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Li X, Zhang H, Wang Y, Li Y, Wang Y, Xiong Y, Liu W, Lin Y. Chi-circ_0009659 modulates goat intramuscular adipocyte differentiation through miR-3431-5p/STEAP4 axis. Anim Biosci 2025; 38:577-587. [PMID: 39483024 PMCID: PMC11917439 DOI: 10.5713/ab.24.0322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 07/25/2024] [Accepted: 09/09/2024] [Indexed: 11/03/2024] Open
Abstract
OBJECTIVE Circular RNAs (circRNAs) are widely involved in the regulation of lipid deposition in animals, but there are few reports on key circRNAs regulating intramuscular adipocyte differentiation in goats. Therefore, this study took an abundantly expressed in goat adipocytes chi-circ_0009659 as the object. METHODS Based on the identification of back splicing site in chi-circ_0009659, its expression level during the goat intramuscular preadipocyte differentiation was detected by quantitative polymerase chain reaction (qPCR) . The chi-circ_0009659 loss-of-function and gain-of-function cell models were obtained by adenovirus and smarter silencer, respectively. and the adipocyte differentiation were explored by Oil Red O staining, Bodipy staining and qPCR. Its major cytoplasmic localization was determined by fluorescence in situ hybridization (FISH), nucleocytoplasmic separation and qPCR. The interaction between chi-circ_0009659, miR-3431-5p, and STEAP family member 4 (STEAP4) was verified by bioinformatics, RNA pull down and dual luciferase reporter assay. RESULTS Silencing chi-circ_0009659 inhibited lipid droplet accumulation and the expression of differentiation-determining genes in goat intramuscular adipocytes, while overexpression of chi-circ_0009659 reversed these results. chi-circ_0009659 was predominantly localized to the cytoplasm and could regulate miR-3431 expression which in turn affects STEAP4. Consistent with expectations, miR-3431-5p acted as a negative regulator of GIMPA differentiation, while STEAP4 promoted differentiation. CONCLUSION We demonstrated chi-circ_0009659 positively regulates goat intramuscular preadipocyte differentiation by sponging miR-3431-5p to further regulate the expression of STEAP4. This research provides a new reference for in-depth understanding of the effects of circRNA on adipocyte differentiation.
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Affiliation(s)
- Xin Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041 ,
China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu 610041,
China
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041,
China
| | - Hao Zhang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041 ,
China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu 610041,
China
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041,
China
| | - Yong Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041 ,
China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu 610041,
China
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041,
China
| | - Yanyan Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041 ,
China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu 610041,
China
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041,
China
| | - Youli Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041 ,
China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu 610041,
China
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041,
China
| | - Yan Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041 ,
China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu 610041,
China
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041,
China
| | - Wei Liu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041 ,
China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu 610041,
China
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041,
China
| | - Yaqiu Lin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041 ,
China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu 610041,
China
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041,
China
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Fang ZX, Chen WJ, Wu Z, Hou YY, Lan YZ, Wu HT, Liu J. Inflammatory response in gastrointestinal cancers: Overview of six transmembrane epithelial antigens of the prostate in pathophysiology and clinical implications. World J Clin Oncol 2024; 15:9-22. [PMID: 38292664 PMCID: PMC10823946 DOI: 10.5306/wjco.v15.i1.9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/24/2023] [Accepted: 12/19/2023] [Indexed: 01/23/2024] Open
Abstract
Chronic inflammation is known to increase the risk of gastrointestinal cancers (GICs), the common solid tumors worldwide. Precancerous lesions, such as chronic atrophic inflammation and ulcers, are related to inflammatory responses in vivo and likely to occur in hyperplasia and tumorigenesis. Unfortunately, due to the lack of effective therapeutic targets, the prognosis of patients with GICs is still unsatisfactory. Interestingly, it is found that six transmembrane epithelial antigens of the prostate (STEAPs), a group of metal reductases, are significantly associated with the progression of malignancies, playing a crucial role in systemic metabolic homeostasis and inflammatory responses. The structure and functions of STEAPs suggest that they are closely related to intracellular oxidative stress, responding to inflammatory reactions. Under the imbalance status of abnormal oxidative stress, STEAP members are involved in cell transformation and the development of GICs by inhibiting or activating inflammatory process. This review focuses on STEAPs in GICs along with exploring their potential molecular regulatory mechanisms, with an aim to provide a theoretical basis for diagnosis and treatment strategies for patients suffering from these types of cancers.
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Affiliation(s)
- Ze-Xuan Fang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yang-Zheng Lan
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Li X, Zhang H, Wang Y, Li Y, Xiong Y, Li R, Zhu J, Lin Y. Overexpression of goat STEAP4 promotes the differentiation of subcutaneous adipocytes. Arch Anim Breed 2022; 65:397-406. [PMID: 36415757 PMCID: PMC9673034 DOI: 10.5194/aab-65-397-2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 10/11/2022] [Indexed: 07/30/2023] Open
Abstract
Objective: The focus of this study was the six-transmembrane epithelial antigen of the prostate 4 (STEAP4) gene, on the basis of the cloned goat STEAP4 gene sequence. Its molecular and expression characteristics were analyzed, and its influence on the differentiation of goat subcutaneous adipocytes was explored through overexpression. Method: Reverse-transcription PCR (RT-PCR) was used to clone the goat STEAP4 sequence, and online tools were used to analyze the molecular characteristic. Real-time quantitative PCR (qPCR) was used to detect the expression level of STEAP4 in goat tissues and subcutaneous adipocyte differentiation. Liposome transfection, BODIPY, Oil Red O staining, and qPCR were used to explore the effect of overexpression of STEAP4 on adipocyte differentiation. Results: The cloned goat STEAP4 gene sequence was 1388 bp, and the complete coding sequence (CDS) region was 1197 bp, which encoded a total of 398 amino acids. Compared with the predicted sequence (XM_005679300.3), there were three base mutations in the CDS region of goat STEAP4, A188G, T281C, and A507G. Among them, A507G changed the amino acid at position 170 from Ile to Val. Analysis of the physical and chemical properties of the protein showed that STEAP4 was a stable hydrophilic basic protein. STEAP4 gene expression level was highest in goat liver tissue ( P < 0.01 ), followed by lung and back subcutaneous adipose tissue. STEAP4 showed different expression levels in goat subcutaneous adipocytes at different times during the induction of differentiation. The expression in the late stage of differentiation was higher than that before differentiation and lowest at 12 h ( P < 0.01 ). Overexpression of STEAP4 promoted the accumulation of intracellular lipid droplets; C/EBP β (CCAAT enhancer binding protein) was extremely significantly up-regulated ( P < 0.01 ), and aP2 (fatty acid binding protein) was significantly up-regulated ( P < 0.05 ). Conclusion: Overexpression of STEAP4 could promote the differentiation of goat subcutaneous preadipocytes. This study lays the foundation for an in-depth study of the role of STEAP4 in goat lipid deposition.
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Affiliation(s)
- Xin Li
- College of Animal &Veterinary Sciences, Southwest Minzu University,
Chengdu 610041, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal
Genetic Resource Protection and Utilization of Ministry of Education/Sichuan
Province, Southwest Minzu University, Chengdu 610041, China
| | - Hao Zhang
- College of Animal &Veterinary Sciences, Southwest Minzu University,
Chengdu 610041, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal
Genetic Resource Protection and Utilization of Ministry of Education/Sichuan
Province, Southwest Minzu University, Chengdu 610041, China
| | - Yong Wang
- College of Animal &Veterinary Sciences, Southwest Minzu University,
Chengdu 610041, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal
Genetic Resource Protection and Utilization of Ministry of Education/Sichuan
Province, Southwest Minzu University, Chengdu 610041, China
| | - Yanyan Li
- College of Animal &Veterinary Sciences, Southwest Minzu University,
Chengdu 610041, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal
Genetic Resource Protection and Utilization of Ministry of Education/Sichuan
Province, Southwest Minzu University, Chengdu 610041, China
| | - Yan Xiong
- College of Animal &Veterinary Sciences, Southwest Minzu University,
Chengdu 610041, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal
Genetic Resource Protection and Utilization of Ministry of Education/Sichuan
Province, Southwest Minzu University, Chengdu 610041, China
| | - Ruiwen Li
- Chengdu
Women's and Children's Central Hospital, School of Medicine, University of
Electronic Science and Technology of China, Chengdu 611731, China
| | - Jiangjiang Zhu
- Key Laboratory of Qinghai-Tibetan Plateau Animal
Genetic Resource Protection and Utilization of Ministry of Education/Sichuan
Province, Southwest Minzu University, Chengdu 610041, China
| | - Yaqiu Lin
- College of Animal &Veterinary Sciences, Southwest Minzu University,
Chengdu 610041, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal
Genetic Resource Protection and Utilization of Ministry of Education/Sichuan
Province, Southwest Minzu University, Chengdu 610041, China
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Comprehensive Landscape of STEAP Family Members Expression in Human Cancers: Unraveling the Potential Usefulness in Clinical Practice Using Integrated Bioinformatics Analysis. DATA 2022. [DOI: 10.3390/data7050064] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The human Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) family comprises STEAP1-4. Several studies have pointed out STEAP proteins as putative biomarkers, as well as therapeutic targets in several types of human cancers, particularly in prostate cancer. However, the relationships and significance of the expression pattern of STEAP1-4 in cancer cases are barely known. Herein, the Oncomine database and cBioPortal platform were selected to predict the differential expression levels of STEAP members and clinical prognosis. The most common expression pattern observed was the combination of the over- and underexpression of distinct STEAP genes, but cervical and gastric cancer and lymphoma showed overexpression of all STEAP genes. It was also found that STEAP genes’ expression levels were already deregulated in benign lesions. Regarding the prognostic value, it was found that STEAP1 (prostate), STEAP2 (brain and central nervous system), STEAP3 (kidney, leukemia and testicular) and STEAP4 (bladder, cervical, gastric) overexpression correlate with lower patient survival rate. However, in prostate cancer, overexpression of the STEAP4 gene was correlated with a higher survival rate. Overall, this study first showed that the expression levels of STEAP genes are highly variable in human cancers, which may be related to different patients’ outcomes.
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5
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Jiang H, Dong Y, Yan D, Wu Y, Wang Y, Ren Y, Mao G, Liang G, Liu W, Zhou Y, Huang Z, Qi L. The expression of STEAP4 in peripheral blood predicts the outcome of septic patients. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1519. [PMID: 34790725 PMCID: PMC8576732 DOI: 10.21037/atm-21-2794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 10/22/2021] [Indexed: 11/30/2022]
Abstract
Background Sepsis is a systemic disease characterized by extensive inflammatory responses and impaired organ function, which are characteristics that make it easily missed and complex to treat. A large number of laboratory and clinical studies on the diagnosis and treatment of sepsis have been continuously carried out, confirming the importance of mitochondrial function during the development of sepsis. STEAP4 is an important metalloreductase in mitochondria, which is involved in the biogenesis and respiratory chain of mitochondria. The role of STEAP4 in inflammation remains controversial. Research in this field may contribute to the development of new diagnostic and treatment options for sepsis. Methods The expression of STEAP4 was measured in the peripheral blood of patients with severe sepsis and compared with healthy controls. Cell and mouse inflammatory models were established to detect the expression of STEAP4 and other inflammatory cytokines. Results (I) The expression of STEAP4 in the peripheral blood of patients with severe sepsis is higher than that of healthy volunteers (P<0.01), which is related to the SOFA score and transaminase. (II) STEAP4 has a certain predictive effect on the outcome of patients [area under curve (AUC) =0.696, P<0.05, 95% CI: 0.528 to 0.833]. (III) Inflammation led to increased expression of STEAP4 gene in RAW264.7 cells and mouse liver tissue. Conclusions The expression of STEAP4 is elevated in the early stage of sepsis and the degree of its elevation can be used to predict the clinical outcome of sepsis patients.
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Affiliation(s)
- Haiyan Jiang
- Department of Health Medicine, Affiliated Hospital of Nantong University, Nantong, China.,Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yansong Dong
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Dajun Yan
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yao Wu
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yue Wang
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yuting Ren
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Guomin Mao
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Guiwen Liang
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Wei Liu
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yang Zhou
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, China
| | - Zhongwei Huang
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Lei Qi
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China.,Rugao Branch (Rugao Bo'ai Hospital), Affiliated Hospital of Nantong University, Nantong, China
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Chen WJ, Wu HT, Li CL, Lin YK, Fang ZX, Lin WT, Liu J. Regulatory Roles of Six-Transmembrane Epithelial Antigen of the Prostate Family Members in the Occurrence and Development of Malignant Tumors. Front Cell Dev Biol 2021; 9:752426. [PMID: 34778263 PMCID: PMC8586211 DOI: 10.3389/fcell.2021.752426] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/04/2021] [Indexed: 02/05/2023] Open
Abstract
The human six-transmembrane epithelial antigen of the prostate (STEAP) proteins, which include STEAP1-4 and atypical STEAP1B, contain six transmembrane domains and are located in the cell membrane. STEAPs are considered archaeal metal oxidoreductases, based on their heme groups and F420H2:NADP+ oxidoreductase (FNO)-like structures, and play an important role in cell metal metabolism. Interestingly, STEAPs not only participate in biological processes, such as molecular transport, cell cycling, immune response, and intracellular and extracellular activities, but also are closely related to the occurrence and development of several diseases, especially malignant tumors. Up to now, the expression patterns of STEAPs have been found to be diverse in different types of tumors, with controversial participation in different aspects of malignancy, such as cell proliferation, migration, invasion, apoptosis, and therapeutic resistance. It is clinically important to explore the potential roles of STEAPs as new immunotherapeutic targets for the treatment of different malignant tumors. Therefore, this review focuses on the molecular mechanism and function of STEAPs in the occurrence and development of different cancers in order to understand the role of STEAPs in cancer and provide a new theoretical basis for the treatment of diverse cancers.
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Affiliation(s)
- Wen-Jia Chen
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer/Department of Physiology, Shantou University Medical College, Shantou, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Chun-Lan Li
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer/Department of Physiology, Shantou University Medical College, Shantou, China
| | - Yi-Ke Lin
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Ze-Xuan Fang
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer/Department of Physiology, Shantou University Medical College, Shantou, China
| | - Wen-Ting Lin
- Department of Pathology, Shantou University Medical College, Shantou, China
| | - Jing Liu
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer/Department of Physiology, Shantou University Medical College, Shantou, China
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Treatment with metformin prevents myocardial ischemia-reperfusion injury via STEAP4 signaling pathway. Anatol J Cardiol 2019; 21:261-271. [PMID: 31062756 PMCID: PMC6528516 DOI: 10.14744/anatoljcardiol.2019.11456] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Objective: The aim of the present study was to investigate the underlying mechanism of metformin in reducing myocardial apoptosis and improving mitochondrial function in rats and H9c2 cells subjected to myocardial ischemia–reperfusion (I/R) or hypoxia–reoxygenation (H/R) injuries, respectively. Methods: Following pretreatment with metformin, male Sprague–Dawley rats were used to establish an I/R model in vivo. Serum creatinine kinase-MB and cardiac troponin T levels were examined by enzyme-linked immunosorbent assay. Infarct size and apoptosis were measured by triphenyl tetrazolium chloride staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Pathological changes were evaluated by hematoxylin and eosin staining. H9c2 cells were used to establish an H/R model in vitro. Cell apoptosis and mitochondrial membrane potential (MMP) were examined by flow cytometry and Rhodamine 123. The expression levels of six-transmembrane epithelial antigen of prostate 4 (STEAP4), B-cell lymphoma 2, Bcl-2-associated X protein, and glyceraldehyde 3-phosphate dehydrogenase in both myocardial tissues and H9c2 cells were determined by western blotting. Results: We found that metformin decreased infarct size, increased STEAP4 expression, mitigated myocardial apoptosis, and increased MMP when the models were subjected to H/R or I/R injuries. However, STEAP4 knockdown significantly abrogated the beneficial effect of metformin. Conclusion: We further demonstrated the protective effect of metformin on cardiomyocytes, which might be at least partly attributable to the upregulation of STEAP4. Therefore, STEAP4 might be a new target to decrease apoptosis and rescue mitochondrial function in myocardial I/R injury.
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Sikkeland J, Lindstad T, Nenseth HZ, Dezitter X, Qu S, Muhumed RM, Ertunc ME, Gregor MF, Saatcioglu F. Inflammation and ER stress differentially regulate STAMP2 expression and localization in adipocytes. Metabolism 2019; 93:75-85. [PMID: 30710574 PMCID: PMC6460919 DOI: 10.1016/j.metabol.2019.01.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 01/11/2019] [Accepted: 01/24/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Chronic ER stress and dysfunction is a hallmark of obesity and a critical contributor to metaflammation, abnormal hormone action and altered substrate metabolism in metabolic tissues, such as liver and adipocytes. Lack of STAMP2 in lean mice induces inflammation and insulin resistance on a regular diet, and it is dysregulated in the adipose tissue of obese mice and humans. We hypothesized that the regulation of STAMP2 is disrupted by ER stress. METHODS 3T3-L1 and MEF adipocytes were treated with ER stress inducers thapsigargin and tunicamycin, and inflammation inducer TNFα. The treatments effect on STAMP2 expression and enzymatic function was assessed. In addition, 3T3-L1 adipocytes and HEK cells were utilized for Stamp2 promoter activity investigation performed with luciferase and ChIP assays. RESULTS ER stress significantly reduced both STAMP2 mRNA and protein expression in cultured adipocytes whereas TNFα had the opposite effect. Concomitant with loss of STAMP2 expression during ER stress, intracellular localization of STAMP2 was altered and total iron reductase activity was reduced. Stamp2 promoter analysis by reporter assays and chromatin immunoprecipitation, showed that induction of ER stress disrupts C/EBPα-mediated STAMP2 expression. CONCLUSION These data suggest a clear link between ER stress and quantitative and functional STAMP2-deficiency.
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Affiliation(s)
- Jørgen Sikkeland
- Department of Biosciences, University of Oslo, Postboks 1066 Blindern, 0316 Oslo, Norway; Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0310 Oslo, Norway
| | - Torstein Lindstad
- Department of Biosciences, University of Oslo, Postboks 1066 Blindern, 0316 Oslo, Norway
| | - Hatice Zeynep Nenseth
- Department of Biosciences, University of Oslo, Postboks 1066 Blindern, 0316 Oslo, Norway
| | - Xavier Dezitter
- Plateforme de Binding et de Biologie Moléculaire, Institut de Chimie Pharmaceutique Albert Lespagnol, Faculté des Sciences Pharmaceutiques et Biologiques - Université de Lille, F-59006 Lille, France
| | - Su Qu
- Department of Biosciences, University of Oslo, Postboks 1066 Blindern, 0316 Oslo, Norway
| | - Ridhwan M Muhumed
- Department of Biosciences, University of Oslo, Postboks 1066 Blindern, 0316 Oslo, Norway
| | - Meric Erikci Ertunc
- Department of Biosciences, University of Oslo, Postboks 1066 Blindern, 0316 Oslo, Norway; Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard TH Chan School of Public Health, Boston, MA 02115, USA
| | - Margaret F Gregor
- Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard TH Chan School of Public Health, Boston, MA 02115, USA
| | - Fahri Saatcioglu
- Department of Biosciences, University of Oslo, Postboks 1066 Blindern, 0316 Oslo, Norway; Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0310 Oslo, Norway.
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9
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Lindstad T, Qu S, Sikkeland J, Jin Y, Kristian A, Mælandsmo GM, Collas P, Saatcioglu F. STAMP2 is required for human adipose-derived stem cell differentiation and adipocyte-facilitated prostate cancer growth in vivo. Oncotarget 2016; 8:91817-91827. [PMID: 29190878 PMCID: PMC5696144 DOI: 10.18632/oncotarget.11131] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 07/01/2016] [Indexed: 01/01/2023] Open
Abstract
Six Transmembrane Protein of Prostate 2 (STAMP2) has been implicated in both prostate cancer (PCa) and metabolic disease. STAMP2 has unique anti-inflammatory and pro-metabolic properties in mouse adipose tissue, but there is limited information on its role in human metabolic tissues. Using human adipose-derived stem cells (ASCs), we report that STAMP2 expression is dramatically upregulated during adipogenesis. shRNA-mediated STAMP2 knockdown in ASCs significantly suppresses adipogenesis and interferes with optimal expression of adipogenic genes and adipocyte metabolic function. Furthermore, ASC-derived adipocyte-mediated stimulation of prostate tumor growth in nude mice is significantly reduced upon STAMP2 knockdown in ASC adipocytes. These results suggest that STAMP2 is crucial for normal ASC conversion into adipocytes and their metabolic function, as well as their ability to facilitate PCa growth in vivo.
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Affiliation(s)
| | - Su Qu
- Department of Biosciences, University of Oslo, Oslo, Norway
| | - Jørgen Sikkeland
- Department of Biosciences, University of Oslo, Oslo, Norway.,Department of Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
| | - Yang Jin
- Department of Biosciences, University of Oslo, Oslo, Norway.,Department of Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
| | - Alexandr Kristian
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Gunhild M Mælandsmo
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Philippe Collas
- Institute of Basic Medical Sciences, Norwegian Center for Stem Cell Research, University of Oslo, Oslo, Norway
| | - Fahri Saatcioglu
- Department of Biosciences, University of Oslo, Oslo, Norway.,Department of Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
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10
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Yoo SK, Cheong J, Kim HY. STAMPing into Mitochondria. Int J Biol Sci 2014; 10:321-6. [PMID: 24643198 PMCID: PMC3957087 DOI: 10.7150/ijbs.8456] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Accepted: 02/25/2014] [Indexed: 12/24/2022] Open
Abstract
Six transmembrane protein of prostate 2 (STAMP2) is a protein that has been extensively studied due to its association with prostate cancer. Currently, STAMP2 is well known for its critical role in metabolism and modulating inflammatory signals. Even so, the molecular mechanism of STAMP2 activity and its downstream effectors are still largely unknown. Here, we review the current knowledge of STAMP2, and suggest possible explanations for some of its less well-understood features. A few studies suggest that STAMP2 may interact with mitochondria. Considering STAMP2 functions as a potential component of mitochondrial biology may yield valuable insight into this protein.
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Affiliation(s)
- Seong Keun Yoo
- 1. Department of Molecular Biology College of Natural Sciences Pusan National University Busan 609-735, Korea; ; 2. Department of Biological Sciences College of Life Science and Bioengineering Korea Advanced Institute of Science and Technology Deajeon 305-701, Korea
| | - JaeHun Cheong
- 1. Department of Molecular Biology College of Natural Sciences Pusan National University Busan 609-735, Korea
| | - Hye Young Kim
- 1. Department of Molecular Biology College of Natural Sciences Pusan National University Busan 609-735, Korea
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Sikkeland J, Saatcioglu F. Differential expression and function of stamp family proteins in adipocyte differentiation. PLoS One 2013; 8:e68249. [PMID: 23874564 PMCID: PMC3707909 DOI: 10.1371/journal.pone.0068249] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 05/27/2013] [Indexed: 12/19/2022] Open
Abstract
Six transmembrane protein of prostate (Stamp) proteins play an important role in prostate cancer cell growth. Recently, we found that Stamp2 has a critical role in the integration of inflammatory and metabolic signals in adipose tissue where it is highly expressed and regulated by nutritional and metabolic cues. In this study, we show that all Stamp family members are differentially regulated during adipogenesis: whereas Stamp1 expression is significantly decreased upon differentiation, Stamp2 expression is increased. In contrast, Stamp3 expression is modestly changed in adipocytes compared to preadipocytes, and has a biphasic expression pattern during the course of differentiation. Suppression of Stamp1 or Stamp2 expression both led to inhibition of 3T3-L1 differentiation in concert with diminished expression of the key regulators of adipogenesis - CCAAT/enhancer binding protein alpha (C/ebpα) and peroxisome proliferator-activated receptor gamma (Pparγ). Upon Stamp1 knockdown, mitotic clonal expansion was also inhibited. In contrast, Stamp2 knockdown did not affect mitotic clonal expansion, but resulted in a marked decrease in superoxide production that is known to affect adipogenesis. These results suggest that Stamp1 and Stamp2 play critical roles in adipogenesis, but through different mechanisms.
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Affiliation(s)
- Jørgen Sikkeland
- Department of Biosciences, University of Oslo, Postboks, Oslo, Norway
| | - Fahri Saatcioglu
- Department of Biosciences, University of Oslo, Postboks, Oslo, Norway
- * E-mail:
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Qin DN, Zhu JG, Ji CB, Chunmei-Shi, Kou CZ, Zhu GZ, Zhang CM, Wang YP, Ni YH, Guo XR. Monoclonal antibody to six transmembrane epithelial antigen of prostate-4 influences insulin sensitivity by attenuating phosphorylation of P13K (P85) and Akt: possible mitochondrial mechanism. J Bioenerg Biomembr 2011; 43:247-55. [PMID: 21647634 DOI: 10.1007/s10863-011-9360-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2010] [Accepted: 04/17/2011] [Indexed: 01/18/2023]
Abstract
We examined the effects of anti-six-transmembrane epithelial antigen of the prostate-4 (STEAP4) antibodies on glucose transport in mature adipocytes and determined the mechanism of insulin resistance in obesity. Western blotting was performed to determine STEAP4 expression, to assess translocation of insulin-sensitive glucose transporter 4 (GLUT4), and to measure phosphorylation and total protein content of insulin-signaling proteins. Confocal laser microscopy and flow cytometry were used to detect intracellular reactive oxygen species (ROS) and fluctuations in mitochondrial membrane potential (ΔΨ). ATP production was measured by using a luciferase-based luminescence assay kit. After the application of anti-STEAP4 antibodies at 0.002 mg/mL, adipocytes exhibited reduced insulin-stimulated glucose transport by attenuating the phosphorylation of IRS-1, PI3K (p85), and Akt. The antibodies also potentially increase the level of ROS and decrease cellular ATP production and ΔΨ. In conclusion, (i) STEAP4 regulates the function of IRS-1, PI3K, and Akt and decreases insulin-induced GLUT4 translocation and glucose uptake; (ii) ROS-related mitochondrial dysfunction may be related to a reduced IRS-1 correlation with the PI3K signaling pathway, leading to insulin resistance. These observations highlight the potential role of STEAP4 in glucose homeostasis and possibly in the pathophysiology of type 2 diabetes related to obesity and may provide new insights into the mechanisms of insulin resistance in obesity.
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Affiliation(s)
- Da-ni Qin
- Department of Pediatrics, Nanjing Maternal and Child Health Hospital of Nanjing Medical University, No.123 Tianfei Road, Nanjing, 210004, China
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