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Wei Z, Ge D, Bu J, Wang X, Zhong T, Gongye X, Zhang B, Yan F, He C, Guo R, Li J, Jin Z. STC2 regulates the proliferation, migration and glycolysis of glioma cells through modulating ITGB2. Metab Brain Dis 2025; 40:156. [PMID: 40126711 DOI: 10.1007/s11011-025-01571-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/04/2025] [Indexed: 03/26/2025]
Abstract
Glioma is a common and aggressive primary malignant brain tumor. However, the progression mechanism of glioma has not been well revealed. In this study, we intend to detect the function and related mechanism of STC2 in glioma. Gene Expression Profiling Interactive Analysis database was used to detect STC2 and ITGB2 expression in glioma samples, as well as the relationship between STC2 and other genes. The relationship between STC2 and ITGB2 was confirmed by co-immunoprecipitation assay. The biology function of glioma cells was determined by cell counting kit-8, colony formation, transwell, ELISA and western blot assays. We discovered that STC2 was highly expressed in glioma samples and cell lines. Knocked down of STC2 inhibited cell proliferation, invasion, migration and glycolysis. Further analysis demonstrated the interaction between ITGB2 and STC2 as well as its involvement in STC2-regulated proliferation, invasion, migration and glycolysis. In summary, our data afforded novel insights into understanding the regulatory mechanism of STC2 and suggested that the STC2/ITGB2 axis might be a potential therapeutic target for glioma.
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Affiliation(s)
- Zefeng Wei
- Center for Reproductive Medicine, Affiliated Hospital of Jining Medical University, Jining, 272029, P. R. China
| | - Dengfeng Ge
- Department of Cardiothoracic Surgery, Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, P. R. China
| | - Jie Bu
- Jining Medical University, Jining, 272067, P. R. China
| | - Xuenan Wang
- Center for Reproductive Medicine, Affiliated Hospital of Jining Medical University, Jining, 272029, P. R. China
| | - Tao Zhong
- Jining Medical University, Jining, 272067, P. R. China
| | | | - Bin Zhang
- Department of Cardiothoracic Surgery, Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, P. R. China
| | - Feng Yan
- The People's Hospital of Qufu, Jining, 273100, P. R. China
| | - Chunyan He
- Jining Medical University, Jining, 272067, P. R. China
| | - Runhan Guo
- Jining Medical University, Jining, 272067, P. R. China
| | - Jiayi Li
- Jining Medical University, Jining, 272067, P. R. China
| | - Zhenzhen Jin
- Center for Reproductive Medicine, Affiliated Hospital of Jining Medical University, Jining, 272029, P. R. China.
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Van Branteghem C, Henry N, Craciun L, Maenhaut C. HMGA2 Overexpression in Papillary Thyroid Cancer Promotes Thyroid Cell Dedifferentiation and Invasion, and These Effects Are Counteracted by Suramin. Int J Mol Sci 2025; 26:1643. [PMID: 40004107 PMCID: PMC11854921 DOI: 10.3390/ijms26041643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 02/10/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Thyroid cancer is the most prevalent endocrine malignancy, and papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy. While PTC generally has a favorable prognosis, a subset dedifferentiates into aggressive forms. However, the molecular mechanisms responsible for aggressiveness and dedifferentiation are still poorly understood. We previously showed that HMGA2, a non-histone architectural transcription factor overexpressed in PTC, is involved in cell invasion. This study aimed to further analyze the role of HMGA2 in PTC tumorigenesis by exploring the expression of thyroid-specific and EMT-related genes following HMGA2 knockdown in thyroid cancer cell lines. Then, the clinical relevance of our data was evaluated in vivo. HMGA2 silencing did not modulate the expression of EMT related genes but led to the increased expression of thyroid differentiation genes. Our data also suggest that the MAPK pathway induces thyroid cell dedifferentiation through HMGA2. On the other hand, forskolin, promoting thyroid differentiation, decreased HMGA2 expression. The negative correlations between HMGA2 and thyroid-specific gene expressions were confirmed in a transgenic mouse model of PTC and in human PTC. Finally, we showed that HMGA2 inhibition by suramin reduced cell invasion and induced differentiation expression in vitro, indicating a new therapeutic strategy for treating thyroid cancer.
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Affiliation(s)
- Cindy Van Branteghem
- IRIBHM—Jacques E. Dumont, Université Libre de Bruxelles, 1070 Brussels, Belgium; (C.V.B.); (N.H.)
| | - Nicolas Henry
- IRIBHM—Jacques E. Dumont, Université Libre de Bruxelles, 1070 Brussels, Belgium; (C.V.B.); (N.H.)
| | - Ligia Craciun
- Anatomie Pathologique, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, 1070 Brussels, Belgium;
| | - Carine Maenhaut
- IRIBHM—Jacques E. Dumont, Université Libre de Bruxelles, 1070 Brussels, Belgium; (C.V.B.); (N.H.)
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Khatun M, Modhukur V, Piltonen TT, Tapanainen JS, Salumets A. Stanniocalcin Protein Expression in Female Reproductive Organs: Literature Review and Public Cancer Database Analysis. Endocrinology 2024; 165:bqae110. [PMID: 39186548 PMCID: PMC11398916 DOI: 10.1210/endocr/bqae110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/05/2024] [Accepted: 08/24/2024] [Indexed: 08/28/2024]
Abstract
Stanniocalcin (STC) 1 and 2 serve as antihyperglycemic polypeptide hormones with critical roles in regulating calcium and phosphate homeostasis. They additionally function as paracrine and/or autocrine factors involved in numerous physiological processes, including female reproduction. STC1 and STC2 contribute to the pathophysiology of several diseases, including female infertility- and pregnancy-associated conditions, and even tumorigenesis of reproductive organs. This comprehensive review highlights the dynamic expression patterns and potential dysregulation of STC1 and STC2, restricted to female fertility, and infertility- and pregnancy-associated diseases and conditions, such as endometriosis, polycystic ovary syndrome (PCOS), abnormal uterine bleeding, uterine polyps, and pregnancy complications, like impaired decidualization, preeclampsia, and preterm labor. Furthermore, the review elucidates the role of dysregulated STC in the progression of cancers of the reproductive system, including endometrial, cervical, and ovarian cancers. Additionally, the review evaluates the expression patterns and prognostic significance of STC in gynecological cancers by utilizing existing public datasets from The Cancer Genome Atlas to help decipher the multifaceted roles of these pleiotropic hormones in disease progression. Understanding the intricate mechanisms by which STC proteins influence all these reviewed conditions could lead to the development of targeted diagnostic and therapeutic strategies in the context of female reproductive health and oncology.
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Affiliation(s)
- Masuma Khatun
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland
| | - Vijayachitra Modhukur
- Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, 50406 Tartu, Estonia
- Competence Centre on Health Technologies, 50411 Tartu, Estonia
| | - Terhi T Piltonen
- Department of Obstetrics and Gynecology, Research Unit of Clinical Medicine, Medical Research Center, Oulu University Hospital, University of Oulu, 90220 Oulu, Finland
| | - Juha S Tapanainen
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland
- Department of Obstetrics and Gynaecology, HFR—Cantonal Hospital of Fribourg and University of Fribourg, 79085 Fribourg, Switzerland
| | - Andres Salumets
- Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, 50406 Tartu, Estonia
- Competence Centre on Health Technologies, 50411 Tartu, Estonia
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Karolinska University Hospital, 14152 Huddinge, Stockholm, Sweden
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Zhong R, Zhan J, Zhang S. Integrative Analysis Reveals STC2 as a Prognostic Biomarker of Laryngeal Squamous Cell Carcinoma. Appl Biochem Biotechnol 2024; 196:3891-3913. [PMID: 37792175 DOI: 10.1007/s12010-023-04727-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2023] [Indexed: 10/05/2023]
Abstract
Stanniocalcin 2 (STC2) is involved in many tumour types, but it remains unclear what its biological function is in laryngeal squamous cell carcinoma (LSCC). Therefore, we investigated STC2's expression, potential function, and prognostic significance of in LSCC. The expression and prognosis of STC2 in LSCC were described using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. In the TCGA database, the relationship between STC2 and immune infiltration, expression of immune cell chemokine and receptor genes, immune cell molecular marker genes, and epithelial‒mesenchymal transition (EMT) marker genes were analysed. The biological processes involved in STC2 and its expression-related genes were analysed comprehensively using bioinformatics. The single-gene ceRNA network of STC2 was constructed in the TCGA database. Finally, LSCC patients' tumour tissue STC2 expression was verified. STC2 silencing with the RNAi technique was used for the determination of cellular functions in a laryngeal cancer cell line. STC2 expression was higher in most tumours, including LSCC, than in normal tissues and was associated with poor prognosis. The relative proportions of naïve B, plasma, follicular helper T, and macrophage M0 cells in LSCC and normal samples differed significantly. STC2 expression correlated significantly positively with that of TGFB1 (biomarker of Tregs) and significantly negatively with that of D79A and CD19 (biomarkers of B cells). Furthermore, STC2 affected chemokine and receptor gene expression in immune cells. STC2 expression correlated with EMT marker gene expression in LSCC. STC2 was enriched in the PI3K/AKT signalling pathway, extracellular matrix (ECM) organisation, ECM-receptor interaction, and other tumour-related signalling pathways. STC2 was highly expressed in our clinical samples. N-cadherin and vimentin expression were decreased in the TU686 cell line after successful silencing of STC2, indicating that high STC2 expression may prompt LSCC cells to adopt a mesenchymal cell phenotype. STC2 silencing substantially reduced proliferation and migration in the TU686 cell line. STC2 may be a promising predictive biomarker for tumours, providing new approaches for LSCC diagnosis and treatment monitoring.
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Affiliation(s)
- Rong Zhong
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Jiandong Zhan
- Department of Otorhinolaryngology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Siyi Zhang
- School of Medicine, South China University of Technology, Guangzhou, China.
- Department of Otorhinolaryngology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 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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Characterization of the Immune Infiltration Landscape and Identification of Prognostic Biomarkers for Esophageal Cancer. Mol Biotechnol 2023; 65:361-383. [PMID: 35780460 PMCID: PMC9935668 DOI: 10.1007/s12033-022-00526-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/15/2022] [Indexed: 10/17/2022]
Abstract
Immunotherapy is an effective treatment for esophageal cancer (ESCA) patients. However, there are no dependable markers for predicting prognosis and immunotherapy responses in ESCA. Our study aims to explore immune gene prognostic models and markers in ESCA as well as predictors for immunotherapy. The expression profiles of ESCA were obtained from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and International Cancer Genome Consortium (ICGC) databases. Cox regression analysis was performed to construct an immune gene prognostic model. ESCA was grouped into three immune cell infiltration (ICI) clusters by CIBERSORT algorithm. The immunotherapy response of patients in different ICI score clusters was also compared. The copy number variations, somatic mutations, and single nucleotide polymorphisms were analyzed. Enrichment analyses were also performed. An immune gene prognostic model was successfully constructed. The ICI score may be used as a predictor independent of tumor mutation burden. Enrichment analyses showed that the differentially expressed genes were mostly enriched in microvillus and the KRAS and IL6/JAK/STAT3 pathways. The top eight genes with the highest mutation frequencies in ESCA were identified and all related to the prognosis of ESCA patients. Our study established an effective immune gene prognostic model and identified markers for predicting the prognosis and immunotherapy response of ESCA patients.
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Combined Efficacy of CXCL5, STC2, and CHI3L1 in the Diagnosis of Colorectal Cancer. JOURNAL OF ONCOLOGY 2022; 2022:7271514. [PMID: 35646113 PMCID: PMC9142324 DOI: 10.1155/2022/7271514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 04/25/2022] [Indexed: 12/23/2022]
Abstract
Objective To improve the diagnostic capacity of serum biomarkers for colorectal cancer (CRC), we introduced three novel indicators, namely, the C-X-C motif chemokine ligand 5 (CXCL5), stanniocalcin 2 (STC2), and chitinase 3 like 1 (CHI3L1) and assessed their performances in the detection of CRC. Methods A total of 887 serum samples (153 health, 342 polyps, and 392 CRCs) were collected. Concentrations of CXCL5, STC2, and CHI3L1 were measured by the ELISA. CEA and CA199 were determined by electrochemiluminescence. Binary logistic regression was used to build the combination model. ROC analysis was used to evaluate the performance of biomarkers alone or in combination. Results Model_2 that based on CXCL5, STC2, and CHI3L1 was the best approach in discriminating CRC from non-CRC controls (AUC, 0.943 (0.922–0.960); sensitivity, 0.848; specificity, 0.917; and accuracy, 0.887 in the training cohort and 0.959 (95% CI 0.927–0.980), 0.878, 0.917, and 0.900 in the testing cohort, respectively). In the detection of early CRC, Model_2 revealed AUC, sensitivity, specificity, and accuracy of 0.925 (0.897–0.947), 0.793, 0.917, and 0.886 in the training cohort and those of 0.926 (0.979–0.959), 0.786, 0.931, and 0.898 in the testing cohort. Furthermore, Model_2 exhibited an excellent diagnostic performance in CEA-negative cases (0.938 (0.913–0.957), 0.826, 0.917, and 0.888 in the training cohort and 0.961 (0.925–0.983), 0.887, 0.931, and 0.918 in the testing cohort). As used alone, STC2 achieved the capacities that is second only to that of Model_2 (0.866 (0.837–0.892), 0.859, 0.842, and 0.853 in the training cohort and 0.887 (0.842–0.923), 0.922, 0.799, and 0.853 in the testing cohort). STC2 alone also yielded acceptable results for early CRC detection (0.815 (0.776–0.849), 0.767, 0.849, and 0.829 in the training cohort and 0.870 (0.812–0.914), 0.952, 0.799, and 0.833 in the testing cohort). Moreover, STC2 maintained diagnostic accuracy for CRC patients with negative CEA (0.874 (0.842–0.901), 0.862, 0.849, and 0.853 in the training cohort and 0.898 (0.848–0.936), 0.930, 0.801, and 0.842 in the testing cohort). In comparison, the performances of the CEA and CA199 based Model_1 were far from satisfactory, especially in early cases (0.767 (0.726–0.805), 0.491, 0.863, and 0.771 in the training cohort and 0.817 (0.754–0.870), 0.476, 0.889, and 0.796 in the testing cohort). Conclusions STC2 was a promising serum biomarker for CRC diagnosis either used alone or in combination with CXCL5 and CHI3L1.
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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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Wu Z, Cheng H, Liu J, Zhang S, Zhang M, Liu F, Li Y, Huang Q, Jiang Y, Chen S, Lv L, Li D, Zeng JZ. The Oncogenic and Diagnostic Potential of Stanniocalcin 2 in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:141-155. [PMID: 35300206 PMCID: PMC8922464 DOI: 10.2147/jhc.s351882] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/26/2022] [Indexed: 02/05/2023] Open
Abstract
PURPOSE Early detection and prognostic prediction of hepatocellular carcinoma (HCC) remain a great challenge. In this study, we explored the role and diagnostic significance of stanniocalcin 2 (STC2), recently identified as a secretory protein, in HCC. METHODS STC2 mRNA and protein in HCC tissues were examined by qRT-PCR and immunohistochemistry. The regulatory role of HCC growth by STC2 was evaluated in vitro and in vivo. Serum STC2 levels were determined in HCC patients and compared to those with liver cirrhosis (LC) and normal controls (NC). The difference and significance of STC2 levels between groups were analyzed by Mann-Whitney U-test. The diagnostic value of serum STC2 in detecting early HCC was assayed with receiver operating characteristics (ROC). The association of STC2 with overall survival (OS) was determined with Kaplan-Meier method. RESULTS STC2 was elevated in about 77.1% HCC patients and correlated with advanced tumor progression. Overexpression or knockdown of STC2 stimulated or suppressed HCC colony formation and xenograft tumor growth. AKT activation played a critical role in tumor-promoting effect of STC2. The median level of serum STC2 in HCC patients (n = 98, 2086.6 ng/L) was 2.6-fold and 4.2-fold that in LC patients (n = 42, 801.9 ng/L) and NC (n = 26, 496.9 ng/L), respectively. A cut-off value 1493 ng/L for STC2 could distinguish early HCC from LC with a sensitivity of 76.9% and a specificity of 76.2%, both of which were superior to AFP at 20 μg/L (sensitivity 69.2%, specificity 52.4%). STC2 was positive in 77.8% (14/18) AFP-negative patients. High STC2 level was correlated with poor overall and disease specific survival. CONCLUSION STC2 is upregulated in both tumor and serum of HCC patients, and its overexpression promotes HCC via AKT pathway. STC2 possesses a diagnostic significance and may serve as an auxiliary biomarker of AFP for detecting early HCC.
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Affiliation(s)
- Zhixian Wu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Hongwei Cheng
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
| | - Jie Liu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
| | - Shuaishuai Zhang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
| | - Minda Zhang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
| | - Fangzhou Liu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
| | - Yinghui Li
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Qian Huang
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Yi Jiang
- Department of Hepatobiliary Surgery, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Shaohua Chen
- Department of Hepatobiliary Surgery, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Lizhi Lv
- Department of Hepatobiliary Surgery, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Dongliang Li
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Jin-Zhang Zeng
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
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OUP accepted manuscript. Carcinogenesis 2022; 43:671-681. [DOI: 10.1093/carcin/bgac030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/15/2022] [Accepted: 03/28/2022] [Indexed: 11/14/2022] Open
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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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Zhang C, Shen B, Chen X, Gao S, Ying X, Dong P. Identification of a prognostic 4-mRNA signature in laryngeal squamous cell carcinoma. J Cancer 2021; 12:5807-5816. [PMID: 34475994 PMCID: PMC8408111 DOI: 10.7150/jca.47557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/18/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignancy in the respiratory tract and could reduce the quality of life seriously like dyspnea, dysphonia and dysphagia. Moreover, 5-year survival rate has decreased over the past 40 years. This study was designed to identify mRNAs that related to prognosis in LSCC to enable early detection and outcome improvement. Methods: Gene expression profiles from Gene Expression Omnibus (GEO) (GSE59102, GSE84957) and The Cancer Genome Atlas (TCGA) were analyzed to identify differentially expressed genes (DEGs) with the help of bioinformatics tools. Functional enrichment analyses including Gene Ontology (GO) and pathway analysis were carried out to investigate the role of those genes and underlying molecular mechanisms in LSCC. Cox's regression analyses (univariate, LASSO and multivariate in order) were utilized to identify DEGs related with patients' overall survival and a 4-mRNA-based prognostic risk score model was established. Univariate and multivariate Cox's regression analyses were then performed on LSCC data (90 patients left) to identify independent predictors of OS, including the signature and clinicopathologic variables. The prognostic value of the gene signature was further validated and the genes were analyzed by GEPIA to get pan-cancer expression profiles. Results: 444 differentially expressed mRNAs (250 up-regulated, 194 down-regulated) were identified based on the threshold of fold change > 2 and adjusted p value < 0.05. Univariate Cox's regression analysis showed that high risk score (HR: 3.056, 95% confidence interval [CI]: 0.135-0.649, p<0.001) and female (HR: 0.296, 95% CI: 2.020-4.624, p=0.002) were associated with relatively poor prognosis. Further multivariate Cox's regression analysis indicated that risk score and gender were independent prognostic factors (p<0.05). The risk score model could stratify patients into high- and low‑risk groups, which presents significantly differential overall survival (p= 8.252e-04). The AUCs of 1-, 3- and 5-year OS were 0.724, 0.783 and 0.818, respectively. Conclusions: Our study provides evidence that the four-mRNA signature could serve as a biomarker to predict prognosis in LSCC, especially in long-term.
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Affiliation(s)
- Cheng Zhang
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Shen
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai, China
| | - Xinwei Chen
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai, China
| | - Shang Gao
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai, China
| | - Xinjiang Ying
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai, China
| | - Pin Dong
- Department of Otorhinolaryngology-head and neck surgery, Shanghai General Hospital, Shanghai, China
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Exploration of prognostic index based on immune-related genes in patients with liver hepatocellular carcinoma. Biosci Rep 2021; 40:225490. [PMID: 32579175 PMCID: PMC7327182 DOI: 10.1042/bsr20194240] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 02/08/2023] Open
Abstract
The present study aimed to screen the immune-related genes (IRGs) in patients with liver hepatocellular carcinoma (LIHC) and construct a synthetic index for indicating the prognostic outcomes. The bioinformatic analysis was performed on the data of 374 cancer tissues and 50 normal tissues, which were downloaded from TCGA database. We observed that 17 differentially expressed IRGs were significantly associated with survival in LIHC patients. These LIHC-specific IRGs were validated with function analysis and molecular characteristics. Cox analysis was applied for constructing a RiskScore for predicting the survival. The RiskScore involved six IRGs and corresponding coefficients, which was calculated with the following formula: RiskScore = [Expression level of FABP5 *(0.064)] + [Expression level of TRAF3 * (0.198)] + [Expression level of CSPG5 * (0.416)] + [Expression level of IL17D * (0.197)] + [Expression level of STC2 * (0.036)] + [Expression level of BRD8 * (0.140)]. The RiskScore was positively associated with the poor survival, which was verified with the dataset from ICGC database. Further analysis revealed that the RiskScore was independent of any other clinical feature, while it was linked with the infiltration levels of six types of immune cells. Our study reported the survival-associated IRGs in LIHC and then constructed IRGs-based RiskScore as prognostic indicator for screening patients with high risk of short survival. Both the screened IRGs and IRGs-based RiskScore were clinically significant, which may be informative for promoting the individualized immunotherapy against LIHC.
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14
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Pham YTH, Utuama O, Thomas CE, Park JA, Vecchia CL, Risch HA, Tran CTD, Le TV, Boffetta P, Raskin L, Luu HN. High mobility group A protein-2 as a tumor cancer diagnostic and prognostic marker: a systematic review and meta-analysis. Eur J Cancer Prev 2020; 29:565-581. [PMID: 32898013 PMCID: PMC11537243 DOI: 10.1097/cej.0000000000000602] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
High mobility group A protein-2 (HMGA2) is an architectural transcription factor that binds to the A/T-rich DNA minor groove and is responsible for regulating transcriptional activity of multiple genes indirectly through chromatin change and assembling enhanceosome. HMGA2 is overexpressed in multiple tumor types, suggesting its involvement in cancer initiation and progression, thus, making it an ideal candidate for cancer diagnostic and prognostic. We performed a systematic review to examine the role of HMGA2 as a universal tumor cancer diagnostic and prognostic marker. We used Reporting Recommendations for Tumor Marker Prognostic Studies to systematically search OvidMedline, PubMed, and the Cochrane Library for English language studies, published between 1995 and June 2019. Meta-analysis provided pooled risk estimates and their 95% confidence intervals (CIs) for an association between overall survival and recurrence of cancers for studies with available estimates. We identified 42 eligible studies with a total of 5123 tumor samples in 15 types of cancer. The pooled percentage of HMGA2 gene expression in tumor samples was 65.14%. Meta-analysis showed that cancer patients with HMGA2 positive have significantly reduced survival, compared to patients without HMGA2 gene [pooled-hazard ratio (HR) = 1.85, 95% CI 1.48-2.22]. There was a positive association between cancer patients with HMGA2 overexpression and cancer recurrence though this association did not reach significance (pooled-HR = 1.44, 95% CI 0.80-2.07). Overexpression of HMGA2 was found in 15 types of cancer. There was an association between HMGA2 overexpression with reduced survival of cancer patients. HMGA2 is thus considered a promising universal tumor marker for prognostics.
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Affiliation(s)
- Yen Thi-Hai Pham
- Department of Rehabilitation, Vinmec Healthcare System, Hanoi, Vietnam
| | - Ovie Utuama
- Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Tampa, Florida
| | - Claire E. Thomas
- Department of Epidemiology, University of Pittsburgh Graduate School of Public Health
- Division of Cancer Control and Population Sciences, University of Pittsburgh Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Jong A. Park
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Carlo La Vecchia
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Harvey A. Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University
- Yale Cancer Center, New Haven, Connecticut, USA
| | - Chi Thi-Du Tran
- Vietnam Colorectal Cancer and Polyps Research, Vinmec Healthcare System
| | - Thanh V. Le
- Department of Hepatobiliary and Pancreatic Surgery, 108 Hospital, Hanoi, Vietnam
| | - Paolo Boffetta
- Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai School of Medicine, New York, New York and
| | - Leon Raskin
- Center for Observational Research, Amgen Inc., Thousand Oaks, California, USA
| | - Hung N. Luu
- Department of Epidemiology, University of Pittsburgh Graduate School of Public Health
- Division of Cancer Control and Population Sciences, University of Pittsburgh Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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15
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Zhang J, Bing Z, Yan P, Tian J, Shi X, Wang Y, Yang K. Identification of 17 mRNAs and a miRNA as an integrated prognostic signature for lung squamous cell carcinoma. J Gene Med 2020; 21:e3105. [PMID: 31215090 DOI: 10.1002/jgm.3105] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 05/22/2019] [Accepted: 06/05/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Gene signatures for predicting the outcome of lung squamous cell carcinoma (LUSC) have been employed for many years. However, various signatures have been applied in clinical practice. Therefore, in the present study, we aimed to filter out an effective LUSC prognostic gene signature by simultaneously integrating mRNA and microRNA (miRNA). METHODS First, based on data from the Cancer Genome Atlas (TCGA) (https://www.cancer.gov/tcga), mRNAs and miRNAs that were related to overall survival of LUSC were obtained by the least absolute shrinkage and selection operator method. Subsequently, the predicting effect was tested by time-dependent receiver operating characteristic curve analysis and Kaplan-Meier survival analysis. Next, related clinical indices were added to evaluate the efficiency of the selected gene signatures. Finally, validation and comparison using three independent gene signatures were performed using data from the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo). RESULTS Our data showed that the prognostic index (PI) contained 17 mRNAs and one miRNA. According to the best normalized cut-off of PI (0.0247), the hazard ratio of the PI was 3.40 (95% confidence interval = 2.33-4.96). Moreover, when clinical factors were introduced, the PI was still the most significant index. In addition, only two Gene Ontology terms with p < 0.05 were reported. Furthermore, validation implied that, using our 18-gene signature, only hazard ratio = 1.36 (95% confidence interval = 1.01-1.83) was significant compared to the other three groups of gene biomarkers. CONCLUSIONS The 18-gene signature selected based on data from the TCGA database had an effective prognostic value for LUSC patients.
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Affiliation(s)
- Jingyun Zhang
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Zhitong Bing
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.,Department of Computational Physics, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Peijing Yan
- Institution of Clinical Research and Evidence Based Medicine, Gansu Provincial Hospital, Lanzhou, China
| | - Jinhui Tian
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Xiue Shi
- Gansu Rehabilitation Center Hospital, Lanzhou, China.,Gansu Evidence-Based Rehabilitation Medicine Center, Lanzhou, China
| | - Yongfeng Wang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Kehu Yang
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.,Institution of Clinical Research and Evidence Based Medicine, Gansu Provincial Hospital, Lanzhou, China.,Gansu Evidence-Based Rehabilitation Medicine Center, Lanzhou, China
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16
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Organophosphate ester tri-o-cresyl phosphate interacts with estrogen receptor α in MCF-7 breast cancer cells promoting cancer growth. Toxicol Appl Pharmacol 2020; 395:114977. [PMID: 32234386 DOI: 10.1016/j.taap.2020.114977] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/12/2020] [Accepted: 03/24/2020] [Indexed: 12/16/2022]
Abstract
Plastic in the ocean degrades to microplastic, thereby enhancing the leaching of incorporated plasticizers due to the increased particle surface. The uptake of microplastic-derived plasticizers by marine animals and the subsequent entry in the food chain raises concerns for adverse health effects in human beings. Frequently used plasticizers as the organophosphate ester tri-o-cresyl phosphate (TOCP) are known to affect the male reproductive system. However, the overall endocrine potential of TOCP and the underlying molecular mechanisms remain elusive as yet. In this study, we investigated the molecular effects of TOCP on estrogen receptor α (ERα)-transfected HEK-ESR1 cells and the human breast cancer cell line MCF-7. Applying virtual screening and molecular docking, we identified TOCP as potent ligand of ERα in silico. Microscale thermophoresis confirmed the binding in vitro with similar intensity as the natural ligand 17-β-estradiol. To identify the molecular mechanisms of TOCP-mediated effects, we used next-generation sequencing to analyze the gene expression pattern of TOCP-treated MCF-7 cells. RNA-sequencing revealed 22 differently expressed genes associated with ESR1 as upstream regulator: CYP1A1, SLC7A11, RUNX2, DDIT4, STC2, KLHL24, CCNG2, CEACAM5, SLC7A2, MAP1B, SLC7A5, IGF1R, CD55, FOSL2, VEGFA, and HSPA13 were upregulated and PRKCD, CCNE1, CEBPA, SFPQ, TNFAIP2, KRT19 were downregulated. The affected genes promote tumor growth by increasing angiogenesis and nutritional supply, favor invasion and metastasis, and interfere with the cell cycle. Based on the gene expression pattern, we conclude TOCP to mediate endocrine effects on MCF-7 cells by interacting with ERα.
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17
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Abstract
BACKGROUND Several studies have explored the prognostic value of stanniocalcin 2 (STC2) in various cancers, but obtained inconsistent results. Therefore, this meta-analysis was performed to determine the prognostic and clinicopathologic significance of STC2 in various cancers. METHODS Eligible studies were identified by searching the online databases PubMed, Embase, Web of Science, and the China National Knowledge Infrastructure up to March 2019. Hazard ratios (HRs) with 95% confidence intervals (CIs) and were calculated to clarify the correlation between STC2 expression and prognosis of different cancers. Odds ratios (ORs) with 95% CI were selected to appraise the correlation between STC2 with clinicopathologic characteristics of patients with cancer. RESULTS A total of 16 eligible studies with 4074 patients with cancer were included in our meta-analysis. The results showed that high STC2 expression can predict poor overall survival (OS) for cancer (HR = 1.48, 95% CI: 1.15-1.90, P = .002). Subgroup analysis found that high STC2 expression was associated with worse OS in Asian (HR = 1.85, 95% CI: 1.35-2.55), the reported directly from articles group (HR = 1.39, 95% CI: 1.05-1.84), survival curves group (HR = 1.93, 95% CI: 1.36-2.74), and gastric cancer (HR = 1.43, 95% CI: 1.04-1.95). Furthermore, high STC2 expression was significantly related to advanced T stage (OR = 1.83, 95% CI: 1.17-2.86, P = .008), lymph node metastasis (OR = 2.29, 95% CI: 1.51-3.45, P < .001), lymphatic invasion (OR = 2.15, 95% CI: 1.53-3.02, P < .001), venous invasion (OR = 1.97, 95% CI: 1.30-2.99, P = .001), and more advanced clinical stage (OR = 2.36, 95% CI: 1.74-3.19, P < .001) CONCLUSION:: Elevated expression of STC2 suggested a poor prognosis in patients with cancer and may serve as a new tumor marker to monitor cancer development and progression.
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Affiliation(s)
- Lixia Hu
- Department of Oncology, The Second People's Hospital of Hefei
| | - Yanyan Zha
- Department of Oncology, The Second People's Hospital of Hefei
| | - Fanliang Kong
- Department of Oncology, The Second People's Hospital of Hefei
| | - Yueyin Pan
- Department of Oncology, Anhui Province Hospital, Hefei, Anhui, China
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18
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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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Gong J, Wang Y, Jiang B, Xu B, Hu C. Impact of high-mobility-group A2 overexpression on epithelial-mesenchymal transition in pancreatic cancer. Cancer Manag Res 2019; 11:4075-4084. [PMID: 31118815 PMCID: PMC6505466 DOI: 10.2147/cmar.s199289] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 03/22/2019] [Indexed: 12/25/2022] Open
Abstract
Background: Tumor metastasis causes high mortality in patients with malignancies. In carcinomas, overexpression of high-mobility-group A2 (HMGA2) in cancer cells would lead to tumor development and epithelial to mesenchymal transition (EMT), promoting metastasis. This study evaluated HMGA2 overexpression for its effects on pancreatic cancer (PC). Methods: HMGA2 protein levels were immunohistochemically assessed in human PC tissue specimens and evaluated for associations with patients’ clinicopathological findings. In human PC CAPAN 1 cells after HMGA2 expression was silenced or overexpressed, Transwell migration and invasion assays were performed, and EMT marker levels (E-cadherin, N-cadherin and Vimentin) were determined by immunoblot. Results: HMGA2 and Vimentin were found in 43% and 45% of PC tissue samples, respectively, while E-cadherin was absent in 60%. HMGA2 expression, loss of E-cadherin and Vimentin expression were significantly associated with clinical stage, tumor differentiation and lymph node metastasis. More importantly, univariate and multivariate analysis demonstrated that HMGA2 expression is an independent prognostic factor for patients with pancreatic cancer. Meanwhile, HMGA2-silenced CAPAN 1 cells showed reduced migration and invasion ability while HMGA2-overexpressed CAPAN 1 cells showed increased migration and invasion ability. Increased E-cadherin (epithelial marker) and reduced N-cadherin and Vimentin (mesenchymal markers) were found in HMGA2-silenced cells, while reduced E-cadherin and increased N-cadherin and Vimentin were found in HMGA2-overexpressed cells. Furthermore, Snail and Zeb1 (transcriptional factors) were reduced in HMGA2-silenced cells and increased in HMGA2-overexpressed cells. Conclusion: Our findings demonstrate that HMGA2 expression correlates with advanced tumor grades, lymph node metastasis and poor prognosis and may be a novel prognosis/therapeutic marker for PC.
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Affiliation(s)
- Jian Gong
- Department of Hepato-Biliary-Pancreatic Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, People's Republic of China
| | - Yuxiang Wang
- Department of Hepato-Biliary-Pancreatic Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, People's Republic of China
| | - Buping Jiang
- Department of Hepato-Biliary-Pancreatic Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, People's Republic of China
| | - Bin Xu
- Department of Hepato-Biliary-Pancreatic Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, People's Republic of China
| | - Chuanzhen Hu
- Department of Orthopaedic Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, People's Republic of China.,Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, People's Republic of China
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20
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Wang Y, Wu J, Xu J, Lin S. Clinical significance of high expression of stanniocalcin-2 in hepatocellular carcinoma. Biosci Rep 2019; 39:BSR20182057. [PMID: 30962272 PMCID: PMC6487261 DOI: 10.1042/bsr20182057] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 04/02/2019] [Accepted: 04/06/2019] [Indexed: 02/05/2023] Open
Abstract
To investigate the significance of stanniocalcin-2 (STC2) expression in hepatocellular carcinoma (HCC) tissues and adjacent tissues. Levels of STC2 in HCC tissue were detected in 200 HCC patients tissues and adjacent tissues as controls by immunohistochemistry technique (IHC) and reverse transcriptase-PCR (RT-PCR). Single factor analysis was used to study the relationship between expression of STC2 mRNA and protein and clinicopathological features of HCC. Multifactor Cox survival analysis was used to relationship between the expression of STC2 and overall survival of postoperative patients with HCC. IHC staining showed that the expression of STC2 protein rate was 81.00% (163/200). And the positive rate of adjacent tissues was 29.00% (58/200). Western blot showed that the expression of STC2 protein in HCC was significantly higher than that in the adjacent tissues (P<0.05). RT-PCR showed that the positive rates of STC2 mRNA expression in HCC were 75.50% (151/200), which was significantly higher than that in adjacent tissues 14.50% (29/200) (P<0.05). Both STC2 mRNA and protein expression are related to tumor diameter, stage, tumor metastasis, carcinoma emboli in the portal vein and the degree of tumor differentiation in HCC. The HCC patients with higher expression of STC2 had shorter median survival time. STC2 expression, tumor diameter, carcinoma emboli in the portal vein, tumor differentiation degree, and tumor stage were independent factors affecting the overall survival of postoperative patients. The high expression of STC2 mRNA and protein expression in HCC may be associated with the occurrence, development, and prognosis of HCC. STC2 may also be possible to help developing new therapeutic strategies for HCC.
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Affiliation(s)
- Yuan Wang
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, P.R. China
- Department of Oncology, Guang Xing Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310007, P.R. China
| | - Jian Wu
- Department of Laboratory Medicine, The First People's Hospital of Yancheng City, Yancheng 224005, Jiangsu, China
| | - Jiangyan Xu
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang, China
| | - Shengyou Lin
- Department of Oncology, Guang Xing Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310007, P.R. China
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Zhang C, Chen S, Ma X, Yang Q, Su F, Shu X, Xie W, Feng M, Xiong B. Upregulation of STC2 in colorectal cancer and its clinicopathological significance. Onco Targets Ther 2019; 12:1249-1258. [PMID: 30863092 PMCID: PMC6389002 DOI: 10.2147/ott.s191609] [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] [Indexed: 12/12/2022] Open
Abstract
Background Stanniocalcin 2 (STC2) is a glycoprotein hormone involved in many biological processes and a secretory protein that regulates malignant tumor progression. The aim of the present study was to further explore the clinicopathological significance and prognostic role of STC2 in colorectal cancer (CRC). Methods In this study, STC2 expression was first investigated in Gene Expression Omnibus and The Cancer Genome Atlas, and then validated with the data from our medical center. Univariate and multivariate analyses were performed to assess the association between prognostic factors and survival outcome. Results In Gene Expression Omnibus and The Cancer Genome Atlas databases, bioinformatics analysis confirmed that STC2 was significantly increased in CRC compared with that in normal tissues (P<0.01), and CRC patients with high STC2 expression had a shorter overall survival. By analyzing data from our medical center, the results also showed that STC2 expression of CRC tissues was higher than that in normal tissues, whether the transcriptional or protein levels. In the CRC tissues, high STC2 expression was significantly correlated with lymph node metastasis (P=0.047), distant metastasis (P=0.040), and advanced clinical stage (P=0.047). Moreover, Kaplan–Meier analyses indicated that high STC2 expression predicted a worse prognosis, and multivariate Cox regression analysis revealed that STC2 was an independent prognostic factor for overall survival (HR =1.976, 95% CI: 1.092–3.576, P=0.024) in patients with CRC. Conclusion Our results suggested that STC2 played an important role in CRC progression and prognosis, and could be a useful biomarker for survival prediction.
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Affiliation(s)
- Chunxiao Zhang
- Department of Gastrointestinal Surgery and Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratoryof Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang District, Wuhan 430071, China, ;
| | - Shuangqian Chen
- Department of Gastrointestinal Surgery and Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratoryof Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang District, Wuhan 430071, China, ;
| | - Xiang Ma
- Department of Gastrointestinal Surgery and Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratoryof Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang District, Wuhan 430071, China, ;
| | - Qian Yang
- Department of Gastrointestinal Surgery and Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratoryof Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang District, Wuhan 430071, China, ;
| | - Fei Su
- Department of Gastrointestinal Surgery and Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratoryof Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang District, Wuhan 430071, China, ;
| | - Xiang Shu
- Department of Technology, Wuhan Hesheng Medical Technological Company, Wuhan 430071, China
| | - Wei Xie
- Department of Gastrointestinal Surgery and Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratoryof Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang District, Wuhan 430071, China, ;
| | - Maohui Feng
- Department of Gastrointestinal Surgery and Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratoryof Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang District, Wuhan 430071, China, ;
| | - Bin Xiong
- Department of Gastrointestinal Surgery and Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratoryof Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang District, Wuhan 430071, China, ;
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Xing F, Song Z, He Y. MiR-219-5p inhibits growth and metastasis of ovarian cancer cells by targeting HMGA2. Biol Res 2018; 51:50. [PMID: 30474570 PMCID: PMC6260846 DOI: 10.1186/s40659-018-0199-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 11/18/2018] [Indexed: 12/31/2022] Open
Abstract
Background Accumulating studies have demonstrated that high-mobility group A2 (HMGA2), an oncofetal protein, plays a role in tumor development and progression. However, the molecular role of HMGA2 in ovarian carcinoma is yet to be established. MicroRNAs (miRNAs), a group of small noncoding RNAs, negatively regulate gene expression and their dysregulation has been implicated in tumorigenesis. The aim of this study was to investigate the potential involvement of a specific miRNA, miR-219-5p, in HMGA2-induced ovarian cancer. Methods The ovarian cancer cell line, SKOV3, was employed, and miR-219-5p and HMGA2 overexpression vectors constructed. The CCK-8 kit was used to determine cell proliferation and the Transwell® assay used to measure cell invasion and migration. RT-PCR and western blot analyses were applied to analyze the expression of miR-219-5p and HMGA2, and the luciferase reporter assay used to examine the interactions between miR-219-5p and HMGA2. Nude mice were employed to characterize in vivo tumor growth regulation. Results Expression of miR-219-5p led to suppression of proliferation, invasion and migration of the ovarian cancer cell line, SKOV3, by targeting HMGA2. The inhibitory effects of miR-219-5p were reversed upon overexpression of HMGA2. Data from the luciferase reporter assay showed that miR-219-5p downregulates HMGA2 via direct integration with its 3′-UTR. Consistent with in vitro findings, expression of miR-219-5p led to significant inhibition of tumor growth in vivo. Conclusion Our results collectively suggest that miR-219-5p inhibits tumor growth and metastasis by targeting HMGA2.
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Affiliation(s)
- Feng Xing
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Tongji University School of Medicine, No 301 Middle Yan Chang Road, Shanghai, 200072, China
| | - Zhijiao Song
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Tongji University School of Medicine, No 301 Middle Yan Chang Road, Shanghai, 200072, China
| | - Yuanying He
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Tongji University School of Medicine, No 301 Middle Yan Chang Road, Shanghai, 200072, China.
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Wang J, Sahengbieke S, Xu X, Zhang L, Xu X, Sun L, Deng Q, Wang D, Chen D, Pan Y, Liu Z, Yu S. Gene expression analyses identify a relationship between stanniocalcin 2 and the malignant behavior of colorectal cancer. Onco Targets Ther 2018; 11:7155-7168. [PMID: 30425508 PMCID: PMC6203107 DOI: 10.2147/ott.s167780] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Colorectal cancer (CRC) is one of the main causes of cancer-related death worldwide. Stanniocalcin 2 (STC2), a secreted glycoprotein, has been suggested to exert various functions in progression of many cancers. However, the precise biological role in CRC is not fully understood. Therefore, this study based on several public datasets aims at investigating the roles of STC2 in CRC. Methods We used The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to evaluate the STC2 expression and its clinical significance in CRC. Cell migration and invasion by STC2 overexpression and knockdown were assessed using Transwell migration and Matrigel invasion assays. We next performed RNAseq analysis on SW480 cells with or without STC2 overexpression. Differentially expressed genes were selected by using fold-change >5 and P-value <0.05. Results In this study, we found that STC2 level was significantly higher in CRC than that in adjacent noncancerous tissues from TCGA and GEO. Tumors with high mRNA levels of STC2 were more common in patients with rectal cancer, left-sided CRC, advanced T-stage (T3-T4), positive lymph node involvement and advanced AJCC-stage (III-IV) from TCGA. STC2 displayed the negative correlation with the expressions of epithelial cell markers, while it was positively correlated with the expressions of mesenchymal cell markers, MMPs and the epithelial-mesenchymal transition (EMT)-related transcriptional factors. Furthermore, we found that STC2 promoted cell migration and invasion in vitro. And a group of differentially expressed genes, which were modulated by STC2, were identified from RNAseq analyses. Conclusion Our study demonstrates that STC2 is overexpressed in CRC compared with normal tissues, and promotes CRC cell migration and invasion. Our data suggest that STC2 may be used as a potential biomarker for clinical application and target therapy in future.
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Affiliation(s)
- Jian Wang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China,
| | - Sana Sahengbieke
- Department of Pathology, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Xiaoping Xu
- Department of Anorectal Surgery, Yuhang District First People's Hospital, Hangzhou, Zhejiang Province, People's Republic of China
| | - Lei Zhang
- Department of Anorectal Surgery, Yuhang District First People's Hospital, Hangzhou, Zhejiang Province, People's Republic of China
| | - Xiaoming Xu
- Department of Pathology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Lifeng Sun
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China,
| | - Qun Deng
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China,
| | - Da Wang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China,
| | - Dong Chen
- Department of Anorectal Surgery, Yuhang District First People's Hospital, Hangzhou, Zhejiang Province, People's Republic of China
| | - Yuan Pan
- Department of Anorectal Surgery, Yuhang District First People's Hospital, Hangzhou, Zhejiang Province, People's Republic of China
| | - Zhaohui Liu
- Department of Anorectal Surgery, Yuhang District First People's Hospital, Hangzhou, Zhejiang Province, People's Republic of China
| | - Shaojun Yu
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China,
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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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25
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Abstract
The zinc metalloproteinase, PAPP-A, enhances local insulin-like growth factor (IGF) action through cleavage of inhibitory IGF-binding proteins, thereby increasing IGF available for IGF receptor-mediated cell proliferation, migration and survival. In many tumors, enhanced IGF receptor signaling is associated with tumor growth, invasion and metastasis. We will first discuss PAPP-A structure and function, and post-translational inhibitors of PAPP-A expression or proteolytic activity. We will then review the evidence supporting an important role for PAPP-A in many cancers, including breast, ovarian and lung cancer, and Ewing sarcoma.
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Affiliation(s)
- Cheryl A Conover
- From the Division of Endocrinology Mayo ClinicRochester, Minnesota, USA
| | - Claus Oxvig
- Department of Molecular Biology and GeneticsAarhus University, Aarhus, Denmark
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26
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Brantley KD, Kjærsgaard A, Cronin-Fenton D, Yacoub R, Nielsen AS, Lauridsen KL, Hamilton-Dutoit S, Lash TL. Stanniocalcin Expression as a Predictor of Late Breast Cancer Recurrence. Cancer Epidemiol Biomarkers Prev 2018; 27:653-659. [PMID: 29593009 DOI: 10.1158/1055-9965.epi-17-0905] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 12/12/2017] [Accepted: 03/20/2018] [Indexed: 11/16/2022] Open
Abstract
Background: Expression of human paracrine hormones stanniocalcin 1 (STC1) and stanniocalcin 2 (STC2) may potentiate late breast cancer recurrence. We tested the hypothesis that expression of STC1 and STC2 in primary breast tumors is more strongly associated with late versus early recurrences.Methods: A total of 541 estrogen receptor-positive, tamoxifen-treated (ER+/TAM+) and 300 ER-negative, tamoxifen-untreated (ER-/TAM-) breast cancer patients who experienced recurrence within 10 years of primary diagnosis and matched recurrence-free controls were selected from a cohort of 11,251 Danish breast cancer patients diagnosed with stage I, II, or III breast cancer during 1985 to 2001. The association between IHC expression of STC1 and STC2 in primary breast tumor tissue microarrays and breast cancer recurrence was evaluated within median time to recurrence quintiles.Results: The association between STC1 expression, dichotomized as positive or negative, and recurrence was strongly positive for the final time quintile (6-10 years postdiagnosis) in the ER+/TAM+ group [aOR = 2.70; 95% confidence interval (CI): 1.22-5.98]. Regression of the log ORs relating dichotomous STC1 and STC2 expression to recurrence by median time to recurrence (year) resulted in a relatively large positive effect estimate for STC1 (β = 0.16; 95% CI, -0.03-0.36) and a near-null positive effect estimate for STC2 (β = 0.04; 95% CI, -0.14-0.21).Conclusions: Our results suggest a stronger association between primary tumor STC1 expression and late recurrence, as opposed to early recurrence, although no clear trend was apparent.Impact: STC1 expression in the primary tumor may potentiate late recurrences, suggesting dormancy pathways that merit further investigation. Cancer Epidemiol Biomarkers Prev; 27(6); 653-9. ©2018 AACR.
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Affiliation(s)
- Kristen D Brantley
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
| | - Anders Kjærsgaard
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Rami Yacoub
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Anja S Nielsen
- Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | | | | | - Timothy L Lash
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.,Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.,Winship Cancer Institute, Atlanta, Georgia
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Martínez M, Sorzano COS, Pascual-Montano A, Carazo JM. Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors. PLoS One 2017; 12:e0178316. [PMID: 28542306 PMCID: PMC5443557 DOI: 10.1371/journal.pone.0178316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 05/11/2017] [Indexed: 11/19/2022] Open
Abstract
Benign neurofibromas, the main phenotypic manifestations of the rare neurological disorder neurofibromatosis type 1, degenerate to malignant tumors associated to poor prognosis in about 10% of patients. Despite efforts in the field of (epi)genomics, the lack of prognostic biomarkers with which to predict disease evolution frustrates the adoption of appropriate early therapeutic measures. To identify potential biomarkers of malignant neurofibroma transformation, we integrated four human experimental studies and one for mouse, using a gene score-based meta-analysis method, from which we obtained a score-ranked signature of 579 genes. Genes with the highest absolute scores were classified as promising disease biomarkers. By grouping genes with similar neurofibromatosis-related profiles, we derived panels of potential biomarkers. The addition of promoter methylation data to gene profiles indicated a panel of genes probably silenced by hypermethylation. To identify possible therapeutic treatments, we used the gene signature to query drug expression databases. Trichostatin A and other histone deacetylase inhibitors, as well as cantharidin and tamoxifen, were retrieved as putative therapeutic means to reverse the aberrant regulation that drives to malignant cell proliferation and metastasis. This in silico prediction corroborated reported experimental results that suggested the inclusion of these compounds in clinical trials. This experimental validation supported the suitability of the meta-analysis method used to integrate several sources of public genomic information, and the reliability of the gene signature associated to the malignant evolution of neurofibromas to generate working hypotheses for prognostic and drug-responsive biomarkers or therapeutic measures, thus showing the potential of this in silico approach for biomarker discovery.
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Affiliation(s)
- Marta Martínez
- Biocomputing Unit, Nacional Center for Biotechnology (CSIC), Campus Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
- * E-mail:
| | - Carlos O. S. Sorzano
- Biocomputing Unit, Nacional Center for Biotechnology (CSIC), Campus Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
- Bioengineering Lab., Universidad CEU San Pablo, Campus Urb. Montepríncipe, Boadilla del Monte, Madrid, Spain
| | - Alberto Pascual-Montano
- Biocomputing Unit, Nacional Center for Biotechnology (CSIC), Campus Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
| | - Jose M. Carazo
- Biocomputing Unit, Nacional Center for Biotechnology (CSIC), Campus Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
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Pacheco J, Vaca L. STIM-TRP Pathways and Microdomain Organization: Auxiliary Proteins of the STIM/Orai Complex. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 993:189-210. [DOI: 10.1007/978-3-319-57732-6_10] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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29
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DNA methylation-regulated microRNA pathways in ovarian serous cystadenocarcinoma: A meta-analysis. Comput Biol Chem 2016; 65:154-164. [DOI: 10.1016/j.compbiolchem.2016.09.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 09/07/2016] [Indexed: 12/31/2022]
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30
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Wu J, Zhang S, Shan J, Hu Z, Liu X, Chen L, Ren X, Yao L, Sheng H, Li L, Ann D, Yen Y, Wang J, Wang X. Elevated HMGA2 expression is associated with cancer aggressiveness and predicts poor outcome in breast cancer. Cancer Lett 2016; 376:284-92. [PMID: 27063096 DOI: 10.1016/j.canlet.2016.04.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 03/29/2016] [Accepted: 04/01/2016] [Indexed: 01/17/2023]
Abstract
High mobility group AT-hook 2 (HMGA2) is involved in a wide spectrum of biological processes and is upregulated in several tumors. Here, we collected 273 breast cancer (BC) specimens as a training set and 310 specimens as a validation set to examine the expression of HMGA2 by immunohistochemical staining. It was found that HMGA2 expression was significantly positively correlated with advanced tumor grade and poor survival. Subgroup analysis indicated that high level of HMGA2 was significantly correlated with poor prognosis, especially in the subgroups of stage II-III, low pathological grade and non-triple negative breast cancer cases. Gene set enrichment analysis (GSEA) demonstrated a significant positive correlation between HMGA2 level and the gene expression signature of metaplastic and mesenchymal phenotype. Importantly, we also observed that ectopic expression of HMGA2 promoted the migration and invasion of breast cancer cells, and protected cancer cells against genotoxic stress from agents stimulating P53 (Ser15) phosphorylation. As a conclusion, expression of HMGA2 might indicate more advanced malignancy of breast cancer. Thus we believe HMGA2 could serve as a biomarker of poor prognosis and a novel target in treating BC tumors.
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Affiliation(s)
- Jingjing Wu
- Department of Pathology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shizhen Zhang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jinlan Shan
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zujian Hu
- Department of Breast Surgery, Hangzhou Traditional Chinese Medical Hospital, Hangzhou, Zhejiang, China
| | - Xiyong Liu
- Biomarker Development, California Cancer Institute, Sino-America Cancer Foundation, Temple City, CA, USA
| | - Lirong Chen
- Department of Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Pathology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xingchang Ren
- Department of Pathology, Hangzhou Traditional Chinese Medical Hospital, Hangzhou, Zhejiang, China
| | - Lifang Yao
- Department of Pathology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Hongqiang Sheng
- Department of Pathology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ling Li
- Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - David Ann
- Department of Diabetes and Metabolic Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Yun Yen
- PhD Program of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
| | - Jian Wang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Xiaochen Wang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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Wu J, Wang Y, Xu X, Cao H, Sahengbieke S, Sheng H, Huang Q, Lai M. Transcriptional activation of FN1 and IL11 by HMGA2 promotes the malignant behavior of colorectal cancer. Carcinogenesis 2016; 37:511-21. [PMID: 26964871 DOI: 10.1093/carcin/bgw029] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 03/04/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, and metastasis is the principle reason for its poor prognosis. Overexpression of high-mobility gene group A2 (HMGA2) contributes to the aggressiveness of CRC. However, the underlying molecular mechanism of its overexpression is still elusive. In this study, we showed that ectopic expression of HMGA2 significantly enhanced cell migration and invasion in vitro and promoted tumor growth and distant metastasis in vivo In contrast, the silencing of HMGA2 produced the opposite effects in vitro and in vivo Chromatin immunoprecipitation-PCR and luciferase assays revealed that HMGA2 bound directly to the promoters of FN1 and IL11 and significantly induced their transcriptional activities. Moreover, as the direct downstream target of HMGA2, IL11 modulated cell migration and invasion through a pSTAT3-dependent signaling pathway. Furthermore, a strong positive correlation between HMGA2 and IL11 expression was identified in 122 CRC tissues. High IL11 expression was associated with poor differentiation, a large tumor size, lymph node metastasis and low overall survival in CRC patients. Collectively, our data reveal novel insights into the molecular mechanisms underlying HMGA2-mediated CRC metastasis and highlight the possibility of targeting HMGA2 and IL11 for treating CRC patients with metastasis.
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Affiliation(s)
- Jingjing Wu
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Yuhong Wang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Xi Xu
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Hui Cao
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Sana Sahengbieke
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Hongqiang Sheng
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Qiong Huang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Maode Lai
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
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