 is associated with calcium and phosphate homeostasis and STC2 with phosphate, but their receptors and signaling pathways have not been elucidated. We undertook a phylogenetic investigation of stanniocalcin beyond the vertebrates using a combination of BLAST and HMMER homology searches in protein, genomic, and expressed sequence tag databases. We identified novel STC homologs in a diverse array of multicellular and unicellular organisms. Within the eukaryotes, almost all major taxonomic groups except plants and algae have STC homologs, although some groups like echinoderms and arthropods lack STC genes. The critical structural feature for recognition of stanniocalcins was the conserved pattern of ten cysteines, even though the amino acid sequence identity was low. Signal peptides in STC sequences suggest they are secreted from the cell of synthesis. The role of glycosylation signals and additional cysteines is not yet clear, although the 11th cysteine, if present, has been shown to form homodimers in some vertebrates. We predict that large secreted stanniocalcin homologs appeared in evolution as early as single-celled eukaryotes. Stanniocalcin's tertiary structure with five disulfide bonds and its primary structure with modest amino acid conservation currently lack an established receptor-signaling system, although we suggest possible alternatives.
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Affiliation(s)
- Graeme J Roch
- Department of Biology, University of Victoria, Victoria, British Columbia, Canada V8W 3N5
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Byun JS, Lee JW, Kim SY, Kwon KJ, Sohn JH, Lee K, Oh D, Kim SS, Chun W, Lee HJ. Neuroprotective effects of stanniocalcin 2 following kainic acid-induced hippocampal degeneration in ICR mice. Peptides 2010; 31:2094-9. [PMID: 20713105 DOI: 10.1016/j.peptides.2010.08.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Revised: 08/04/2010] [Accepted: 08/08/2010] [Indexed: 02/06/2023]
Abstract
Stanniocalcin 2 (STC2), the paralog of STC1, has been shown to act as a novel target of the mammalian unfolded protein response. We investigated the potential neuroprotective actions of STC2 against kainic acid toxicity in the hippocampus of ICR mice. STC2-treated mice experienced less neuronal cell loss in the CA3 area of the hippocampus. Also, microglial activation and heme oxygenase 1 expression were attenuated in the hippocampus of STC2-treated mice. To confirm whether STC2 regulates microglial activation directly, nitric oxide levels were measured in BV2 cells cultured with and without 10nM STC2. STC2 decreased the level of nitric oxide induced by lipopolysaccharide (LPS) treatment significantly. Also, STC2 pretreatment significantly decreased TNF-α and IL-1β expression induced by LPS treatment. These observations demonstrated that STC2 exerts neuroprotective actions against excitotoxic insults through the inhibition of microglial activation.
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Affiliation(s)
- Jong-Seon Byun
- Department of Pharmacology, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea
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Law AYS, Wong CKC. Stanniocalcin-2 promotes epithelial-mesenchymal transition and invasiveness in hypoxic human ovarian cancer cells. Exp Cell Res 2010; 316:3425-34. [PMID: 20619259 DOI: 10.1016/j.yexcr.2010.06.026] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2010] [Revised: 06/11/2010] [Accepted: 06/29/2010] [Indexed: 12/24/2022]
Abstract
The human glycoprotein, stanniocalcin-2 (STC2) is a HIF-1 target gene that is found to be associated with tumor development. The relationship of the prognostic outcome to the level of its expression in cancer tissues is controversial; however experimental evidence suggests that STC2 is a positive regulator of cancer progression. In the present study, we investigated if the expression of STC2 in hypoxic cells is associated with cancer invasion and metastasis. We studied the epithelial-mesenchymal transition (EMT) markers in STC2-silenced and over-expressed SKOV3 cells maintained in hypoxic condition. Western blot and immunocytochemical analysis revealed that the stable expression of exogenous STC2 promoted EMT, as revealed by the increase of N-cadherin/vimentin but a decrease of E-cadherin levels. This observation was further confirmed by colony formation assay where the STC2 stably transfected cells showed high degree of motility with fibroblast morphology under hypoxic condition. In conducting invasion assay in hypoxia, the STC2 stably transfected cells showed high degree of invasiveness. This observation was correlated with the significant increase of MMP2 and MMP9 expression in the STC2 stably transfected cells. In HUVEC/SKOV3 co-culture invasion study, endothelial invasion was found to be enhanced by the seeding of STC2 stably transfected cells in the lower compartment. These observations were possibly mediated by an increase of ROS and activated ERK1/2 levels in the cells. Collectively, the finding provides the first evidence that STC2 is a positive regulator in tumor progression at hypoxia.
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Affiliation(s)
- Alice Y S Law
- Department of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong
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Block GJ, DiMattia GD, Prockop DJ. Stanniocalcin-1 regulates extracellular ATP-induced calcium waves in human epithelial cancer cells by stimulating ATP release from bystander cells. PLoS One 2010; 5:e10237. [PMID: 20422040 PMCID: PMC2857883 DOI: 10.1371/journal.pone.0010237] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2009] [Accepted: 03/16/2010] [Indexed: 11/29/2022] Open
Abstract
Background The epithelial cell response to stress involves the transmission of signals between contiguous cells that can be visualized as a calcium wave. In some cell types, this wave is dependent on the release of extracellular trinucleotides from injured cells. In particular, extracellular ATP has been reported to be critical for the epithelial cell response to stress and has recently been shown to be upregulated in tumors in vivo. Methodology/Principal Findings Here, we identify stanniocalcin-1 (STC1), a secreted pleiotrophic protein, as a critical mediator of calcium wave propagation in monolayers of pulmonary (A549) and prostate (PC3) epithelial cells. Addition of STC1 enhanced and blocking STC1 decreased the distance traveled by an extracellular ATP-dependent calcium wave. The same effects were observed when calcium was stimulated by the addition of exogenous ATP. We uncover a positive feedback loop in which STC1 promotes the release of ATP from cells in vitro and in vivo. Conclusions/Significance The results indicated that STC1 plays an important role in the early response to mechanical injury by epithelial cells by modulating signaling of extracellular ATP. This is the first report to describe STC1 as a modulator or purinergic receptor signaling.
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Affiliation(s)
- Gregory J. Block
- Institute for Regenerative Medicine at Scott and White Hospital, Texas A&M Health Sciences Center, Temple, Texas, United States of America
| | - Gabriel D. DiMattia
- London Regional Cancer Program and the Department of Oncology, Biochemistry, University of Western Ontario, London, Ontario, Canada
| | - Darwin J. Prockop
- Institute for Regenerative Medicine at Scott and White Hospital, Texas A&M Health Sciences Center, Temple, Texas, United States of America
- * E-mail:
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Roch GJ, Sherwood NM. Genomics Reveal Ancient Forms of Stanniocalcin in Amphioxus and Tunicate. Integr Comp Biol 2010; 50:86-97. [DOI: 10.1093/icb/icq010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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Parathyroid Hormone and Parathyroid Hormone–Related Peptide in the Regulation of Calcium Homeostasis and Bone Development. Endocrinology 2010. [DOI: 10.1016/b978-1-4160-5583-9.00056-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Law AYS, Wong CKC. Stanniocalcin-2 is a HIF-1 target gene that promotes cell proliferation in hypoxia. Exp Cell Res 2009; 316:466-76. [PMID: 19786016 DOI: 10.1016/j.yexcr.2009.09.018] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2009] [Revised: 09/21/2009] [Accepted: 09/21/2009] [Indexed: 12/14/2022]
Abstract
Stanniocalcin-2 (STC2), the paralog of STC1, has been suggested as a novel target of oxidative stress response to protect cells from apoptosis. The expression of STC2 has been reported to be highly correlated with human cancer development. In this study, we reported that STC2 is a HIF-1 target gene and is involved in the regulation of cell proliferation. STC2 was shown to be up-regulated in different breast and ovarian cancer cells, following exposure to hypoxia. Using ovarian cancer cells (SKOV3), the underlying mechanism of HIF-1 mediated STC2 gene transactivation was characterized. Hypoxia-induced STC2 expression was found to be HIF-1alpha dependent and required the recruitment of p300 and HDAC7. Using STC2 promoter deletion constructs and site-directed mutagenesis, two authentic consensus HIF-1 binding sites were identified. Under hypoxic condition, the silencing of STC2 reduced while the overexpression of STC2 increased the levels of phosphorylated retinoblastoma and cyclin D in both SKOV3 and MCF7 cells. The change in cell cycle proteins correlated with the data of the serial cell counts. The results indicated that cell proliferation was reduced in STC2-silenced cells but was increased in STC2-overexpressing hypoxic cells. Solid tumor progression is usually associated with hypoxia. The identification and functional analysis of STC2 up-regulation by hypoxia, a feature of the tumor microenvironment, sheds light on a possible role for STC2 in tumors.
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Affiliation(s)
- Alice Y S Law
- Department of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong
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Expression of stanniocalcin-1 in gastrointestinal tracts of neonatal and mature rats. Biochem Biophys Res Commun 2009; 389:478-83. [PMID: 19732741 DOI: 10.1016/j.bbrc.2009.08.169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2009] [Accepted: 08/31/2009] [Indexed: 11/22/2022]
Abstract
Stanniocalcin-1 (STC-1) produced by ovaries endocrinologically targets to mammary glands and is secreted into milk during lactation. The decline of mother's serum level by STC-1 antiserum administration reduced the milk fat content and the pups' body fat content. Nevertheless, the pups' fecal fat content was increased, suggesting that milk-derived STC-1 could influence intestinal fat absorption. We investigated the STC-1 expression in rat gastrointestinal tissues using immunocytochemistry and in situ hybridization. STC-1 was widely expressed in the chief cells of gastric pits and the cells of intestinal glands. Goblet cells in the small intestine contained STC-1 protein in their mucus. The distribution shows that this peptide is secreted exocrinologically into the gastrointestinal lumen. Quantitative RT-PCR analysis revealed that the expression ratio was higher in the periods of heavy nutritional demand, such as growing and lactation. The endogenous STC-1, similar to milk-derived STC-1, may be involved in digestion and/or absorption in gastrointestinal organs.
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Trindade DM, Silva JC, Navarro MS, Torriani ICL, Kobarg J. Low-resolution structural studies of human Stanniocalcin-1. BMC STRUCTURAL BIOLOGY 2009; 9:57. [PMID: 19712479 PMCID: PMC2744999 DOI: 10.1186/1472-6807-9-57] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2009] [Accepted: 08/27/2009] [Indexed: 11/10/2022]
Abstract
BACKGROUND Stanniocalcins (STCs) represent small glycoprotein hormones, found in all vertebrates, which have been functionally implicated in Calcium homeostasis. However, recent data from mammalian systems indicated that they may be also involved in embryogenesis, tumorigenesis and in the context of the latter especially in angiogenesis. Human STC1 is a 247 amino acids protein with a predicted molecular mass of 27 kDa, but preliminary data suggested its di- or multimerization. The latter in conjunction with alternative splicing and/or post-translational modification gives rise to forms described as STC50 and "big STC", which molecular weights range from 56 to 135 kDa. RESULTS In this study we performed a biochemical and structural analysis of STC1 with the aim of obtaining low resolution structural information about the human STC1, since structural information in this protein family is scarce. We expressed STC1 in both E. coli and insect cells using the baculo virus system with a C-terminal 6 x His fusion tag. From the latter we obtained reasonable amounts of soluble protein. Circular dichroism analysis showed STC1 as a well structured protein with 52% of alpha-helical content. Mass spectroscopy analysis of the recombinant protein allowed to assign the five intramolecular disulfide bridges as well as the dimerization Cys202, thereby confirming the conservation of the disulfide pattern previously described for fish STC1. SAXS data also clearly demonstrated that STC1 adopts a dimeric, slightly elongated structure in solution. CONCLUSION Our data reveal the first low resolution, structural information for human STC1. Theoretical predictions and circular dichroism spectroscopy both suggested that STC1 has a high content of alpha-helices and SAXS experiments revealed that STC1 is a dimer of slightly elongated shape in solution. The dimerization was confirmed by mass spectrometry as was the highly conserved disulfide pattern, which is identical to that found in fish STC1.
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Affiliation(s)
- Daniel M Trindade
- Centro de Biologia Molecular Estrutural (CEBIME), Campinas, SP, Brazil
- Instituto de Biologia, Departamento de Bioquímica, Universidade Estadual de Campinas, Campinas, SP, Brazil
| | - Júlio C Silva
- Instituto de Física "Gleb Wataghin", Universidade Estadual de Campinas, Campinas, SP, Brazil
- Laboratório Nacional de Luz Síncrotron (LNLS), Campinas, SP, Brazil
| | | | - Iris CL Torriani
- Instituto de Física "Gleb Wataghin", Universidade Estadual de Campinas, Campinas, SP, Brazil
- Laboratório Nacional de Luz Síncrotron (LNLS), Campinas, SP, Brazil
| | - Jörg Kobarg
- Centro de Biologia Molecular Estrutural (CEBIME), Campinas, SP, Brazil
- Instituto de Biologia, Departamento de Bioquímica, Universidade Estadual de Campinas, Campinas, SP, Brazil
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Sheikh-Hamad D. Mammalian stanniocalcin-1 activates mitochondrial antioxidant pathways: new paradigms for regulation of macrophages and endothelium. Am J Physiol Renal Physiol 2009; 298:F248-54. [PMID: 19656913 DOI: 10.1152/ajprenal.00260.2009] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The mammalian homolog of the fish calcium regulatory hormone stanniocalcin-1 (STC1) is ubiquitously expressed and likely functions in an autocrine/paracrine fashion. Mammalian STC1 does not appear to exert significant effects on serum calcium, and its physiological role remains to be determined. In macrophages, STC1 decreases intracellular calcium and cell mobility; attenuates the response to chemoattractants; and diminishes superoxide generation through induction of uncoupling protein-2 (UCP2). In cytokine-treated endothelial cells, STC1 attenuates superoxide generation and the activation of inflammatory pathways [c-Jun NH(2)-terminal kinase (JNK) and NF-kappaB]; maintains the expression of tight junction proteins, preserving the endothelial monolayer seal; and decreases transendothelial migration of leukocytes. Combined, the effects of STC1 on endothelial cells and macrophages predict potent anti-inflammatory action. Indeed, application of the anti-glomerular basement membrane (GBM) glomerulonephritis model to STC1 transgenic mice that display increased expression of STC1 transgene in endothelial cells and macrophages yields renal protection. Our data suggest that STC1 activates antioxidant pathways in endothelial cells and macrophages and displays cytoprotective and anti-inflammatory actions.
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Affiliation(s)
- David Sheikh-Hamad
- Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
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Ieta K, Tanaka F, Yokobori T, Kita Y, Haraguchi N, Mimori K, Kato H, Asao T, Inoue H, Kuwano H, Mori M. Clinicopathological significance of stanniocalcin 2 gene expression in colorectal cancer. Int J Cancer 2009; 125:926-31. [PMID: 19415750 DOI: 10.1002/ijc.24453] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Laser microdissection (LMD) and microarray were used to identify genes associated with colorectal cancer. Stanniocalcin 2 (STC2) expression and clinicopathological significance in 139 clinical colorectal cancer samples were specifically investigated using real-time quantitative reverse transcription-polymerase chain reaction. A number of genes upregulated in colorectal cancer cells compared to normal colorectal epithelial cells were identified including STC2. STC2 gene expression in cancer tissue was higher than in corresponding normal colorectal epithelial tissue in 124 of 139 cases (89.2%, p < 0.01). Tumors with high STC2 expression showed higher frequencies of lymph node metastasis, lymphatic invasion, tumor depth, tumor size and AJCC Stage classification (p < 0.01). Patients with high STC2 expression also showed significantly worse overall survival rates than those with low STC2 expression (p < 0.01). Furthermore, STC2 gene appeared to be associated with colorectal cancer progression and may be a useful prognostic indicator for colorectal cancer.
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Affiliation(s)
- Keisuke Ieta
- Department of Surgery and Molecular Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Oita, Japan
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Volland S, Kugler W, Schweigerer L, Wilting J, Becker J. Stanniocalcin 2 promotes invasion and is associated with metastatic stages in neuroblastoma. Int J Cancer 2009; 125:2049-57. [DOI: 10.1002/ijc.24564] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Sonja Volland
- Abteilung Anatomie und Zellbiologie, Zentrum Anatomie, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Wilfried Kugler
- Abteilung Pädiatrie I, Zentrum Kinderheilkunde und Jugendmedizin, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Lothar Schweigerer
- Helios Klinikum Berlin‐Buch, Klinik für Kinder und Jugendmedizin, Berlin, Germany
| | - Jörg Wilting
- Abteilung Anatomie und Zellbiologie, Zentrum Anatomie, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Jürgen Becker
- Abteilung Anatomie und Zellbiologie, Zentrum Anatomie, Universitätsmedizin Göttingen, Göttingen, Germany
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Tamura K, Furihata M, Chung SY, Uemura M, Yoshioka H, Iiyama T, Ashida S, Nasu Y, Fujioka T, Shuin T, Nakamura Y, Nakagawa H. Stanniocalcin 2 overexpression in castration-resistant prostate cancer and aggressive prostate cancer. Cancer Sci 2009; 100:914-9. [PMID: 19298603 PMCID: PMC11159977 DOI: 10.1111/j.1349-7006.2009.01117.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Prostate cancer is usually androgen-dependent and responds well to androgen ablation therapy based on castration. However, at a certain stage some prostate cancers eventually acquire a castration-resistant phenotype where they progress aggressively and show very poor response to any anticancer therapies. To characterize the molecular features of these clinical castration-resistant prostate cancers, we previously analyzed gene expression profiles by genome-wide cDNA microarrays combined with microdissection and found dozens of trans-activated genes in clinical castration-resistant prostate cancers. Among them, we report the identification of a new biomarker, stanniocalcin 2, as an overexpressed gene in castration-resistant prostate cancer cells. Real-time polymerase chain reaction and immunohistochemical analysis confirmed overexpression of stanniocalcin 2, a 302-amino-acid glycoprotein hormone, specifically in castration-resistant prostate cancer cells and aggressive castration-naïve prostate cancers with high Gleason scores (8-10). The gene was not expressed in normal prostate, nor in most indolent castration-naïve prostate cancers. Knockdown of stanniocalcin 2 expression by short interfering RNA in a prostate cancer cell line resulted in drastic attenuation of prostate cancer cell growth. Concordantly, stanniocalcin 2 overexpression in a prostate cancer cell line promoted prostate cancer cell growth, indicating its oncogenic property. These findings suggest that stanniocalcin 2 could be involved in aggressive phenotyping of prostate cancers, including castration-resistant prostate cancers, and that it should be a potential molecular target for development of new therapeutics and a diagnostic biomarker for aggressive prostate cancers.
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Affiliation(s)
- Kenji Tamura
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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