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1
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Kim YS, Tang PW, Welles JE, Pan W, Javed Z, Elhaw AT, Mythreye K, Kimball SR, Hempel N. HuR-dependent SOD2 protein synthesis is an early adaptation to anchorage-independence. Redox Biol 2022; 53:102329. [PMID: 35594792 PMCID: PMC9121325 DOI: 10.1016/j.redox.2022.102329] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/18/2022] [Accepted: 05/02/2022] [Indexed: 11/16/2022] Open
Abstract
During metastasis cancer cells must adapt to survive loss of anchorage and evade anoikis. An important pro-survival adaptation is the ability of metastatic tumor cells to increase their antioxidant capacity and restore cellular redox balance. Although much is known about the transcriptional regulation of antioxidant enzymes in response to stress, how cells acutely adapt to alter antioxidant enzyme levels is less well understood. Using ovarian cancer cells as a model, we demonstrate that an increase in mitochondrial superoxide dismutase SOD2 protein expression is a very early event initiated in response to detachment, an important step during metastasis that has been associated with increased oxidative stress. SOD2 protein synthesis is rapidly induced within 0.5-2 h of matrix detachment, and polyribosome profiling demonstrates an increase in the number of ribosomes bound to SOD2 mRNA, indicating an increase in SOD2 mRNA translation in response to anchorage-independence. Mechanistically, we find that anchorage-independence induces cytosolic accumulation of the RNA binding protein HuR/ELAVL1 and promotes HuR binding to SOD2 mRNA. Using HuR siRNA-mediated knockdown, we show that the presence of HuR is necessary for the increase in SOD2 mRNA association with the heavy polyribosome fraction and consequent nascent SOD2 protein synthesis in anchorage-independence. Cellular detachment also activates the stress-response mitogen-activated kinase p38, which is necessary for HuR-SOD2 mRNA interactions and induction of SOD2 protein output. These findings illustrate a novel translational regulatory mechanism of SOD2 by which ovarian cancer cells rapidly increase their mitochondrial antioxidant capacity as an acute stress response to anchorage-independence.
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Affiliation(s)
- Yeon Soo Kim
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Priscilla W Tang
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA; Department of Medicine, Division of Hematology/Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, PA, USA
| | - Jaclyn E Welles
- Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Weihua Pan
- Department of Medicine, Division of Hematology/Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, PA, USA
| | - Zaineb Javed
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA; Department of Medicine, Division of Hematology/Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, PA, USA
| | - Amal Taher Elhaw
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA; Department of Medicine, Division of Hematology/Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, PA, USA
| | - Karthikeyan Mythreye
- Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Scot R Kimball
- Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Nadine Hempel
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA; Department of Medicine, Division of Hematology/Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, PA, USA.
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Aksoy Saraç G, Kader S, Akdağ T. Elevated survivin levels in patients with acne vulgaris. J Cosmet Dermatol 2022; 21:1744-1748. [PMID: 35037363 DOI: 10.1111/jocd.14742] [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: 12/11/2021] [Revised: 12/23/2021] [Accepted: 12/29/2021] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Acne vulgaris is a multifactorial disease of the pilosebaceous unit. As the most common skin disease, it may affect approximately 85% of the young population. Survivin, a member of the inhibitors of the apoptosis (IAP) gene family, can inhibit apoptosis and regulate cell division and proliferation. In the study, we aimed to investigate the potential role of serum survivin in acne vulgaris. METHODS Forty individuals who were diagnosed with acne vulgaris and forty healthy subjects as the control group were enrolled in the study. Venous blood samples were collected from each participant, and the serum levels of survivin were measured by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using SPSS software version 25. RESULTS The serum survivin levels were statistically significant between the groups, and the levels of survivin were measured as acne vulgaris patients group 153.44 and control group 104.17 pg/ml, respectively (p < 0.018). When the serum survivin levels were compared according to gender, females had higher levels of survivin than the males (168.16 versus 50.45 pg/mL, p = 0.001). A significant correlation was found between acne severity (p = 0.017) and Scale for Acne Scar severity (SCAR-S) score (p = 0.001) according to the survivin levels. In terms of age, no significant relationship was found between age and survivin (p = 0.4048). CONCLUSION Elevated serum levels of survivin were determined in acne vulgaris. Moreover, there was a significant correlation between acne stage and SCAR-S score according to survivin levels.
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Affiliation(s)
- Gülhan Aksoy Saraç
- Department of Dermatology, Ufuk University Faculty of Medicine, Ankara, Turkey
| | - Saadet Kader
- Karapınar State Hospital Biochemistry Laboratory Karapınar, Konya, Turkey
| | - Turan Akdağ
- Meram Vocational School, Necmettin Erbakan University, Konya, Turkey
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3
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Raguraman R, Shanmugarama S, Mehta M, Elle Peterson J, Zhao YD, Munshi A, Ramesh R. Drug delivery approaches for HuR-targeted therapy for lung cancer. Adv Drug Deliv Rev 2022; 180:114068. [PMID: 34822926 PMCID: PMC8724414 DOI: 10.1016/j.addr.2021.114068] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 11/18/2021] [Indexed: 01/03/2023]
Abstract
Lung cancer (LC) is often diagnosed at an advanced stage and conventional treatments for disease management have limitations associated with them. Novel therapeutic targets are thus avidly sought for the effective management of LC. RNA binding proteins (RBPs) have been convincingly established as key players in tumorigenesis, and their dysregulation is linked to multiple cancers, including LC. In this context, we review the role of Human antigen R (HuR), an RBP that is overexpressed in LC, and further associated with various aspects of LC tumor growth and response to therapy. Herein, we describe the role of HuR in LC progression and outline the evidences supporting various pharmacologic and biologic approaches for inhibiting HuR expression and function. These approaches, including use of small molecule inhibitors, siRNAs and shRNAs, have demonstrated favorable results in reducing tumor cell growth, invasion and migration, angiogenesis and metastasis. Hence, HuR has significant potential as a key therapeutic target in LC. Use of siRNA-based approaches, however, have certain limitations that prevent their maximal exploitation as cancer therapies. To address this, in the conclusion of this review, we provide a list of nanomedicine-based HuR targeting approaches currently being employed for siRNA and shRNA delivery, and provide a rationale for the immense potential therapeutic benefits offered by nanocarrier-based HuR targeting and its promise for treating patients with LC.
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Affiliation(s)
- Rajeswari Raguraman
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Santny Shanmugarama
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Meghna Mehta
- Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jo Elle Peterson
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Yan D Zhao
- Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Anupama Munshi
- Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Rajagopal Ramesh
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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Clinicopathological and Prognostic Significance of Inhibitor of Apoptosis Protein (IAP) Family Members in Lung Cancer: A Meta-Analysis. Cancers (Basel) 2021; 13:cancers13164098. [PMID: 34439255 PMCID: PMC8392569 DOI: 10.3390/cancers13164098] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 08/07/2021] [Accepted: 08/11/2021] [Indexed: 12/25/2022] Open
Abstract
Lung cancer is the most common cause of cancer-related death worldwide. Approximately 85% is non-small-cell and 15% is small-cell lung cancer. The inhibitor of apoptosis proteins (IAPs) represent a heterogeneous family of anti-apoptotic proteins, some members of which have been reported to correlate with clinical outcome in lung cancer. We screened PubMed, Web of Science, and Scopus for studies that investigated the prognostic value and clinicopathological features of IAPs in lung cancer. Forty-five eligible studies with 4428 patients assessed the expression of the IAPs survivin, XIAP, livin, and BRUCE. The pooled hazard ratio (HR) of 33 studies that analyzed overall survival (OS) revealed a positive correlation between survivin expression and poor prognosis. Seven studies displayed a strong association between survivin and disease recurrence. Two studies that assessed the expression of XIAP and livin, respectively, proved a significant relationship of these IAPs with poor OS. Meta-analyses of clinicopathological variables revealed a significant association between survivin and T stage, UICC stage, the presence of lymph node metastasis, and grade of differentiation. In conclusion, high expression of distinct IAPs significantly correlates with prognosis in lung cancer. Therefore, lung cancer patients might benefit from a targeted therapy against specific IAPs.
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Meng X, Lu H, Jiang X, Huang B, Wu S, Yu G, Cao H. Understanding the molecular association between hyperkalemia and lung squamous cell carcinomas. BMC MEDICAL GENETICS 2020; 21:176. [PMID: 33092550 PMCID: PMC7579872 DOI: 10.1186/s12881-020-01099-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 08/03/2020] [Indexed: 12/02/2022]
Abstract
Background Previous studies indicated a strong association between hyperkalemia and lung squamous cell carcinomas (LSCC). However, the underlying mechanism is not fully understood so far. Methods Literature-based data mining was conducted to identify genes, molecule, and cell processes linked to both hyperkalemia and LSCC. Pathway analysis was performed to explore the interactive network, common-target network, and common-regulator network for both disorders. Then, a mega-analysis using 11 independent LSCC RNA expression datasets (358 LSCCs and 278 healthy controls) was performed to test the hypothesis that genes influencing hyperkalemia may also play roles in LSCC. Results There was a significant overlap between the genes implicated with both diseases (20 genes, p-value = 4.98e-15), which counts for 16% of all hyperkalemia genes (125 genes). Network analysis identified 12 molecules as common targets for hyperkalemia and LSCC, and 19 molecules as common regulators. Moreover, 19 molecules were identified within an interactive network, through which hyperkalemia and LSCC could exert influence on each other. In addition, meta-analysis identified one hyperkalemia promoter, SPP1, as a novel contributor for LSCC (LFC = 2.64; p-value = 2.81e-6). MLR analysis suggests geographical region as an influential factor for the expression levels of SPP1 in LSCC patients (p value = 0.036, 0.054). Conclusion Our results showed that there was a common molecular basis for the pathology of both hyperkalemia and LSCC, and that genes promoting hyperkalemia might also play roles in the development of LSCC. However, this study did not suggest hypercalcemia as a casual factor for LSCC.
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Affiliation(s)
- Xianping Meng
- Department of Radiology, Jiangyin People's Hospital, Jiangyin, 214400, Jiangsu Province, China
| | - Hongyan Lu
- Department of Cardiothoracic Surgery, The affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, 214400, Jiangsu, China
| | - Xia Jiang
- Department of Cardiothoracic Surgery, The affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, 214400, Jiangsu, China
| | - Bin Huang
- Department of Cardiothoracic Surgery, The affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, 214400, Jiangsu, China
| | - Song Wu
- Department of Cardiothoracic Surgery, The affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, 214400, Jiangsu, China
| | - Guiping Yu
- Department of Cardiothoracic Surgery, The affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, 214400, Jiangsu, China.
| | - Hongbao Cao
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, 030001, Shanxi Province, China. .,Department of Genomics Research, RD Solutions, Elsevier Inc, Rockville, MD, 20852, USA.
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Blanchard EL, Argyropoulou D, Zurla C, Bhosle SM, Vanover D, Santangelo PJ. Quantification and Localization of Protein-RNA Interactions in Patient-Derived Archival Tumor Tissue. Cancer Res 2019; 79:5418-5431. [PMID: 31481502 DOI: 10.1158/0008-5472.can-19-1094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 07/24/2019] [Accepted: 08/27/2019] [Indexed: 12/22/2022]
Abstract
Abnormal post-transcriptional regulation induced by alterations of mRNA-protein interactions is critical during tumorigenesis and cancer progression and is a hallmark of cancer cells. A more thorough understanding is needed to develop treatments and foresee outcomes. Cellular and mouse tumor models are insufficient for vigorous investigation as they lack consistency and translatability to humans. Moreover, to date, studies in human tumor tissue are predominately limited to expression analysis of proteins and mRNA, which do not necessarily provide information about the frequency of mRNA-protein interactions. Here, we demonstrate novel optimization of a method that is based on FISH and proximity ligation techniques to quantify mRNA interactions with RNA-binding proteins relevant for tumorigenesis and cancer progression in archival patient-derived tumor tissue. This method was validated for multiple mRNA-protein pairs in several cellular models and in multiple types of archival human tumor samples. Furthermore, this approach allowed high-throughput analysis of mRNA-protein interactions across a wide range of tumor types and stages through tumor microarrays. This method is quantitative, specific, and sensitive for detecting interactions and their localization at both the individual cell and whole-tissue scales with single interaction sensitivity. This work presents an important tool in investigating post-transcriptional regulation in cancer on a high-throughput scale, with great potential for translatability into any applications where mRNA-protein interactions are of interest. SIGNIFICANCE: This work presents an approach to sensitively, specifically, and quantitatively detect and localize native mRNA and protein interactions for analysis of abnormal post-transcriptional regulation in patient-derived archival tumor samples.
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Affiliation(s)
- Emmeline L Blanchard
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia
| | - Danae Argyropoulou
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia
| | - Chiara Zurla
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia
| | - Sushma M Bhosle
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia
| | - Daryll Vanover
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia
| | - Philip J Santangelo
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia
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Lukosiute-Urboniene A, Jasukaitiene A, Silkuniene G, Barauskas V, Gulbinas A, Dambrauskas Z. Human antigen R mediated post-transcriptional regulation of inhibitors of apoptosis proteins in pancreatic cancer. World J Gastroenterol 2019; 25:205-219. [PMID: 30670910 PMCID: PMC6337016 DOI: 10.3748/wjg.v25.i2.205] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/06/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the association of human antigen R (HuR) and inhibitors of apoptosis proteins (IAP1, IAP2) and prognosis in pancreatic cancer. METHODS Protein and mRNA expression levels of IAP1, IAP2 and HuR in pancreatic ductal adenocarcinoma (PDAC) were compared with normal pancreatic tissue. The correlations among IAP1/IAP2 and HuR as well as their respective correlations with clinicopathological parameters were analyzed. The Kaplan-Meier method and log-rank tests were used for survival analysis. Immunoprecipitation assay was performed to demonstrate HuR binding to IAP1, IAP2 mRNA. PANC1 cells were transfected with either anti-HuR siRNA or control siRNA for 72 h and quantitative reverse transcription polymerase chain reaction (RT-PCR), western blot analysis was carried out. RESULTS RT-PCR analysis revealed that HuR, IAP1, IAP2 mRNA expression were accordingly 3.3-fold, 5.5-fold and 8.4 higher in the PDAC when compared to normal pancreas (P < 0.05). Expression of IAP1 was positively strongly correlated with HuR expression (P < 0.05, r = 0.783). Western blot analysis confirmed RT-PCR results. High IAP1 expression, tumor resection status, T stage, lymph-node metastases, tumor differentiation grade, perineural and lymphatic invasion were identified as significant factors for shorter survival in PDAC patients (P < 0.05). Immunohistological analysis showed that HuR was mainly expressed in the ductal cancer cell's nucleus and less so in cytoplasm. RNA immunoprecipitation analysis confirmed IAP1 and IAP2 post-transcriptional regulation by HuR protein. Following siHuR transfection, IAP1 mRNA and protein levels were decreased, however IAP2 expression levels were increased. CONCLUSION HuR mediated overexpression of IAP1 significantly correlates with poor outcomes and early progression of pancreatic cancer. Further studies are needed to assess the underlying mechanisms.
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MESH Headings
- Aged
- Aged, 80 and over
- Baculoviral IAP Repeat-Containing 3 Protein/genetics
- Baculoviral IAP Repeat-Containing 3 Protein/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- ELAV-Like Protein 1/genetics
- ELAV-Like Protein 1/metabolism
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Inhibitor of Apoptosis Proteins/genetics
- Inhibitor of Apoptosis Proteins/metabolism
- Kaplan-Meier Estimate
- Lymphatic Metastasis
- Male
- Middle Aged
- Neoplasm Grading
- Pancreas/pathology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/mortality
- Pancreatic Neoplasms/pathology
- Prognosis
- RNA, Messenger/metabolism
- RNA, Small Interfering/metabolism
- Ubiquitin-Protein Ligases/genetics
- Ubiquitin-Protein Ligases/metabolism
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Affiliation(s)
- Ausra Lukosiute-Urboniene
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
- Department of Pediatric Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Aldona Jasukaitiene
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Giedre Silkuniene
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Vidmantas Barauskas
- Department of Pediatric Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Antanas Gulbinas
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Zilvinas Dambrauskas
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
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Expression analysis of cyclooxygenase-2 in patients suffering from esophageal squamous cell carcinoma. PLoS One 2018; 13:e0205508. [PMID: 30339710 PMCID: PMC6195262 DOI: 10.1371/journal.pone.0205508] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 09/26/2018] [Indexed: 12/27/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the aggressive malignancies and mechanisms underlying its pathogenesis remain unclear. Cyclooxygenase-2 (COX-2) enzyme system plays a crucial role in many gastrointestinal malignancies and is an important regulator of cell growth, proliferation, apoptosis, differentiation and transformation. More precise outcome of COX-2 in ESCC is less investigated. In this study we investigated the risk factors of ESCC and expression of COX-2 in Carcinoma in situ (CIS) and ESCC compared to normal esophageal mucosa. ESCC relationship to clinico-pathological parameters using immunohistochemistry was also part of this investigation. Current study was conducted in the Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan. A total of 69 diagnosed patients of ESCC, both Pakistanis and Afghans were enrolled. Various risk factors associated with ESCC were recorded. Mean age at the time of diagnosis was 55 years. Out of 69 patients of ESCC 46 (67%) were users of dipping tobacco (Naswar). Expression of COX-2 was determined in normal esophageal mucosa, CIS and invasive ESCC using Immunohistochemistry (IHC). Differences of mean were computed using ANOVA followed by applying Post Hoc test. Patients were categorized as positive with high expression or negative with low to nil expression. ANOVA showed large differences in expression of COX-2 in normal healthy mucosa compared with CIS and ESCC with the mean difference of -9.529 and -7.370 respectively, p-value being <.05 at 95% confidence interval (CI). No significant difference was noticed in the expression of COX-2 in CIS compared with ESCC with p-value >.05 at 95% CI. Our complete cohort (23-85 years) showed statistically significant difference in the expression of COX-2 gene in ESCC and CIS tissue samples compared with normal healthy mucosa. Results of this study indicate that over-expression of COX-2 is positively associated with ESCC.
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Sui X, Yu S, Dou L, Chen X, Li X, Yang J, Su Y, Wang S, Wang F, Li J. miR-291b-3p mediated ROS-induced endothelial cell dysfunction by targeting HUR. Int J Mol Med 2018; 42:2383-2392. [PMID: 30106126 PMCID: PMC6192777 DOI: 10.3892/ijmm.2018.3821] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 08/06/2018] [Indexed: 12/04/2022] Open
Abstract
Endothelial dysfunction is an early marker of atherosclerosis. Previous studies have indicated that microRNA (miR)-291b-3p regulates the metabolism of lipids and glucose in the liver via targeting adenosine monophosphate-activated kinase α1 and transcription factor p65. The present study investigated whether miR-291b-3p mediated H2O2-mediated endothelial dysfunction. The level of apoptosis of EOMA mouse endothelial cells was analyzed by terminal deoxynucleotidyl-transferase-mediated dUTP nick end labelling staining. The mRNA levels of miR-291b-3p, intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) were determined by quantitative polymerase chain reaction. The level of phosphorylated extracellular signal-regulated kinase, and levels of B-cell lymphoma 2 (Bcl-2)-associated X protein and Bcl-2 protein were detected by western blot analysis. The treatment of H2O2 induced the apoptosis and increased the mRNA levels of miR-291b-3p, ICAM-1 and VCAM-1 in EOMA cells. It was also demonstrated that the overexpression of miR-291b-3p promoted EOMA cell apoptosis and dysfunction. In contrast, the downregulation of miR-291b-3p rescued the effect of H2O2 on EOMA cell dysfunction. In addition, Hu antigen R (HuR) was identified as a target gene of miR-291b-3p in EOMA cells. The overexpression of HuR reversed the endothelial dysfunction induced by miR-291b-3p mimics. The present study provides novel insight into the critical role of miR-291b-3p on the endothelial dysfunction induced by H2O2. miR-291b-3p may mediate H2O2-induced endothelial dysfunction via targeting HuR.
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Affiliation(s)
- Xiaofang Sui
- Department of Geriatrics, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China
| | - Shuqian Yu
- Department of Geriatrics, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China
| | - Lin Dou
- The Ministry of Health Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing 100730, P.R. China
| | - Xiehui Chen
- Department of Geriatric Cardiovascular Medicine, Shenzhen Sun Yat‑Sen Cardiovascular Hospital, Shenzhen, Guangdong 518112, P.R. China
| | - Xuejie Li
- Department of Geriatrics, Clinical Medical School, Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China
| | - Jun Yang
- Department of Geriatrics, Clinical Medical School, Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China
| | - Yanan Su
- Department of Geriatrics, Clinical Medical School, Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China
| | - Shuyue Wang
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, Jilin, P.R. China
| | - Fengling Wang
- Department of Geriatrics, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China
| | - Jian Li
- The Ministry of Health Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing 100730, P.R. China
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Isik Z, Ercan ME. Integration of RNA-Seq and RPPA data for survival time prediction in cancer patients. Comput Biol Med 2017; 89:397-404. [PMID: 28869900 DOI: 10.1016/j.compbiomed.2017.08.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 08/20/2017] [Accepted: 08/25/2017] [Indexed: 10/19/2022]
Abstract
Integration of several types of patient data in a computational framework can accelerate the identification of more reliable biomarkers, especially for prognostic purposes. This study aims to identify biomarkers that can successfully predict the potential survival time of a cancer patient by integrating the transcriptomic (RNA-Seq), proteomic (RPPA), and protein-protein interaction (PPI) data. The proposed method -RPBioNet- employs a random walk-based algorithm that works on a PPI network to identify a limited number of protein biomarkers. Later, the method uses gene expression measurements of the selected biomarkers to train a classifier for the survival time prediction of patients. RPBioNet was applied to classify kidney renal clear cell carcinoma (KIRC), glioblastoma multiforme (GBM), and lung squamous cell carcinoma (LUSC) patients based on their survival time classes (long- or short-term). The RPBioNet method correctly identified the survival time classes of patients with between 66% and 78% average accuracy for three data sets. RPBioNet operates with only 20 to 50 biomarkers and can achieve on average 6% higher accuracy compared to the closest alternative method, which uses only RNA-Seq data in the biomarker selection. Further analysis of the most predictive biomarkers highlighted genes that are common for both cancer types, as they may be driver proteins responsible for cancer progression. The novelty of this study is the integration of a PPI network with mRNA and protein expression data to identify more accurate prognostic biomarkers that can be used for clinical purposes in the future.
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Affiliation(s)
- Zerrin Isik
- Computer Engineering Department, Dokuz Eylul Universitesi, 35160, Izmir, Turkey.
| | - Muserref Ece Ercan
- Computer Engineering Department, Dokuz Eylul Universitesi, 35160, Izmir, Turkey
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Vaklavas C, Blume SW, Grizzle WE. Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development. Front Oncol 2017; 7:158. [PMID: 28798901 PMCID: PMC5526920 DOI: 10.3389/fonc.2017.00158] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 07/06/2017] [Indexed: 01/04/2023] Open
Abstract
Although transcript levels have been traditionally used as a surrogate measure of gene expression, it is increasingly recognized that the latter is extensively and dynamically modulated at the level of translation (messenger RNA to protein). Over the recent years, significant progress has been made in dissecting the complex posttranscriptional mechanisms that regulate gene expression. This advancement in knowledge came hand in hand with the progress made in the methodologies to study translation both at gene-specific as well as global genomic level. The majority of translational control is exerted at the level of initiation; nonetheless, protein synthesis can be modulated at the level of translation elongation, termination, and recycling. Sequence and structural elements and epitranscriptomic modifications of individual transcripts allow for dynamic gene-specific modulation of translation. Cancer cells usurp the regulatory mechanisms that govern translation to carry out translational programs that lead to the phenotypic hallmarks of cancer. Translation is a critical nexus in neoplastic transformation. Multiple oncogenes and signaling pathways that are activated, upregulated, or mutated in cancer converge on translation and their transformative impact "bottlenecks" at the level of translation. Moreover, this translational dysregulation allows cancer cells to adapt to a diverse array of stresses associated with a hostile microenviroment and antitumor therapies. All elements involved in the process of translation, from the transcriptional template, the components of the translational machinery, to the proteins that interact with the transcriptome, have been found to be qualitatively and/or quantitatively perturbed in cancer. This review discusses the regulatory mechanisms that govern translation in normal cells and how translation becomes dysregulated in cancer leading to the phenotypic hallmarks of malignancy. We also discuss how dysregulated mediators or components of translation can be utilized as biomarkers with potential diagnostic, prognostic, or predictive significance. Such biomarkers have the potential advantage of uniform applicability in the face of inherent tumor heterogeneity and deoxyribonucleic acid instability. As translation becomes increasingly recognized as a process gone awry in cancer and agents are developed to target it, the utility and significance of these potential biomarkers is expected to increase.
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Affiliation(s)
- Christos Vaklavas
- Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Scott W Blume
- Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - William E Grizzle
- Department of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
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12
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Manimaran A, Buddhan R, Manoharan S. EMODIN DOWNREGULATES CELL PROLIFERATION MARKERS DURING DMBA INDUCED ORAL CARCINOGENESIS IN GOLDEN SYRIAN HAMSTERS. AFRICAN JOURNAL OF TRADITIONAL, COMPLEMENTARY, AND ALTERNATIVE MEDICINES 2017; 14:83-91. [PMID: 28573225 PMCID: PMC5446469 DOI: 10.21010/ajtcam.v14i2.10] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background: Cell-cycle disruption is the major characteristic features of neoplastic transformation and the status of cell-cycle regulators can thus be utilized to assess the prognostic significance in patients with cancer. The PCNA, cyclin D1, CDK4, CDK6 and survivin expression in the buccal mucosa was utilized to evaluate the Emodin efficacy on abnormal cell proliferation during 7,12-dimethylbenz(a)anthracene (DMBA) induced oral carcinogenesis in golden Syrian hamsters. Materials and methods: Topical application of DMBA, three times a week for 14 weeks, on the hamsters’ buccal pouches developed well differentiated squamous cell carcinoma. Results: Cyclin D1 and PCNA over-expression and up-regulation of CDK4, CDK6 and survivin were noticed in the buccal mucosa of hamsters treated with DMBA alone. Emodin administration (50mg/kg b.w) orally to hamsters treated with DMBA down-regulated the expression of cell proliferation markers in the buccal mucosa. Conclusions: The anti-cell proliferative role of Emodin is owing to its modulating efficacy on cell-cycle markers towards the tumor suppression during DMBA induced oral carcinogenesis.
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Affiliation(s)
- Asokan Manimaran
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamilnadu, India
| | - Rajamanickam Buddhan
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamilnadu, India
| | - Shanmugam Manoharan
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamilnadu, India
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13
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Vlasova-St Louis I, Bohjanen PR. Post-transcriptional regulation of cytokine and growth factor signaling in cancer. Cytokine Growth Factor Rev 2016; 33:83-93. [PMID: 27956133 DOI: 10.1016/j.cytogfr.2016.11.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 11/28/2016] [Indexed: 12/11/2022]
Abstract
Cytokines and growth factors regulate cell proliferation, differentiation, migration and apoptosis, and play important roles in coordinating growth signal responses during development. The expression of cytokine genes and the signals transmitted through cytokine receptors are tightly regulated at several levels, including transcriptional and post-transcriptional levels. A majority of cytokine mRNAs, including growth factor transcripts, contain AU-rich elements (AREs) in their 3' untranslated regions that control gene expression by regulating mRNA degradation and changing translational rates. In addition, numerous proteins involved in transmitting signals downstream of cytokine receptors are regulated at the level of mRNA degradation by GU-rich elements (GREs) found in their 3' untranslated regions. Abnormal stabilization and overexpression of ARE or GRE-containing transcripts had been observed in many malignancies, which is a consequence of the malfunction of RNA-binding proteins. In this review, we briefly summarize the role of AREs and GREs in regulating mRNA turnover to coordinate cytokine and growth factor expression, and we describe how dysregulation of mRNA degradation mechanisms contributes to the development and progression of cancer.
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Affiliation(s)
| | - Paul R Bohjanen
- Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA
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14
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Assaf HA, Abdel-Maged WM, Elsadek BEM, Hassan MH, Adly MA, Ali SA. Survivin as a Novel Biomarker in the Pathogenesis of Acne Vulgaris and Its Correlation to Insulin-Like Growth Factor-I. DISEASE MARKERS 2016; 2016:7040312. [PMID: 27803511 PMCID: PMC5075610 DOI: 10.1155/2016/7040312] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 09/01/2016] [Accepted: 09/07/2016] [Indexed: 01/10/2023]
Abstract
Survivin, a member of the inhibitor of apoptosis protein family, has an important role in cell cycle regulation. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone with wide range of biologic effects including stimulation of lipogenesis in sebaceous glands. Their overexpression in some fibrotic disorders suggests a possible implication of both IGF-I and survivin in the pathogenesis of acne and/or acne scars. The current study aimed to assess and correlate serum levels of IGF-I and survivin in patients with active acne vulgaris and postinflammatory acne scars and to evaluate their lesional expressions in comparison to healthy controls. Serum IGF-I and survivin were estimated using commercially available ELISA kits and their tissues expressions were investigated using Western blotting. Our findings suggest that IGF-I and survivin could play potential roles in the pathogenesis of active acne vulgaris and more importantly in postinflammatory acne scars with significant positive correlation coefficient between serum levels of IGF-I and survivin which support IGF-I-/PI3K-/AKT-mediated downregulation of nuclear expression of FoxO transcription factors resulting in enhanced survivin expression.
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Affiliation(s)
- Hanan A. Assaf
- Department of Dermatology, Faculty of Medicine, Sohag University, P.O. Box 82524, Sohag, Egypt
| | - Wafaa M. Abdel-Maged
- Department of Dermatology, Faculty of Medicine, Sohag University, P.O. Box 82524, Sohag, Egypt
| | - Bakheet E. M. Elsadek
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, P.O. Box 71524, Assiut, Egypt
| | - Mohammed H. Hassan
- Department of Biochemistry and Molecular Biology, Qena Faculty of Medicine, South Valley University, P.O. Box 83523, Qena, Egypt
| | - Mohamed A. Adly
- Department of Zoology, Faculty of Science, Sohag University, P.O. Box 82524, Sohag, Egypt
| | - Soher A. Ali
- Department of Dermatology, Faculty of Medicine, Sohag University, P.O. Box 82524, Sohag, Egypt
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15
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Jimbo M, Blanco FF, Huang YH, Telonis AG, Screnci BA, Cosma GL, Alexeev V, Gonye GE, Yeo CJ, Sawicki JA, Winter JM, Brody JR. Targeting the mRNA-binding protein HuR impairs malignant characteristics of pancreatic ductal adenocarcinoma cells. Oncotarget 2016; 6:27312-31. [PMID: 26314962 PMCID: PMC4694992 DOI: 10.18632/oncotarget.4743] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 07/13/2015] [Indexed: 12/21/2022] Open
Abstract
Post-transcriptional regulation is a powerful mediator of gene expression, and can rapidly alter the expression of numerous transcripts involved in tumorigenesis. We have previously shown that the mRNA-binding protein HuR (ELAVL1) is elevated in human pancreatic ductal adenocarcinoma (PDA) specimens compared to normal pancreatic tissues, and its cytoplasmic localization is associated with increased tumor stage. To gain a better insight into HuR’s role in PDA biology and to assess it as a candidate therapeutic target, we altered HuR expression in PDA cell lines and characterized the resulting phenotype in preclinical models. HuR silencing by short hairpin and small interfering RNAs significantly decreased cell proliferation and anchorage-independent growth, as well as impaired migration and invasion. In comparison, HuR overexpression increased migration and invasion, but had no significant effects on cell proliferation and anchorage-independent growth. Importantly, two distinct targeted approaches to HuR silencing showed marked impairment in tumor growth in mouse xenografts. NanoString nCounter® analyses demonstrated that HuR regulates core biological processes, highlighting that HuR inhibition likely thwarts PDA viability through post-transcriptional regulation of diverse signaling pathways (e.g. cell cycle, apoptosis, DNA repair). Taken together, our study suggests that targeted inhibition of HuR may be a novel, promising approach to the treatment of PDA.
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Affiliation(s)
- Masaya Jimbo
- Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Fernando F Blanco
- Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.,Department of Pharmacology & Experimental Therapeutics, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Yu-Hung Huang
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Aristeidis G Telonis
- Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Brad A Screnci
- Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Gabriela L Cosma
- Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Vitali Alexeev
- Department of Dermatology, Thomas Jefferson University, Philadelphia, PA, USA
| | | | - Charles J Yeo
- Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | | | - Jordan M Winter
- Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jonathan R Brody
- Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
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Lafzi A, Kazan H. Inferring RBP-Mediated Regulation in Lung Squamous Cell Carcinoma. PLoS One 2016; 11:e0155354. [PMID: 27186987 PMCID: PMC4871487 DOI: 10.1371/journal.pone.0155354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 04/27/2016] [Indexed: 12/11/2022] Open
Abstract
RNA-binding proteins (RBPs) play key roles in post-transcriptional regulation of mRNAs. Dysregulations in RBP-mediated mechanisms have been found to be associated with many steps of cancer initiation and progression. Despite this, previous studies of gene expression in cancer have ignored the effect of RBPs. To this end, we developed a lasso regression model that predicts gene expression in cancer by incorporating RBP-mediated regulation as well as the effects of other well-studied factors such as copy-number variation, DNA methylation, TFs and miRNAs. As a case study, we applied our model to Lung squamous cell carcinoma (LUSC) data as we found that there are several RBPs differentially expressed in LUSC. Including RBP-mediated regulatory effects in addition to the other features significantly increased the Spearman rank correlation between predicted and measured expression of held-out genes. Using a feature selection procedure that accounts for the adaptive search employed by lasso regularization, we identified the candidate regulators in LUSC. Remarkably, several of these candidate regulators are RBPs. Furthermore, majority of the candidate regulators have been previously found to be associated with lung cancer. To investigate the mechanisms that are controlled by these regulators, we predicted their target gene sets based on our model. We validated the target gene sets by comparing against experimentally verified targets. Our results suggest that the future studies of gene expression in cancer must consider the effect of RBP-mediated regulation.
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Affiliation(s)
- Atefeh Lafzi
- Department of Health Informatics, Middle East Technical University, Ankara, Turkey
| | - Hilal Kazan
- Department of Computer Engineering, Antalya International University, Antalya, Turkey
- * E-mail:
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17
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Yin H, Sun Y, Wang X, Park J, Zhang Y, Li M, Yin J, Liu Q, Wei M. Progress on the relationship between miR-125 family and tumorigenesis. Exp Cell Res 2015; 339:252-60. [PMID: 26407906 DOI: 10.1016/j.yexcr.2015.09.015] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 08/25/2015] [Accepted: 09/19/2015] [Indexed: 12/21/2022]
Abstract
miRNA-125 family, which is a highly conserved miRNA family throughout evolution, is consist of miRNA-125a-3p, miRNA-125a-5p, miRNA-125b-1 and miRNA-125b-2.The aberrant expression of miR-125 familyis tightly related to tumorigenesis and tumor development. The downstream targets of miRNA-125 include transcription factors like STAT3, cytokines like IL-6 and TGF-β, tumor suppressing protein p53, pro-apoptotic protein Bak1 and RNA binding protein HuR et al. Through regulating these downstream targets miR-125 family is involved in regulating tumorigenesis and tumor development. Nowadays, miR-125b have already became a putative and valuable biomarker for cancer diagnosis, treatment and prognosis. In this review, we mainly summarize the dual function of miRNA-125 family in suppression and promotion of cancer cells and further elaborate its regulatory mechanisms from four facets, proliferation, apoptosis, invasion or metastasis and immune response.
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Affiliation(s)
- Hang Yin
- Dalian 24 High School, Dalian 116023, China
| | - Yuqiang Sun
- Department of Neurosurgery, The Second Afiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Xiaofeng Wang
- Department of Neurosurgery, The Second Afiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Jeiyoun Park
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA
| | - Yuanyang Zhang
- Department of Ultrasonography, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Molin Li
- Department of Pathophysiology, Dalian Medical University, Dalian 116044, China
| | - Jian Yin
- Department of Neurosurgery, The Second Afiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Qiang Liu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Minghai Wei
- Department of Neurosurgery, The Second Afiliated Hospital of Dalian Medical University, Dalian 116023, China.
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18
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Cho HJ, Kim HR, Park YS, Kim YH, Kim DK, Park SI. Prognostic value of survivin expression in stage III non-small cell lung cancer patients treated with platinum-based therapy. Surg Oncol 2015; 24:329-34. [PMID: 26690822 DOI: 10.1016/j.suronc.2015.09.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 09/13/2015] [Indexed: 11/16/2022]
Abstract
BACKGROUND The potential prognostic value of survivin is variably reported depending on the lung cancer stage. This study examines the correlation between tumor survivin expression before and after chemoradiation therapy, therapeutic response, and prognosis in stage III non-small cell lung cancer (NSCLC) patients who were treated with platinum-based chemoradiation therapy and surgery. METHODS This retrospective study included stage III NSCLC patients with adequate pre- and posttreatment tumor tissues. Tissues were stained using immunohistochemistry, and the degree of staining was scored. Clinical and biological variables were assessed using univariate and multivariate analyses to determine the prognostic relationship with overall survival (OS) and time to recurrence (TTR). RESULTS Fifty-three patients were enrolled. Tumor survivin expression in pretreatment tissues was determined in 47 patients (88.7%). The pretreatment survivin score was unrelated with TTR and OS (p = 0.249 and 0.601, respectively). There was no correlation between the pre- and posttreatment survivin scores (p = 0.309). Downregulated survivin and the posttreatment survivin score (0-1) after chemoradiation were significantly correlated with improved OS (p = 0.04 and p = 0.033, respectively). Age, downregulated survivin score, and posttreatment survivin score (0-1) were significant prognostic factors for survival according to the multivariate analysis. CONCLUSION Downregulated and low posttreatment survivin scores are prognostic in stage III NSCLC patients who receive platinum-based chemoradiation therapy followed by surgery regardless of the pretreatment survivin score. These results suggest that additional studies on the relationship between survivin and platinum-based chemoradiation therapy are warranted in NSCLC patients.
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Affiliation(s)
- Hyun Jin Cho
- Department of Thoracic and Cardiovascular Surgery, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Hyeong Ryul Kim
- Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yong-Hee Kim
- Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong Kwan Kim
- Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seung-Il Park
- Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Ji ZJ, Wang JL, Chen L. Inhibition of skin squamous cell carcinoma proliferation and promote apoptosis by dual silencing of NET-1 and survivin. Oncol Rep 2015; 34:811-22. [PMID: 26080853 DOI: 10.3892/or.2015.4062] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 05/29/2015] [Indexed: 11/05/2022] Open
Abstract
The simultaneous silencing of multiple upregulated genes is an attractive and viable strategy to treat many incurable diseases including cancer. In the present study, skin squamous cell carcinoma (SSCC) tissue microarray was constructed and the expression of NET-1 and survivin was identified. The high expression of NET-1 and survivin gene in SSCC was confirmed as an important event for the formation and development of the cancer. A total of 100 primary SSCC patients were included in the present study. Expression of NET-1 and survivin in cancer cells was evaluated immunohistochemically in tissue microarrays. The interaction between NET-1 and survivin in SSCC by co-immunoprecipitation was subsequently verified by producing the siRNA sequence targeting the single gene (siRNA-NET-1 and siRNA-survivin) as well as NET-1 and survivin gene (one-chain-double-target siRNA). The levels of NET-1 and survivin mRNA and protein expression in A431 cells were detected by RT-qPCR and western blotting, and the expression of related genes including vascular endothelial growth factor (VEGF), cortactin, Bcl-2, caspase-3 and -8 was identified using RT-qPCR. The protein localization and expression of NET-1 and survivin in A431 cells were documented by immunohistochemistry and immuno-fluorescence staining. The proliferation and apoptosis of A431 cells were detected by CCK-8 assay and flow cytometry (FCM). The tissue microarray showed that NET-1 and survivin were highly expressed in SSCC, while the correlation analysis showed NET-1 expression was positively associated with survivin. In addition, we reported that using the one-chain-double-target siRNA conjugate composed of NET-1 and survivin siRNA sequences in the same backbone inhibited proliferation and promoted apoptosis of SSCC. The one-chain-double-target siRNA showed further downregulation on NET-1 and survivin mRNA and protein levels compared with NET-1 siRNA or survivin siRNA. It also exhibited greater suppression on proliferation and triggering of apoptosis in A431 cells than NET-1 siRNA or survivin siRNA. This result may be explained by the significant downregulation of VEGF, cortactin and Bcl-2, and upregulation of caspase-3 and -8. NET-1 and survivin were overexpressed in SSCC and an interaction between NET-1 and survivin was identified. The one-chain-double-target siRNA appears to be superior in inhibiting cell proliferation and promoting apoptosis compared with the single target siRNA. NET-1 and survivin may have correlative signaling pathways with VEGF, cortactin, Bcl-2, caspase-3 and -8. Simultaneous silencing of NET-1 and survivin using one-chain-double-target siRNA thus provides an advantageous alternative in the development of therapeutics for SSCC.
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Affiliation(s)
- Zhou-Jing Ji
- Department of Dermatology and Venereology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Jian-Li Wang
- Department of Dermatology and Venereology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Li Chen
- Department of Pathological Anatomy, Nantong University, Nantong, Jiangsu, P.R. China
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20
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Vigouroux C, Casse JM, Battaglia-Hsu SF, Brochin L, Luc A, Paris C, Lacomme S, Gueant JL, Vignaud JM, Gauchotte G. Methyl(R217)HuR and MCM6 are inversely correlated and are prognostic markers in non small cell lung carcinoma. Lung Cancer 2015; 89:189-96. [PMID: 26013954 DOI: 10.1016/j.lungcan.2015.05.008] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 05/02/2015] [Accepted: 05/09/2015] [Indexed: 01/24/2023]
Abstract
OBJECTIVES In non small cell lung carcinoma (NSCLC), earlier studies supported a prognostic value of intra-cytoplasmic HuR expression. HuR is a RNA binding protein previously shown to stimulate proliferation, but the link between HuR and proliferation in NSCLC has not yet been evaluated. The first objective of this study was to analyze the expression of HuR in a series of NSCLC and to correlate this to two proliferation markers, Ki-67 and MCM6. As potential post-transcriptional regulatory mechanisms for HuR expression, two miRNAs, miR16 and miR519, were also analyzed. Finally, because HuR methylation could be involved in its nucleocytoplasmic shuttling, the expression of methyl(R217)HuR and its relation to cancer survival were determined. MATERIALS AND METHODS Immunohistochemistry was used to evaluate the expression of HuR, methy(R217)HuR, Ki-67 and MCM6 in a series of 190 NSCLCs. The level of miR16 and miR519 was determined by qRT-PCR. RESULTS Higher cytoplasmic HuR staining was found in tumor vs. control paired normal lung (p<0.0001), but without correlation with survival. The level of methyl(R217)HuR was correlated both significantly with intra-cytoplasmic HuR staining (p<0.001), and overall survival (p=0.01). MCM6 correlated to a poorer overall survival (p<0.01). Both MCM6 and Ki-67 were positively correlated with HuR nuclear staining (p<0.0001 and p<0.001, respectively). On the contrary, MCM6 and Ki-67 correlated inversely to methyl(R217)HuR (p<0.001 and p=0.01, respectively). The levels of miR16 and miR519 were significantly lower in tumor tissue vs. paired normal lung (p<0.0001), but only miR519 correlated inversely to HuR expression (p=0.01). CONCLUSION While overall cytoplasmic HuR level was higher in tumor tissues, we found unexpectedly that methyl(R217)HuR was a marker of good prognosis. Furthermore, our data suggest that HuR level could be regulated by miR519. Finally, we demonstrated that Ki-67 and MCM6, both correlated with HuR, are valuable markers of poor prognosis in NSCLC.
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Affiliation(s)
| | - Jean-Matthieu Casse
- Department of Pathology, CHU Nancy, France; INSERM U954, Faculty of Medicine, Université de Lorraine, Nancy, France
| | - Shyue-Fang Battaglia-Hsu
- INSERM U954, Faculty of Medicine, Université de Lorraine, Nancy, France; Department of Molecular Biology and Biochemistry, CHU Nancy, France
| | | | - Amandine Luc
- INGRES, EA7298, Faculty of Medicine, Université de Lorraine, Nancy, France
| | - Christophe Paris
- INGRES, EA7298, Faculty of Medicine, Université de Lorraine, Nancy, France; Department of Occupational Diseases, CHU Nancy, France
| | | | - Jean-Louis Gueant
- INSERM U954, Faculty of Medicine, Université de Lorraine, Nancy, France; Department of Molecular Biology and Biochemistry, CHU Nancy, France
| | - Jean-Michel Vignaud
- Department of Pathology, CHU Nancy, France; INSERM U954, Faculty of Medicine, Université de Lorraine, Nancy, France; Centre de Ressources Biologiques, BB-0033-00035, CHU Nancy, France
| | - Guillaume Gauchotte
- Department of Pathology, CHU Nancy, France; INSERM U954, Faculty of Medicine, Université de Lorraine, Nancy, France.
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21
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Growth factor dependent regulation of centrosome function and genomic instability by HuR. Biomolecules 2015; 5:263-81. [PMID: 25803745 PMCID: PMC4384122 DOI: 10.3390/biom5010263] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 03/06/2015] [Accepted: 03/11/2015] [Indexed: 01/10/2023] Open
Abstract
The mRNA binding protein HuR is over expressed in cancer cells and contributes to disease progression through post-transcriptional regulation of mRNA. The regulation of HuR and how this relates to glioma is the focus of this report. SRC and c-Abl kinases regulate HuR sub-cellular trafficking and influence accumulation in the pericentriolar matrix (PCM) via a growth factor dependent signaling mechanism. Growth factor stimulation of glioma cell lines results in the associate of HuR with the PCM and amplification of centrosome number. This process is regulated by tyrosine phosphorylation of HuR and is abolished by mutating tyrosine residues. HuR is overexpressed in tumor samples from patients with glioblastoma and associated with a reduced survival. These findings suggest HuR plays a significant role in centrosome amplification and genomic instability, which contributes to a worse disease outcome.
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22
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Ma R, Yi B, Piazza GA, Xi Y. Mechanistic Role of MicroRNA in Cancer Chemoprevention by Nonsteroidal Anti-inflammatory Drugs. ACTA ACUST UNITED AC 2015. [PMID: 26213681 DOI: 10.1007/s40495-014-0011-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Over the past several decades, studies have documented the significance of nonsteroidal anti-inflammatory drugs (NSAIDs) on cancer chemoprevention by lowering incidence and slowing down progression of malignant disease, which consequently lead to decline of cancer-related mortality and improvement of disease progression free survival (PFS). Inhibition of cyclooxygenase (COX) has been primarily believed to be the key mechanism responsible for anticancer activity of NSAIDs, while the serious toxicity caused by COX inhibitory effect reduces the enthusiasm to use NSAIDs as chemoprevention agents in the clinic. Recently, more and more studies demonstrate that non-COX inhibitory mechanisms may account for anticancer properties of NSAIDs, at least partially, which potentially support the indication of NSAIDs on cancer chemoprevention. MicroRNAs (miRNAs) are a set of non-coding and small RNA molecules with master regulatory effect on over 30% human genes through the post-transcriptional and translational modulation. Although miRNAs have been reported to be involved in many normal and pathological processes including cell proliferation, apoptosis, differentiation, as well as tumorigenesis, their roles in NSAIDs' properties of cancer chemoprevention have not yet been studied exclusively. Here, we will review the prior studies reporting interactions between miRNAs and COX/non-COX pathways with intent to provide insights into better understanding molecular mechanisms of cancer chemoprevention by NSAIDs.
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Affiliation(s)
- Ruixia Ma
- University of South Alabama Mitchell Cancer Institute, Mobile, AL, USA
| | - Bin Yi
- University of South Alabama Mitchell Cancer Institute, Mobile, AL, USA
| | - Gary A Piazza
- University of South Alabama Mitchell Cancer Institute, Mobile, AL, USA
| | - Yaguang Xi
- University of South Alabama Mitchell Cancer Institute, Mobile, AL, USA
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23
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Porębska I, Kosacka M, Sobańska E, Wyrodek E, Jankowska R. Comparative Expression of Apoptotic Markers in Lung Adenocarcinoma and Squamous Cell Carcinoma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 873:101-7. [PMID: 26022894 DOI: 10.1007/5584_2015_121] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Lung cancer is still an oncology challenge. A 5-year survival reaches less than 20 % of patients. Apoptosis disturbances are a key step in cancer development. The evaluation of apoptosis markers has a great potential in lung cancer. The goal of our study was a comparative evaluation of apoptosis regulators: p53, Bcl-2, Bax, COX-2, and survivin in lung adenocarcinoma (AC) and squamous cell carcinoma (SCC). We also evaluated the relationship between apoptosis markers and clinicopathological parameters. Fifty six patients with non-small cell lung cancer (NSCLC) were included into the study (20 women and 36 men). AC was diagnosed in 30 and SCC in 26 cases. The evaluation of markers was performed using an immunohistochemical method on paraffin embedded tissue specimens. We used monoclonal antibodies for p53, bcl-2, and COX2-proteins (clone DO7, bcl-2/100/D5, and 4H12, respectively), Bax (B-9 clone) and survivin (clone 12C4). The results of immunostaining were viewed by light microscopy. We revealed significantly more frequent expression of Bax and survivin in lung AC than SCC (p < 0.01 and p < 0.019). Bcl-2 immunoreactivity was seen more often in AC without lymph node metastases than with metastases (p = 0.046). There was no correlation between the apoptosis markers and gender or the presence of vessel emboli. A greater variability in markers expression was seen in lung AC than SCC. There were significant differences in the Bax and survivin expression in the two major pathological types of NSCLC. We did not revealed any correlation between the markers and TNM characteristics, accept for Bcl-2 presence along with the lymph node involvement in the AC group.
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Affiliation(s)
- I Porębska
- Department of Pulmonology and Lung Cancer, Silesian Piasts University of Medicine, 105 Grabiszyńska St., 53-439, Wroclaw, Poland.
| | - M Kosacka
- Department of Pulmonology and Lung Cancer, Silesian Piasts University of Medicine, 105 Grabiszyńska St., 53-439, Wroclaw, Poland
| | - E Sobańska
- Department of Clinical Immunology, Silesian Piasts University of Medicine, Wroclaw, Poland
| | - E Wyrodek
- Department of Clinical Immunology, Silesian Piasts University of Medicine, Wroclaw, Poland
| | - R Jankowska
- Department of Pulmonology and Lung Cancer, Silesian Piasts University of Medicine, 105 Grabiszyńska St., 53-439, Wroclaw, Poland
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24
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Giaginis C, Alexandrou P, Tsoukalas N, Sfiniadakis I, Kavantzas N, Agapitos E, Patsouris E, Theocharis S. Hu-antigen receptor (HuR) and cyclooxygenase-2 (COX-2) expression in human non-small-cell lung carcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients' survival. Tumour Biol 2014; 36:315-27. [PMID: 25252849 DOI: 10.1007/s13277-014-2637-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2014] [Accepted: 09/12/2014] [Indexed: 10/24/2022] Open
Abstract
Hu-antigen R (HuR) is considered to play a central role in tumor formation, growth, and metastasis by binding to messenger RNAs (mRNAs) encoding proteins such as cyclooxygenase-2 (COX-2) and inducing their expression via mRNA stabilization and/or altered translation. The present study aimed to evaluate the clinical significance of HuR and COX-2 protein expression in non-small-cell lung carcinoma (NSCLC). HuR and COX-2 expression was assessed immunohistochemically on tissue microarrays of 81 surgically resected NSCLC and was analyzed in relation with clinicopathological characteristics and patients' survival. Enhanced total HuR expression was significantly associated with tumor histological type and presence of lymph node metastases, as well as with increased tumor proliferative capacity and poor patients' outcome (p = 0.039, p = 0.017, p = 0.033, and p = 0.022, respectively). Enhanced COX-2 expression was significantly associated with the presence of lymphovascular invasion and increased tumor proliferative capacity (p = 0.031 and p = 0.023, respectively). Concomitant elevated HuR/COX-2 expression levels were significantly associated with tumor histological type and increased proliferative capacity (p = 0.002 and p = 0.045, respectively). Enhanced total HuR expression, as well as its cytoplasmic localization, was significantly associated with increased COX-2 expression (p = 0.015 and p = 0.001, respectively). The present study supported evidence that HuR may participate in malignant transformation of NSCLC, reinforcing its usefulness as potential therapeutic target in this type of neoplasia.
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Affiliation(s)
- Constantinos Giaginis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias str, Goudi, Athens, 11527, Greece
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25
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Kotta-Loizou I, Giaginis C, Theocharis S. Clinical significance of HuR expression in human malignancy. Med Oncol 2014; 31:161. [PMID: 25112469 DOI: 10.1007/s12032-014-0161-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 08/01/2014] [Indexed: 12/28/2022]
Abstract
Hu-antigen R (HuR) is an RNA-binding protein that regulates the stability, translation, and nucleus-to-cytoplasm translocation of target mRNAs. The aim of the present review was to summarize and present the currently available information in the English literature on HuR expression in various human tumors, verifying its possible clinical significance. HuR function is directly linked to its subcellular localization. In normal cells, HuR is mostly localized in the nucleus, while in malignant cells, an increase in cytoplasmic HuR levels has been noted, in both cell lines and tissue samples. Moreover, in malignancy, elevated HuR expression levels and cytoplasmic immunohistochemical pattern have been correlated with advanced clinicopathological parameters and altered expression levels of proteins implicated in neoplasia. Additionally, elevated HuR expression levels and mainly cytoplasmic immunohistochemical pattern were correlated with decreased patients' survival rate in various human tumors. HuR is a putative drug target for cancer therapy, since it is expressed ubiquitously in malignant clinical samples and has an apparently consistent role in tumor formation and progression.
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Affiliation(s)
- Ioly Kotta-Loizou
- Division of Cell and Molecular Biology, Imperial College London, London, UK
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26
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Bhat IA, Rasool R, Qasim I, Masoodi KZ, Paul SA, Bhat BA, Ganaie FA, Aziz SA, Shah ZA. COX-2 overexpression and -8473 T/C polymorphism in 3' UTR in non-small cell lung cancer. Tumour Biol 2014; 35:11209-18. [PMID: 25113252 DOI: 10.1007/s13277-014-2420-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 07/29/2014] [Indexed: 01/07/2023] Open
Abstract
A new class of compounds targeting cyclooxygenase 2 (COX-2) together with other different clinically used therapeutic strategies has recently shown a promise for the chemoprevention of several solid tumors including lung cancer. The aim was to study the possible role of COX-2 -8473 T/C NP and its expression in the pathogenesis of non-small cell lung cancer. One hundred ninety non-small cell lung cancer (NSCLC) patients and 200 healthy age-, sex-, and smoking-matched controls were used for polymorphic analysis, and 48 histopathologically confirmed NSCLC patients were analyzed for COX-2 messenger RNA (mRNA) and protein expression. Our results showed that the frequencies of variant genotypes 8473 CT/CC were significantly less common in the cases (30.0%) than in the controls (36%), suggesting that the 8473 C variant allele is related with lower susceptibility in NSCLC (OR = 0.79, 95% CI 0.54-1.4). However, the frequency of COX-2 -8473 TC and CC genotypes were significantly associated with age in NSCLC (P = 0.02). Quantitative real-time expression analysis showed a significant increase in the COX-2 mRNA in tumor tissues as compared to their adjacent normal tissues [delta cycle threshold (ΔCT) = 9.25 ± 4.67 vs 5.63 ± 3.85, P = 0.0001]. Multivariate logistic regression analyses revealed that the COX-2 expression was associated significantly with age (P = 0.044). Also, an increasing trend was observed in stages I and II and in female patients compared to stages III and IV and male patients, respectively, but no statistical significance was observed. However, COX-2 mRNA expression shown no association with the -8473 C variant allele. Our findings indicate that the COX-2 T8473C polymorphism may contribute to NSCLC cancer susceptibility in the Kashmiri population, while our expression analysis revealed a significant increase of COX-2 in tumor tissues as compared to their adjacent normal tissues, suggesting that it could become an important therapeutic marker in NSCLC in the future.
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Affiliation(s)
- Imtiyaz A Bhat
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, 190011, India,
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27
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Li YJ, Wang CH, Zhou Y, Liao ZY, Zhu SF, Hu Y, Chen C, Luo JM, Wen ZK, Xu L. TLR9 signaling repressed tumor suppressor miR-7 expression through up-regulation of HuR in human lung cancer cells. Cancer Cell Int 2013; 13:90. [PMID: 24004462 PMCID: PMC3847485 DOI: 10.1186/1475-2867-13-90] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 08/30/2013] [Indexed: 11/24/2022] Open
Abstract
Background Our recent evidence showed that Toll like receptor 9 (TLR9) signaling could enhance the growth and metastatic potential of human lung cancer cells through repressing microRNA-7 (miR-7) expression. Human antigen R (HuR) has been involved in stabilizing multiple mRNAs in cellular biology. However, whether HuR also contributed to the altered expression of miR-7 in TLR9 signaling stimulated human lung cancer cells remains to be elucidated. Methods The expression of HuR in human lung cancer 95D cells treated with TLR9 agonist CpG Oligonucleotides (ODNs) was detected by Real-time PCR and Western blot assay. To explore the possible role of HuR on miR-7 expression, eukaryotic expression vector encoding HuR was transiently transfected into 95D cells and then the expression of miR-7 was detected by Real-time PCR assay. Moreover, RNA interference, western blot, Real-time PCR, MTT assay, BrdU labeling, invasion assay and scratch assay were employed to examine the disrupt effect of HuR on miR-7 expression in human lung cancer cells treated with CpG ODNs. Finally, inhibitors for PI3K, Akt or Erk respectively, and western blot were performed to explore the possible signaling pathway related to HuR expression in CpG ODNs treated human lung cancer cells. Results Our data showed that TLR9 agonist CpG ODNs could induce the expression of HuR in human lung cancer cells. Moreover, overexpression of HuR could reduce the expression of miR-7 in lung cancer cells. Notably, down-regulation of HuR using RNA interference restored miR-7 expression in CpG ODNs treated lung cancer cells, accompanied by enhanced growth and metastatic potential. Finally, CpG ODNs could induce HuR expression through Akt pathway. Conclusion Our findings indicated that HuR could act as regulator in regulating TLR9 signaling associated biological effect in human lung cancer cells, which might be helpful for the understanding of the potential role of HuR in tumor biology.
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Affiliation(s)
- Yong-Ju Li
- Department of Immunology, Zunyi Medical College, Guizhou 563000, China.
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28
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Wang J, Guo Y, Chu H, Guan Y, Bi J, Wang B. Multiple functions of the RNA-binding protein HuR in cancer progression, treatment responses and prognosis. Int J Mol Sci 2013; 14:10015-41. [PMID: 23665903 PMCID: PMC3676826 DOI: 10.3390/ijms140510015] [Citation(s) in RCA: 218] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 04/22/2013] [Accepted: 04/25/2013] [Indexed: 12/16/2022] Open
Abstract
The human embryonic lethal abnormal vision-like protein, HuR, is a member of the Hu family of RNA-binding proteins. Over the past decade, this ubiquitously expressed protein has been extensively investigated in cancer research because it is involved in the regulation of mRNA stability and translation in many cell types. HuR activity and function is associated with its subcellular distribution, transcriptional regulation, translational and post-translational modifications. HuR regulation of target mRNAs is based on the interaction between the three specific domains of HuR protein and one or several U- or AU-rich elements (AREs) in the untranslated region of target mRNAs. A number of cancer-related transcripts containing AREs, including mRNAs for proto-oncogenes, cytokines, growth factors, and invasion factors, have been characterized as HuR targets. It has been proposed that HuR has a central tumorigenic activity by enabling multiple cancer phenotypes. In this review, we comprehensively survey the existing evidence with regard to the diverse functions of HuR in caner development and progression. The current data also suggest that HuR might be a novel and promising therapeutic target and a marker for treatment response and prognostic evaluation.
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Affiliation(s)
- Jun Wang
- Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan 250031, China; E-Mails: (H.C.); (Y.G.); (J.B.); (B.W.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +86-531-5166-5336; Fax: +86-531-5166-6649
| | - Yan Guo
- Department of Outpatient, Military Command of Shandong Province, Jinan 250013, China; E-Mail:
| | - Huili Chu
- Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan 250031, China; E-Mails: (H.C.); (Y.G.); (J.B.); (B.W.)
| | - Yaping Guan
- Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan 250031, China; E-Mails: (H.C.); (Y.G.); (J.B.); (B.W.)
| | - Jingwang Bi
- Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan 250031, China; E-Mails: (H.C.); (Y.G.); (J.B.); (B.W.)
| | - Baocheng Wang
- Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan 250031, China; E-Mails: (H.C.); (Y.G.); (J.B.); (B.W.)
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29
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Jiang H, Wang J, Zhao W. Cox-2 in non-small cell lung cancer: a meta-analysis. Clin Chim Acta 2013; 419:26-32. [PMID: 23384501 DOI: 10.1016/j.cca.2013.01.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Revised: 01/09/2013] [Accepted: 01/12/2013] [Indexed: 12/21/2022]
Abstract
BACKGROUND We investigated the prognostic value of cyclooxygenase-2 (COX-2) for survival of patients with non-small cell lung cancer (NSCLC). METHODS We performed a meta-analysis of literature to aggregate the available survival results, using studies published in English until June 2012. Eligible studies dealt with COX-2 protein assessment in NSCLC patients on primary lesions and reported survival data according to COX-2 expression. RESULTS Nineteen trials, comprising 2651 patients, provided sufficient information for the meta-analysis. Overall combined hazard ratio (HR) was 1.86 (95% CI: 1.58-2.20); it was calculated using a random-effects model, and associates high COX-2 expression with poor survival in all NSCLC patients. Aggregate survival data showed poor survival for patients with adenocarcinoma (ADC), squamous cell cancer (SCC) and Stage I NSCLC with high COX-2 expression, at 2.00 (95% CI: 1.38-2.88), 2.29 (95% CI: 1.58-3.33) and 1.95 (95% CI: 1.31-2.91) respectively. CONCLUSIONS Our meta-analysis shows that the COX-2 expression status is an independent prognostic factor in NSCLC, and this tendency applies to SCC, ADC and stage I NSCLC.
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Affiliation(s)
- Hao Jiang
- Department of Geriatric Oncology, the Second Affiliated Hospital, Southeast University, Nanjing, Jiangsu 210003, PR China.
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30
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Xie YL, An L, Jiang H, Wang J. Nuclear survivin expression is associated with a poor prognosis in Caucasian non-small cell lung cancer patients. Clin Chim Acta 2012; 414:41-3. [PMID: 22981350 DOI: 10.1016/j.cca.2012.08.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Revised: 08/09/2012] [Accepted: 08/11/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND The role of the nuclear protein survivin in non-small cell lung cancer (NSCLC) remains controversial. To clarify the association of survivin with survival in NSCLC, we performed a meta-analysis of the literature with meta-analysis. METHODS Trials were selected for further analysis if they provided an independent assessment of nuclear survivin in NSCLC and reported the survival data in the context of survivin status. A total of 7 trials, which comprised 823 patients, were included in the meta-analysis. Sensitivity analyses were conducted using the patient's disease stage, IHC cutoff value, and ethnicity. RESULTS The combined hazard ratio (HR) of 1.54 [95% CI, 0.79-3.02; test for heterogeneity p<0.001] suggests that high nuclear survivin expression has no impact on patient survival. However, when the studies were restricted to Caucasian patients, high levels of nuclear survivin expression were correlated with reduced survival (HR 2.38, 95% CI=1.60-3.52; p=0.189 for heterogeneity). In addition, the heterogeneity disappeared when the analysis was restricted to Caucasians. CONCLUSION Nuclear survivin expression is associated with poor prognosis for Caucasian NSCLC patients.
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Affiliation(s)
- Yu-Lan Xie
- Department of Gerontology, The Affiliated Zhong Da Hospital of Southeast University, 87# Dingjiaqiao, Nanjing 210009, PR China.
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31
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Zhang LQ, Wang J, Jiang F, Xu L, Liu FY, Yin R. Prognostic value of survivin in patients with non-small cell lung carcinoma: a systematic review with meta-analysis. PLoS One 2012; 7:e34100. [PMID: 22457815 PMCID: PMC3311582 DOI: 10.1371/journal.pone.0034100] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Accepted: 02/21/2012] [Indexed: 01/05/2023] Open
Abstract
PURPOSE The potential prognostic value of survivin in resected non-small cell lung carcinoma (NSCLC) is variably reported. The objective of this study was to conduct a systematic review of literatures evaluating survivin expression in resected NSCLC as a prognostic indicator. METHODS Relevant literatures were identified using PubMed, EMBASE and Chinese Biomedicine Databases. We present the results of a meta-analysis of the association between survivin expression and overall survival (OS) in NSCLC patients. Studies were pooled and summary hazard ratios (HR) were calculated. Subgroup analyses and publication bias were also conducted. RESULTS We performed a final analysis of 2703 patients from 28 evaluable studies. Combined HRs suggested that survivin overexpression had an unfavorable impact on NSCLC patients' survival with no evidence of any significant publication bias (HR = 2.03, 95%CI: 1.78-2.33, Egger's test, P = 0.24) and no severe heterogeneity between studies (I² = 26.9%). Its effect also appeared significant when stratified according to the studies categorized by histological type, HR estimate, patient race, cutoff point (5%, 10%), detection methods and literature written language except for disease stage. Survivin was identified as a prognostic marker of advanced-stage NSCLC (HR = 1.93, 95%CI: 1.49-2.51), but not early-stage NSCLC (HR = 1.97, 95%CI: 0.76-5.14), in spite of the combined data being relatively small. CONCLUSION This study shows that survivin expression appears to be a pejorative prognostic factor in terms of overall survival in surgically treated NSCLC. Large prospective studies are now needed to confirm the clinical utility of survivin as an independent prognostic marker.
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Affiliation(s)
- Lou Qian Zhang
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Jun Wang
- Department of Chemotherapy, Jiangsu Province Geriatric Institute, Jiangsu Province Official Hospital, Nanjing, China
| | - Feng Jiang
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Lin Xu
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Fu Yin Liu
- Department of Chemotherapy, Jiangsu Province Geriatric Institute, Jiangsu Province Official Hospital, Nanjing, China
| | - Rong Yin
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
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Dai W, Zhang G, Makeyev EV. RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage. Nucleic Acids Res 2011; 40:787-800. [PMID: 21948791 PMCID: PMC3258158 DOI: 10.1093/nar/gkr783] [Citation(s) in RCA: 118] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
RNA-binding protein HuR modulates the stability and translational efficiency of messenger RNAs (mRNAs) encoding essential components of the cellular proliferation, growth and survival pathways. Consistent with these functions, HuR levels are often elevated in cancer cells and reduced in senescent and quiescent cells. However, the molecular mechanisms that control HuR expression are poorly understood. Here we show that HuR protein autoregulates its abundance through a negative feedback loop that involves interaction of the nuclear HuR protein with a GU-rich element (GRE) overlapping with the HuR major polyadenylation signal (PAS2). An increase in the cellular HuR protein levels stimulates the expression of long HuR mRNA species containing an AU-rich element (ARE) that destabilizes the mRNAs and thus reduces the protein production output. The PAS2 read-through occurs due to a reduced recruitment of the CstF-64 subunit of the pre-mRNA cleavage stimulation factor in the presence of the GRE-bound HuR. We propose that this mechanism maintains HuR homeostasis in proliferating cells. Since only the nuclear HuR is expected to contribute to the auto-regulation, our model may explain the longstanding observation that the increase in the total HuR expression in cancer cells often correlates with the accumulation of its substantial fraction in the cytoplasm.
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Affiliation(s)
- Weijun Dai
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, SBS-02n-45, Singapore, 637551, Singapore
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