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Deniz AH, Aydemir E, Ekimci Gürcan N, Dabo Jakir A, Faruk Bayrak Ö, Şahin F, Ayaz F. Improved Malignancy of Colon Cancer Cells at Gene Expression Level With Constitutive Activation of the Eukaryotic Elongation Factor 2 Under Nutrition-Deficient Conditions. Chem Biodivers 2025; 22:e202402547. [PMID: 39803701 DOI: 10.1002/cbdv.202402547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 01/08/2025] [Accepted: 01/13/2025] [Indexed: 02/08/2025]
Abstract
Regulation of protein production in response to physiological signals is achieved through precise control of eukaryotic Elongation Factor 2 (eEF2), whose distinct translocase function is crucial for cell survival. Phosphorylation of eEF2 at its Thr56 (T56) residue inactivates this function in translation. Using a genetically modified paralogue of a colon cancer cell line, HCT116 which carries a point mutation at Ser595-to-Alanine in the eEF2 gene we were able to create a constitutively active form of eEF2. Then, we compared these cells with their wild-type counterparts under complete growth and nutrient deprivation conditions. The mutant forms were created by using the CRISPR/Cas9-mediated gene cassette knock-in (KI) strategy. The samples were analyzed by a microarray-based approach. Carrying out a WikiPath analysis, we identified distinct signaling pathways and gene expression patterns that are differentially regulated in the mutant cells (HCT116KI), but not in wild-type HCT116 (HCT116WT) cells, particularly under nutrient-deprived conditions. Our results suggest that the constitutive activation of eEF2 enables an increase in the malignant gene expression in colon cancer cells compared to the wild-type counterparts under nutrient-deprived conditions.
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Affiliation(s)
- Aslı Hızlı Deniz
- Department of Molecular Biology and Genetics Faculty of Engineering and Natural Sciences, Atlas Vadi Kampüsü 2020, Istanbul, Turkey
| | - Esra Aydemir
- Faculty of Pharmacy, Biruni University, Istanbul, Turkey
| | - Nur Ekimci Gürcan
- Department of Molecular Biology and Genetics Faculty of Engineering and Natural Sciences, Biruni University, Istanbul, Turkey
| | - Abdulahi Dabo Jakir
- Department of Molecular Biology and Genetics Faculty of Engineering and Natural Sciences, Biruni University, Istanbul, Turkey
| | - Ömer Faruk Bayrak
- Department of Medical Genetics, Yeditepe University Medical School and Yeditepe University Hospital, Istanbul, Turkey
| | - Fikrettin Şahin
- Department of Genetics and Bioengineering Faculty of Engineering, Yeditepe University, Istanbul, Turkey
| | - Furkan Ayaz
- Faculty of Pharmacy, Biruni University, Istanbul, Turkey
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Giler MK, Tucker HA, Foote AK, Francis AG, Madsen SD, Liu YZ, O’Connor KC. RNA sequencing identifies MAP1A and PTTG1 as predictive genes of aging CD264 + human mesenchymal stem cells at an early passage. Cytotechnology 2025; 77:63. [PMID: 39980838 PMCID: PMC11839963 DOI: 10.1007/s10616-025-00724-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 02/05/2025] [Indexed: 02/22/2025] Open
Abstract
Molecular profiles of mesenchymal stem cells (MSCs) are needed to standardize the composition and effectiveness of MSC therapeutics. This study employs RNA sequencing to identify genes to be used in concert with CD264 as a molecular profile of aging MSCs at a clinically relevant culture passage. CD264- and CD264+ populations were isolated by fluorescence-activated cell sorting from passage 4 MSC cultures. CD264+ MSCs exhibited an aging phenotype relative to their CD264- counterpart. Donor-matched CD264-/+ mRNA samples from 5 donors were subjected to pair-ended, next-generation sequencing. An independent set of 5 donor MSCs was used to validate differential expression of select genes with quantitative reverse transcription PCR. Pairwise differential expression analysis identified 2,322 downregulated genes and 2,695 upregulated genes in CD264+ MSCs relative to donor-matched CD264- MSCs with a Benjamini-Hochberg adjusted p-value (BH p adj ) < 0.1. Nearly 25% of these genes were unique to CD264-/+ MSCs and not differentially expressed at a significance level of BH p adj < 0.1 in previous RNA sequencing studies of early- vs. late-passage MSCs. Least Absolute Shrinkage and Selection Operator regression identified microtubule-associated protein 1A (MAP1A) and pituitary tumor-transforming gene 1 (PTTG1) as predictive genes of CD264+ MSCs. Combined MAP1A and PTTG1 expression correctly classified CD264 status of MSC samples with an accuracy of 100%. Differential expression and predictive ability of MAP1A and PTTG1 compared favorably with that of existing senescence markers expressed in early passage CD264-/+ MSCs. This study provides the first linkage of MAP1A to CD264, aging and senescence. Our findings have application as quality metrics to standardize the composition of MSC therapies and as molecular targets to slow/reverse cellular aging. Supplementary Information The online version contains supplementary material available at 10.1007/s10616-025-00724-8.
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Affiliation(s)
- Margaret K. Giler
- Department of Chemical and Biomolecular Engineering, School of Science and Engineering, Tulane University, New Orleans, LA USA
| | - H. Alan Tucker
- Center for Stem Cell Research and Regenerative Medicine, School of Medicine, Tulane University, New Orleans, LA USA
| | - Amanda K. Foote
- Department of Chemical and Biomolecular Engineering, School of Science and Engineering, Tulane University, New Orleans, LA USA
| | - Avery G. Francis
- Department of Chemical and Biomolecular Engineering, School of Science and Engineering, Tulane University, New Orleans, LA USA
| | - Sean D. Madsen
- Department of Chemical and Biomolecular Engineering, School of Science and Engineering, Tulane University, New Orleans, LA USA
| | - Yao-Zhong Liu
- Department of Biostatistics and Data Science, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA USA
| | - Kim C. O’Connor
- Department of Chemical and Biomolecular Engineering, School of Science and Engineering, Tulane University, New Orleans, LA USA
- Center for Stem Cell Research and Regenerative Medicine, School of Medicine, Tulane University, New Orleans, LA USA
- Center for Aging, School of Medicine, Tulane University, New Orleans, LA USA
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Lu Y, Wang D, Chen G, Shan Z, Li D. Exploring the molecular landscape of osteosarcoma through PTTG family genes using a detailed multi-level methodology. Front Genet 2024; 15:1431668. [PMID: 39139816 PMCID: PMC11319144 DOI: 10.3389/fgene.2024.1431668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 07/10/2024] [Indexed: 08/15/2024] Open
Abstract
Background Osteosarcoma (OS) poses a significant clinical challenge, necessitating a comprehensive exploration of its molecular underpinnings. Methods This study explored the roles of PTTG family genes (PTTG1, PTTG2, and PTTG3P) in OS, employing a multifaceted approach encompassing molecular experiments, including OS cell lines culturing, RT-qPCR, bisulfite and Whole Exome Sequencing (WES) and in silico experiments, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets-based validation, overall survival, gene enrichment, functional assays, and molecular docking analyses. Results Our findings reveal a consistent up-regulation of PTTG genes in OS cell lines, supported by RT-qPCR experiments and corroborated across various publically available expression datasets databases. Importantly, ROC curve analyses highlight their potential as diagnostic markers. Moving beyond expression profiles, we unveil the epigenetic landscape by demonstrating significant hypomethylation of CpG islands associated with PTTG genes in OS. The negative correlation between methylation status and mRNA expression emphasizes the regulatory role of promoter methylation in PTTG gene expression. Contrary to expectations, genetic mutations in PTTG genes are rare in OS, with only benign mutations observed. Moreover, functional assays also confirmed the oncogenic roles of the PTTG gene in the development of OS. Lastly, we also revealed that Calcitriol is the most appropriate drug that can be utilized to treat OS in the context of PTTG genes. Conclusion The identification of PTTG genes as potential diagnostic markers and their association with epigenetic alterations opens new avenues for understanding OS pathogenesis and developing targeted therapies. As we navigate the complex landscape of OS, this study contributes essential insights that may pave the way for improved diagnostic and therapeutic strategies in its management.
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Affiliation(s)
- Yulin Lu
- School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Danjun Wang
- School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Guoao Chen
- School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Zitong Shan
- School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Dongmei Li
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
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Li Z, Yan G, Yang M, Liu X, Lian Y, Sun M, Pan W. CBLC promotes the development of colorectal cancer by promoting ABI1 degradation to activate the ERK signaling pathway. Transl Oncol 2024; 45:101992. [PMID: 38743987 PMCID: PMC11109901 DOI: 10.1016/j.tranon.2024.101992] [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: 11/10/2023] [Revised: 04/11/2024] [Accepted: 05/07/2024] [Indexed: 05/16/2024] Open
Abstract
CBLC (CBL proto-oncogene C) is an E3 ubiquitin protein ligase that plays a key role in cancers. However, the function and mechanism of CBLC in colorectal cancer (CRC) has not been fully elucidated. The aim of this study was to investigate the function of CBLC in CRC and its underlying molecular mechanism. High CBLC levels were certified in tumor tissues of CRC patients, and its expression was positively associated with TNM stage. Next, we explored the role of CBLC in CRC using gain or loss of function. For biological function analysis, CCK-8 cell proliferation, colony formation, flow cytometry, scratch, and transwell assays collectively suggested that CBLC overexpression promoted cell proliferation, cell cycle progression, migration and invasion. As observed, CBLC knockdown exhibited exactly opposite effects, resulting in impaired tumorigenicity in vitro. Xenograft studies displayed that CBLC overexpression accelerated tumor growth and promoted tumor metastasis to the lung, while the inhibitory effects of CBLC knockdown on tumorigenicity and metastasis ability of CRC cells was also confirmed. Furthermore, the molecular mechanism of CBLC in CRC was explored. CBLC induced the activation of ERK signaling pathway, further leading to its pro-tumor role. Notably, CBLC decreased ABI1 (Abelson interactor protein-1, a candidate tumor suppressor) protein levels through its ubiquitin ligase activity, while ABI1 upregulation abolished the effects of CBLC on the tumorigenesis of CRC. Taken together, these results demonstrate that CBLC acts as a tumor promoter in CRC through triggering the ubiquitination and degradation of ABI1 and activating the ERK signaling pathway. CBLC may be a potential novel target for CRC.
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Affiliation(s)
- Zhan Li
- Department of General Surgery, Liaoyang City Central Hospital, Liaoyang, Liaoning Province, China
| | - Guanyu Yan
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Meiqi Yang
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Xingwu Liu
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yuan Lian
- General Hospital of Fuxin Mining Industry Group of Liaoning Health Industry Group, Fuxin, Liaoning Province, China
| | - Mingjun Sun
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China.
| | - Wenjun Pan
- Department of General Surgery, Liaoyang City Central Hospital, Liaoyang, Liaoning Province, China.
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Cao F, Chen YY, Wang HC. GLI1 and PTTG1 expression in colorectal carcinoma patients undergoing radical surgery and their correlation with lymph node metastasis. World J Gastrointest Surg 2024; 16:1328-1335. [PMID: 38817299 PMCID: PMC11135310 DOI: 10.4240/wjgs.v16.i5.1328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/11/2024] [Accepted: 04/12/2024] [Indexed: 05/23/2024] Open
Abstract
BACKGROUND Few studies have investigated the expression of GLI1 and PTTG1 in patients undergoing radical surgery for colorectal carcinoma (CRC) and their association with lymph node metastasis (LNM). Therefore, more relevant studies and analyses need to be conducted. AIM To explore GLI1 and PTTG1 expression in patients undergoing radical surgery for CRC and their correlation with LNM. METHODS This study selected 103 patients with CRC admitted to our hospital between April 2020 and April 2023. Sample specimens of CRC and adjacent tissues were collected to determine the positive rates and expression levels of GLI1 and PTTG1. The correlation of the two genes with patients' clinicopathological data (e.g., LNM) was explored, and differences in GLI1 and PTTG1 expression between patients with LNM and those without were analyzed. Receiver operating characteristic (ROC) curves were plotted to evaluate the predictive potential of the two genes for LNM in patients with CRC. RESULTS Significantly higher positive rates and expression levels of GLI1 and PTTG1 were observed in CRC tissue samples compared with adjacent tissues. GLI1 and PTTG1 were strongly linked to LNM in patients undergoing radical surgery for CRC, with higher GLI1 and PTTG1 levels found in patients with LNM than in those without. The areas under the ROC curve of GLI1 and PTTG1 in assessing LNM in patients with CRC were 0.824 and 0.811, respectively. CONCLUSION GLI1 and PTTG1 expression was upregulated in patients undergoing radical surgery for CRC and are significantly related to LNM in these patients. Moreover, high GLI1 and PTTG1 expression can indicate LNM in patients with CRC undergoing radical surgery. The expression of both genes has certain diagnostic and therapeutic significance.
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Affiliation(s)
- Feng Cao
- Department of Care Section, Beijing Geriatric Hospital, Beijing 100095, China
| | - Yang-Yan Chen
- Research Department, Shanghai Zhangjiang Institute of Medical Innovation, Shanghai 200000, China
| | - Hong-Cheng Wang
- Care Department, Beijing Geriatric Hospital, Beijing 100095, China
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Wang R, Li S, Hu H, Hou Q, Chu H, Hou Y, Ni C, Ran Y, Zheng H. Transcriptomic analysis and experiments revealed that remimazolam promotes proliferation and G1/S transition in HCT8 cells. Front Oncol 2024; 14:1345656. [PMID: 38725628 PMCID: PMC11079263 DOI: 10.3389/fonc.2024.1345656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 04/09/2024] [Indexed: 05/12/2024] Open
Abstract
Background Remimazolam is a new ultrashort-acting benzodiazepine for sedation and anesthesia. The effects of remimazolam and the mechanism by which it functions in cancer cells have not been determined. This research aimed to explore the mechanism of remimazolam action in colon cancer treatment, using bioinformatics analysis and in vitro experiments. Methods Cell cycle progression, colony formation, self-renewal capacity, and apoptosis detection were performed in HCT8 cells treated with or without remimazolam. Transcriptome sequencing, Gene Ontology, Kyoto Encyclopedia of Genes and Genome, Protein-Protein Interaction, Gene Set Enrichment Analysis, Western blotting, and qPCR were performed to investigate the mechanism of action of remimazolam in HCT8 colon cancer cells. Results Remimazolam promoted proliferation and cell-cycle progression of HCT8 cells. After remimazolam treatment, a total of 1,096 differentially expressed genes (DEGs) were identified: 673 genes were downregulated, and 423 genes were upregulated. The DEGs were enriched mainly in "DNA replication", "cell cycle", and "G1/S transition" related pathways. There were 15 DEGs verified by qPCR, and representative biomarkers were detected by Western Bloting. The remimazolam-mediated promotion of cell proliferation and cell cycle was reversed by G1T28, a CDK4/6 inhibitor. Conclusion Remimazolam promoted cell-cycle progression and proliferation in HCT8 colon cancer cells, indicating that the long-term use of remimazolam has potential adverse effects in the anesthesia of patients with colon cancer.
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Affiliation(s)
- Runjia Wang
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuai Li
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Han Hu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qi Hou
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huaqing Chu
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Hou
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Cheng Ni
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuliang Ran
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hui Zheng
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Meneveau MO, Vavolizza RD, Mohammad A, Kumar P, Manderfield JT, Callahan C, Lynch KT, Abbas T, Slingluff CL, Bekiranov S. A Step Toward Personalized Surgical Decision Making: Machine Learning Predicts 1 Versus Numerous Melanoma Lymph Node Metastases Using RNA-sequencing. Ann Surg 2023; 278:e589-e597. [PMID: 36538614 PMCID: PMC10209351 DOI: 10.1097/sla.0000000000005761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Develop a predictive model to identify patients with 1 pathologic lymph node (pLN) versus >1 pLN using machine learning applied to gene expression profiles and clinical data as input variables. BACKGROUND Standard management for clinically detected melanoma lymph node metastases is complete therapeutic LN dissection (TLND). However, >40% of patients with a clinically detected melanoma lymph node will only have 1 pLN on final review. Recent data suggest that targeted excision of just the single enlarged LN may provide excellent regional control, with less morbidity than TLND. The selection of patients for less morbid surgery requires accurate identification of those with only 1 pLN. METHODS The Cancer Genome Atlas database was used to identify patients who underwent TLND for melanoma. Pathology reports in The Cancer Genome Atlas were reviewed to identify the number of pLNs. Patients were included for machine learning analyses if RNA sequencing data were available from a pLN. After feature selection, the top 20 gene expression and clinical input features were used to train a ridge logistic regression model to predict patients with 1 pLN versus >1 pLN using 10-fold cross-validation on 80% of samples. The model was then tested on the remaining holdout samples. RESULTS A total of 153 patients met inclusion criteria: 64 with one pLN (42%) and 89 with >1 pLNs (58%). Feature selection identified 1 clinical (extranodal extension) and 19 gene expression variables used to predict patients with 1 pLN versus >1 pLN. The ridge logistic regression model identified patient groups with an accuracy of 90% and an area under the receiver operating characteristic curve of 0.97. CONCLUSIONS Gene expression profiles together with clinical variables can distinguish melanoma metastasis patients with 1 pLN versus >1 pLN. Future models trained using positron emission tomography/computed tomography imaging, gene expression, and relevant clinical variables may further improve accuracy and may predict patients who can be managed with a targeted LN excision rather than a complete TLND.
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Affiliation(s)
- Max O. Meneveau
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Rick D. Vavolizza
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Anwaruddin Mohammad
- Bioinformatics Core, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Pankaj Kumar
- Bioinformatics Core, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
| | | | - Colleen Callahan
- University of Virginia, School of Data Science, Charlottesville, VA, USA
| | - Kevin T. Lynch
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Tarek Abbas
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
| | - Craig L. Slingluff
- Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, Charlottesville, VA, USA
| | - Stefan Bekiranov
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
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Shen X, Su Z, Dou Y, Song X. A novel investigation into an E2F transcription factor-related prognostic model with seven signatures for colon cancer patients. IET Syst Biol 2023; 17:187-197. [PMID: 37431829 PMCID: PMC10439494 DOI: 10.1049/syb2.12069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 06/14/2023] [Accepted: 06/19/2023] [Indexed: 07/12/2023] Open
Abstract
The pathogenesis of colon cancer, a common gastrointestinal tumour, involves complicated factors, especially a series of cell cycle-related genes. E2F transcription factors during the cell cycle play an essential role in the occurrence of colon cancer. It is meaningful to establish an efficient prognostic model of colon cancer targeting cellular E2F-associated genes. This has not been reported previously. The authors first aimed to explore the links of E2F genes with the clinical outcomes of colon cancer patients by integrating data from the TCGA-COAD (n = 521), GSE17536 (n = 177) and GSE39582 (n = 585) cohorts. The Cox regression and Lasso modelling approach to identify a novel colon cancer prognostic model involving several hub genes (CDKN2A, GSPT1, PNN, POLD3, PPP1R8, PTTG1 and RFC1) were utilised. Moreover, an E2F-related nomogram that efficiently predicted the survival rates of colon cancer patients was created. Additionally, the authors first identified two E2F tumour clusters, which showed distinct prognostic features. Interestingly, the potential links of E2F-based classification and 'protein secretion' issues of multiorgans and tumour infiltration of 'T-cell regulatory (Tregs)' and 'CD56dim natural killer cell' were detected. The authors' findings are of potential clinical significance for the prognosis assessment and mechanistic exploration of colon cancer.
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Affiliation(s)
- Xiaoyong Shen
- National Demonstration Center for Experimental Basic Medicine EducationSchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Zheng Su
- National Demonstration Center for Experimental Basic Medicine EducationSchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Yan Dou
- National Demonstration Center for Experimental Basic Medicine EducationSchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Xin Song
- National Demonstration Center for Experimental Basic Medicine EducationSchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
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Mokhtari K, Peymani M, Rashidi M, Hushmandi K, Ghaedi K, Taheriazam A, Hashemi M. Colon cancer transcriptome. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 180-181:49-82. [PMID: 37059270 DOI: 10.1016/j.pbiomolbio.2023.04.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/31/2023] [Accepted: 04/06/2023] [Indexed: 04/16/2023]
Abstract
Over the last four decades, methodological innovations have continuously changed transcriptome profiling. It is now feasible to sequence and quantify the transcriptional outputs of individual cells or thousands of samples using RNA sequencing (RNA-seq). These transcriptomes serve as a connection between cellular behaviors and their underlying molecular mechanisms, such as mutations. This relationship, in the context of cancer, provides a chance to unravel tumor complexity and heterogeneity and uncover novel biomarkers or treatment options. Since colon cancer is one of the most frequent malignancies, its prognosis and diagnosis seem to be critical. The transcriptome technology is developing for an earlier and more accurate diagnosis of cancer which can provide better protectivity and prognostic utility to medical teams and patients. A transcriptome is a whole set of expressed coding and non-coding RNAs in an individual or cell population. The cancer transcriptome includes RNA-based changes. The combined genome and transcriptome of a patient may provide a comprehensive picture of their cancer, and this information is beginning to affect treatment decision-making in real-time. A full assessment of the transcriptome of colon (colorectal) cancer has been assessed in this review paper based on risk factors such as age, obesity, gender, alcohol use, race, and also different stages of cancer, as well as non-coding RNAs like circRNAs, miRNAs, lncRNAs, and siRNAs. Similarly, they have been examined independently in the transcriptome study of colon cancer.
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Affiliation(s)
- Khatere Mokhtari
- Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, 4815733971, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, 4815733971, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Fei L, Hou G, Lu Z, Yang X, Ji Z. High expression of pituitary tumor gene family is a predictor for poor prognosis of gastric cancer. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2101548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
Affiliation(s)
- Lihong Fei
- Department of Gastroenterology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China
| | - Guoxin Hou
- Department of Oncology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China
| | - Zhimin Lu
- Department of outpatient, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China
| | - Xinmei Yang
- Department of Oncology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China
| | - Zizhong Ji
- Department of Gastroenterology, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China
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Liu X, Zeng W, Zheng D, Tang M, Zhou W. Clinical significance of securin expression in solid cancers: A PRISMA-compliant meta-analysis of published studies and bioinformatics analysis based on TCGA dataset. Medicine (Baltimore) 2022; 101:e30440. [PMID: 36123907 PMCID: PMC9478268 DOI: 10.1097/md.0000000000030440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Numerous studies have investigated the clinical significance of securin expression in solid cancers; however, the results have been inconsistent. Hence, we performed a meta-analysis of published studies to assess the clinical value of securin expression in patients with solid cancers. METHODS The Chinese National Knowledge Infrastructure, Web of Science, PubMed, and EMDASE databases were searched for eligible studies (from inception up to April 2021). Bioinformatics analysis based on The Cancer Genome Atlas dataset was also performed to evaluate the prognostic value of securin expression. RESULTS A total of 25 articles with 26 studies were included in the meta-analysis. The results of the meta-analysis implied that high securin expression was positively correlated with unfavorable overall survival (OS) (hazard ratio = 1.52, 95% CI, 1.33-1.73; P < .001) and lymph node metastasis (odd ratio = 2.96, 95% CI, 2.26-3.86; P < .001). Consistently, our bioinformatics analysis showed that increased securin expression was associated with worse OS and shorter disease-free survival in cancer patients. CONCLUSION Our study indicated that securin overexpression was positively associated with metastasis and inversely related to the prognosis of patients with solid cancers. However, additional high-quality studies should be conducted to validate these findings.
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Affiliation(s)
- Xiang Liu
- Department of Cardiothoracic Surgery, the Second Affiliated Hospital, University of South China, Hengyang, China
| | - Wei Zeng
- Department of Cardiothoracic Surgery, the Second Affiliated Hospital, University of South China, Hengyang, China
| | - Dayang Zheng
- Department of Cardiothoracic Surgery, the Second Affiliated Hospital, University of South China, Hengyang, China
| | - Min Tang
- Department of Cardiothoracic Surgery, the Second Affiliated Hospital, University of South China, Hengyang, China
| | - Wangyan Zhou
- Department of Medical Humanities and Education Department, the First Affiliated Hospital, University of South China, Hengyang, China
- * Correspondence: Wangyan Zhou, Department of Medical Humanities and Education Department, the First Affiliated Hospital, University of South China, No. 69 Chuanshan Road, Hengyang 421001, China (e-mail: )
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Li JD, Farah AA, Huang ZG, Zhai GQ, Wang RG, Liu JL, Wang QJ, Zhang GL, Lei ZL, Dang YW, Li SH. Clinical significance and potential regulatory mechanism of overexpression of pituitary tumor-transforming gene transcription factor in bladder cancer. BMC Cancer 2022; 22:713. [PMID: 35768832 PMCID: PMC9241226 DOI: 10.1186/s12885-022-09810-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/21/2022] [Indexed: 11/30/2022] Open
Abstract
Background Pituitary tumor transforming gene-1 (PTTG1) transcription factor is identified as carcinogenic and associated with tumor invasiveness, but its role in bladder cancer (BLCA) remains obscure. This research is intended to analyze the aberrant expression and clinical significance of PTTG1 in BLCA, explore the relationship between PTTG1 and tumor microenvironment characteristics and predict its potential transcriptional activity in BLCA tissue. Methods We compared the expression discrepancy of PTTG1 mRNA in BLCA and normal bladder tissue, using the BLCA transcriptomic datasets from GEO, ArrayExpress, TCGA, and GTEx. In-house immunohistochemical staining was implemented to determine the PTTG1 protein intensity. The prognostic value of PTTG1 was evaluated using the Kaplan-Meier Plotter. CRISPR screen data was utilized to estimate the effect PTTG1 interference has on BLCA cell lines. We predicted the abundance of the immune cells in the BLCA tumor microenvironment using the microenvironment cell populations-counter and ESTIMATE algorithms. Single-cell RNA sequencing data was applied to identify the major cell types in BLCA, and the dynamics of BLCA progression were revealed using pseudotime analysis. PTTG1 target genes were predicted by CistromeDB. Results The elevated expression level of PTTG1 was confirmed in 1037 BLCA samples compared with 127 non-BLCA samples, with a standardized mean difference value of 1.04. Higher PTTG1 expression status exhibited a poorer BLCA prognosis. Moreover, the PTTG1 Chronos genetic effect scores were negative, indicating that PTTG1 silence may inhibit the proliferation and survival of BLCA cells. With PTTG1 mRNA expression level increasing, higher natural killer, cytotoxic lymphocyte, and monocyte lineage cell infiltration levels were observed. A total of four candidate targets containing CHEK2, OCIAD2, UBE2L3, and ZNF367 were determined ultimately. Conclusions PTTG1 mRNA over-expression may become a potential biomarker for BLCA prognosis. Additionally, PTTG1 may correlate with the BLCA tumor microenvironment and exert transcriptional activity by targeting CHEK2, OCIAD2, UBE2L3, and ZNF367 in BLCA tissue. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09810-y.
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Affiliation(s)
- Jian-Di Li
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Rd, Guangxi Zhuang Autonomous Region, 530021, Nanning, People's Republic of China
| | - Abdirahman Ahmed Farah
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Rd, Guangxi Zhuang Autonomous Region, 530021, Nanning, People's Republic of China
| | - Zhi-Guang Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Rd, Guangxi Zhuang Autonomous Region, 530021, Nanning, People's Republic of China
| | - Gao-Qiang Zhai
- Department of Urology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Rd, Guangxi Zhuang Autonomous Region, 530021, Nanning, People's Republic of China
| | - Rui-Gong Wang
- Department of Urology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Rd, Guangxi Zhuang Autonomous Region, 530021, Nanning, People's Republic of China
| | - Jia-Lin Liu
- Department of Urology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Rd, Guangxi Zhuang Autonomous Region, 530021, Nanning, People's Republic of China
| | - Qin-Jie Wang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Rd, Guangxi Zhuang Autonomous Region, 530021, Nanning, People's Republic of China
| | - Guan-Lan Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Rd, Guangxi Zhuang Autonomous Region, 530021, Nanning, People's Republic of China
| | - Zi-Long Lei
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Rd, Guangxi Zhuang Autonomous Region, 530021, Nanning, People's Republic of China
| | - Yi-Wu Dang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Rd, Guangxi Zhuang Autonomous Region, 530021, Nanning, People's Republic of China
| | - Sheng-Hua Li
- Department of Urology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Rd, Guangxi Zhuang Autonomous Region, 530021, Nanning, People's Republic of China.
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Pituitary Tumor-Transforming Gene 1/Delta like Non-Canonical Notch Ligand 1 Signaling in Chronic Liver Diseases. Int J Mol Sci 2022; 23:ijms23136897. [PMID: 35805898 PMCID: PMC9267054 DOI: 10.3390/ijms23136897] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/17/2022] [Accepted: 06/18/2022] [Indexed: 02/06/2023] Open
Abstract
The management of chronic liver diseases (CLDs) remains a challenge, and identifying effective treatments is a major unmet medical need. In the current review we focus on the pituitary tumor transforming gene (PTTG1)/delta like non-canonical notch ligand 1 (DLK1) axis as a potential therapeutic target to attenuate the progression of these pathological conditions. PTTG1 is a proto-oncogene involved in proliferation and metabolism. PTTG1 expression has been related to inflammation, angiogenesis, and fibrogenesis in cancer and experimental fibrosis. On the other hand, DLK1 has been identified as one of the most abundantly expressed PTTG1 targets in adipose tissue and has shown to contribute to hepatic fibrosis by promoting the activation of hepatic stellate cells. Here, we extensively analyze the increasing amount of information pointing to the PTTG1/DLK1 signaling pathway as an important player in the regulation of these disturbances. These data prompted us to hypothesize that activation of the PTTG1/DLK1 axis is a key factor upregulating the tissue remodeling mechanisms characteristic of CLDs. Therefore, disruption of this signaling pathway could be useful in the therapeutic management of CLDs.
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14
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Mei L. Multiple types of noncoding RNA are involved in potential modulation of PTTG1's expression and function in breast cancer. Genomics 2022; 114:110352. [PMID: 35351581 DOI: 10.1016/j.ygeno.2022.110352] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 02/17/2022] [Accepted: 03/24/2022] [Indexed: 01/14/2023]
Abstract
Breast cancer is a malignant type with morbidity ranking the first of women globally. As widely acknowledged, there exist close links between ncRNA-mRNA axis and breast cancer. In this study, we first overviewed expression and prognostic values of pituitary tumor transforming gene (PTTGs) in breast cancer. Next, two binding miRNAs (miR-186-5p and miR-655-3p) of PTTG1 in breast cancer were identified. Subsequently, several potential upstream ncRNAs of PTTG1-miR-186-5p/miR-655-3p axis in breast cancer were successively screened out, consisting of 11 lncRNAs, 17 circRNAs and 12 pseudogene-derived RNAs. Enrichment analysis for downstream target genes of PTTG1-miR-186-5p/miR-655-3p axis revealed that this axis is associated with TGF-beta signaling and MAPK signaling pathways. Further investigation demonstrated AURKA was one of the most key hub genes. Collectively, we established a potential PTTG1-related ncRNA-mRNA regulatory network in breast cancer.
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Affiliation(s)
- Linhang Mei
- Department of Oncological surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, Zhejiang 317000, China.
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15
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Yang G, Xiog Y, Wang G, Li W, Tang T, Sun J, Li J. miR‑374c‑5p regulates PTTG1 and inhibits cell growth and metastasis in hepatocellular carcinoma by regulating epithelial‑mesenchymal transition. Mol Med Rep 2022; 25:148. [PMID: 35234260 PMCID: PMC8915393 DOI: 10.3892/mmr.2022.12664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 02/15/2022] [Indexed: 11/25/2022] Open
Abstract
A large number of studies have reported that microRNA (miR)-374c-5p plays an important role in the occurrence and development of malignant tumors, but there is no research on the role of miR-374c-5p in hepatocellular carcinoma (HCC). The aim of the present study was to investigate the role of miR-374c-5p in HCC and the underlying molecular mechanism. The expression of miR-374c-5p in HCC tissues and HCC cell lines was analyzed via reverse transcription-quantitative PCR. The association between miR-374c-5p and clinical pathology was also analyzed in patients with HCC. Kaplan-Meier analysis and Cox multivariate analysis were used to evaluate the prognostic significance of miR-374c-5p in HCC. The biological functions of miR-374c-5p, including cell proliferation, migration and invasion and its potential molecular mechanism were analyzed in vivo and in vitro. In addition, the molecular mechanism of miR-374c-5p in HCC was further explored. The results demonstrated that miR-374c-5p expression was lower in HCC than in matched adjacent tissue samples. Patients with low expression of miR-374c-5p had poor prognosis and short survival time. Overexpression of miR-374c-5p inhibited HCC cell proliferation, migration and invasion in vitro. In vivo, it was found that overexpression of miR-374c-5p significantly inhibited the growth and proliferation of HCC cells. Dual-luciferase reporter assays verified that miR-374c-5p directly targets the 3′-untranslated region of pituitary tumor-transforming 1 (PTTG1) and regulates PTTG1 expression. In general, it was revealed that miR-374c-5p regulates the malignant biological behavior of HCC through PTTG1, thereby affecting epithelial-mesenchymal transition. Thus, miR-374c-5p is a potential biological indicator to predict poor prognosis in patients with HCC.
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Affiliation(s)
- Gang Yang
- First Clinical Medical College, Jinan University, Tianhe, Guangzhou, Guangdong 510632, P.R. China
| | - Yongfu Xiog
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Guan Wang
- Physical Examination Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Weinan Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Tao Tang
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Ji Sun
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Jingdong Li
- First Clinical Medical College, Jinan University, Tianhe, Guangzhou, Guangdong 510632, P.R. China
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Das B, Jain N, Mallick B. Ribonucleotide reductase subunit M2 is a potential prognostic marker and therapeutic target for soft tissue sarcoma. Gene 2022; 808:145988. [PMID: 34624457 DOI: 10.1016/j.gene.2021.145988] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 09/08/2021] [Accepted: 10/01/2021] [Indexed: 12/19/2022]
Abstract
Soft tissue sarcomas (STSs) are highly aggressive malignant tumors that exhibit poor therapeutic outcomes. Hence, we aimed to track down a potential gene that can be used as a prognostic marker and therapeutic target for this malignancy. We integrated omics analysis of clinical data and in vitro studies and identified Ribonucleotide reductase subunit M2 (RRM2) as a potential oncogene associated with STS prognosis. We found RRM2 is highly expressed in STS cell lines and tissues. STS patients with increased RRM2 levels showed worse overall survival, disease-free survival, progression-free survival, and disease-specific survival. Further, overexpression of RRM2 in HT1080 cells induces proliferation, migration, invasion, and colony formation, whereas its silencing arrest the cell cycle at G0/G1 phase and induces apoptosis. Taken together, we established RRM2 to be positively associated with oncogenesis and prognosis of STS and therefore could be a promising prognostic marker and therapeutic target.
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Affiliation(s)
- Basudeb Das
- RNAi and Functional Genomics Lab., Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Neha Jain
- RNAi and Functional Genomics Lab., Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Bibekanand Mallick
- RNAi and Functional Genomics Lab., Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
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Cheng G, Liu X, Li P, Li Y. Down-regulation of PTTG1 suppresses PDGF-BB-induced proliferation, migration and extracellular matrix production of airway smooth muscle cells (ASMCs) by regulating PI3K/AKT/mTOR signaling pathway. Mol Cell Toxicol 2021. [DOI: 10.1007/s13273-021-00155-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Lei X, Zhang M, Guan B, Chen Q, Dong Z, Wang C. Identification of hub genes associated with prognosis, diagnosis, immune infiltration and therapeutic drug in liver cancer by integrated analysis. Hum Genomics 2021; 15:39. [PMID: 34187556 PMCID: PMC8243535 DOI: 10.1186/s40246-021-00341-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 06/16/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Liver cancer is one of the most common cancers and causes of cancer death worldwide. The objective was to elucidate novel hub genes which were benefit for diagnosis, prognosis, and targeted therapy in liver cancer via integrated analysis. METHODS GSE84402, GSE101685, and GSE112791 were filtered from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified by using the GEO2R. The GO and KEGG pathway of DEGs were analyzed in the DAVID. PPI and TF network of the DEGs were constructed by using the STRING, TRANSFAC, and Harmonizome. The relationship between hub genes and prognoses in liver cancer was analyzed in UALCAN based on The Cancer Genome Atlas (TCGA). The diagnostic value of hub genes was evaluated by ROC. The relationship between hub genes and tumor-infiltrate lymphocytes was analyzed in TIMER. The protein levels of hub genes were verified in HPA. The interaction between the hub genes and the drug were identified in DGIdb. RESULTS In total, 108 upregulated and 60 downregulated DEGs were enriched in 148 GO terms and 20 KEGG pathways. The mRNA levels and protein levels of CDK1, HMMR, PTTG1, and TTK were higher in liver cancer tissues compared to normal tissues, which showed excellent diagnostic and prognostic value. CDK1, HMMR, PTTG1, and TTK were positively correlated with tumor-infiltrate lymphocytes, which might involve tumor immune response. The CDK1, HMMR, and TTK had close interaction with anticancer agents. CONCLUSIONS The CDK1, HMMR, PTTG1, and TTK were hub genes in liver cancer; hence, they might be potential biomarkers for diagnosis, prognosis, and targeted therapy of liver cancer.
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Affiliation(s)
- Xinyi Lei
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Jinan University, No.613 Huangpu Road West, Guangzhou, 510630, China
| | - Miao Zhang
- Department of Respiratory, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Bingsheng Guan
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Jinan University, No.613 Huangpu Road West, Guangzhou, 510630, China
| | - Qiang Chen
- Department of Oncology, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Zhiyong Dong
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Jinan University, No.613 Huangpu Road West, Guangzhou, 510630, China.
| | - Cunchuan Wang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Jinan University, No.613 Huangpu Road West, Guangzhou, 510630, China.
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Patil AR, Leung MY, Roy S. Identification of Hub Genes in Different Stages of Colorectal Cancer through an Integrated Bioinformatics Approach. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:5564. [PMID: 34070979 PMCID: PMC8197092 DOI: 10.3390/ijerph18115564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 11/16/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer that contributes to cancer-related morbidity. However, the differential expression of genes in different phases of CRC is largely unknown. Moreover, very little is known about the role of stress-survival pathways in CRC. We sought to discover the hub genes and identify their roles in several key pathways, including oxidative stress and apoptosis in the different stages of CRC. To identify the hub genes that may be involved in the different stages of CRC, gene expression datasets were obtained from the gene expression omnibus (GEO) database. The differentially expressed genes (DEGs) common among the different datasets for each group were obtained using the robust rank aggregation method. Then, gene enrichment analysis was carried out with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. Finally, the protein-protein interaction networks were constructed using the Cytoscape software. We identified 40 hub genes and performed enrichment analysis for each group. We also used the Oncomine database to identify the DEGs related to stress-survival and apoptosis pathways involved in different stages of CRC. In conclusion, the hub genes were found to be enriched in several key pathways, including the cell cycle and p53 signaling pathway. Some of the hub genes were also reported in the stress-survival and apoptosis pathways. The hub DEGs revealed from our study may be used as biomarkers and may explain CRC development and progression mechanisms.
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Affiliation(s)
- Abhijeet R. Patil
- Computational Science Program, The University of Texas at El Paso, El Paso, TX 79968, USA; (A.R.P.); (M.-Y.L.)
| | - Ming-Ying Leung
- Computational Science Program, The University of Texas at El Paso, El Paso, TX 79968, USA; (A.R.P.); (M.-Y.L.)
- Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA
- Department of Mathematical Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA
| | - Sourav Roy
- Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA
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Hong H, Jin Z, Qian T, Xu X, Zhu X, Fei Q, Yang J, Sui C, Xu M. Falcarindiol Enhances Cisplatin Chemosensitivity of Hepatocellular Carcinoma via Down-Regulating the STAT3-Modulated PTTG1 Pathway. Front Pharmacol 2021; 12:656697. [PMID: 34025420 PMCID: PMC8138572 DOI: 10.3389/fphar.2021.656697] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/09/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy globally and the third leading cause of cancer-related death. Chemotherapy is one of the main methods in treating HCC, while recent studies have found that the resistance of HCC to chemotherapeutic drugs reduces the efficacy of the chemotherapy. Falcarindiol (FAD) is a cytotoxic and anti-inflammatory polyacetylenic oxylipin found in food plants of the carrot family (Apiaceae), while its role in HCC remains to be explored. Here, HCC cells (Huh7 and LM3) were treated with FAD at different doses. Cell proliferation was tested by the cell counting kit-8 (CCK-8) method and colony formation assay, while the apoptosis was monitored by flow cytometry. The profiles of apoptosis-related proteins (Bax, bcl2, and Caspase-3), DNA repair proteins (Rad51, BRCA1, and MDC1), and the signal transducer and activator of transcription 3 (STAT3)/Pituitary Tumor Transforming Gene 1 (PTTG1) were verified by western blot (WB) or quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The interaction between STAT3 and PTTG1 was verified by immunoprecipitation (IP). In addition, a xenograft tumor model was constructed in mice to explore the anti-tumor effects of FAD in vivo, and immunohistochemistry (IHC) was performed to count the number of Ki67-stained cells. As a result, FAD inhibited HCC cell proliferation and DNA repair, facilitated their apoptosis, and also enhanced cisplatin (DDP) chemosensitivity. The Combination Index (CI) evaluation showed that FAD and DDP had synergistic effects in repressing HCC cell proliferation. Besides, FAD dampened the STAT3/PTTG1 pathway expression. Further studies revealed that inhibiting STAT3 enhanced the inhibitive effect of FAD on HCC cells, whereas overexpressing PTTG1 attenuated the anti-tumor effect of FAD. Overall, our study illustrated that FAD is a potential anticancer drug and strengthens the chemosensitivity of HCC cells to DDP by inhibiting the STAT3/PTTG1 pathway.
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Affiliation(s)
- Han Hong
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Zhengkang Jin
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Tao Qian
- Department of General Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaoyong Xu
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Xiang Zhu
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Qiang Fei
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jiamei Yang
- Department of Special Treatment I and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Chengjun Sui
- Department of Special Treatment I and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Minhui Xu
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
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Chen SW, Zhou HF, Zhang HJ, He RQ, Huang ZG, Dang YW, Yang X, Liu J, Fu ZW, Mo JX, Tang ZQ, Li CB, Li R, Yang LH, Ma J, Yang LJ, Chen G. The Clinical Significance and Potential Molecular Mechanism of PTTG1 in Esophageal Squamous Cell Carcinoma. Front Genet 2021; 11:583085. [PMID: 33552118 PMCID: PMC7863988 DOI: 10.3389/fgene.2020.583085] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 11/30/2020] [Indexed: 12/24/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the major histological type of esophageal cancers worldwide. Transcription factor PTTG1 was seen highly expressed in a variety of tumors and was related to the degree of tumor differentiation, invasion, and metastasis. However, the clinical significance of PTTG1 had yet to be verified, and the mechanism of abnormal PTTG1 expression in ESCC was not clear. In this study, the comprehensive analysis and evaluation of PTTG1 expression in ESCC were completed by synthesizing in-house immunohistochemistry (IHC), clinical sample tissue RNA-seq (in-house RNA-seq), public high-throughput data, and literature data. We also explored the possible signaling pathways and target genes of PTTG1 in ESCC by combining the target genes of PTTG1 (displayed by ChIP-seq), differentially expressed genes (DEGs) of ESCC, and PTTG1-related genes, revealing the potential molecular mechanism of PTTG1 in ESCC. In the present study, PTTG1 protein and mRNA expression levels in ESCC tissues were all significantly higher than in non-cancerous tissues. The pool standard mean difference (SMD) of the overall PTTG1 expression was 1.17 (95% CI: 0.72-1.62, P < 0.01), and the area under curve (AUC) of the summary receiver operating characteristic (SROC) was 0.86 (95% CI: 0.83-0.89). By combining the target genes displayed by ChIP-seq of PTTG1, DEGs of ESCC, and PTTG1-related genes, it was observed that PTTG1 may interact with these genes through chemokines and cytokine signaling pathways. By constructing a protein-protein interaction (PPI) network and combining ChIP-seq data, we obtained four PTTG1 potential target genes, SPTAN1, SLC25A17, IKBKB, and ERH. The gene expression of PTTG1 had a strong positive correlation with SLC25A17 and ERH, which suggested that PTTG1 might positively regulate the expression of these two genes. In summary, the high expression of PTTG1 may play an important role in the formation of ESCC. These roles may be completed by PTTG1 regulating the downstream target genes SLC25A17 and ERH.
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Affiliation(s)
- Shang-Wei Chen
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hua-Fu Zhou
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Han-Jie Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Rong-Quan He
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhi-Guang Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yi-Wu Dang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xia Yang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jun Liu
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zong-Wang Fu
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jun-Xian Mo
- Department of Cardio-Thoracic Surgery, The Seventh Affiliated Hospital of Guangxi Medical University/Wuzhou Gongren Hospital, Wuzhou, China
| | - Zhong-Qing Tang
- Department of Pathology, Wuzhou Gongren Hospital/The Seventh Affiliated Hospital of Guangxi Medical University, Wuzhou, China
| | - Chang-Bo Li
- Department of Cardio-Thoracic Surgery, The Seventh Affiliated Hospital of Guangxi Medical University/Wuzhou Gongren Hospital, Wuzhou, China
| | - Rong Li
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li-Hua Yang
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jie Ma
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lin-Jie Yang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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22
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Li YL, Gao YL, Niu XL, Wu YT, Du YM, Tang MS, Li JY, Guan XH, Song B. Identification of Subtype-Specific Metastasis-Related Genetic Signatures in Sarcoma. Front Oncol 2020; 10:544956. [PMID: 33123466 PMCID: PMC7573283 DOI: 10.3389/fonc.2020.544956] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 08/28/2020] [Indexed: 12/18/2022] Open
Abstract
Background: Sarcomas are heterogeneous rare malignancies constituting approximately 1% of all solid cancers in adults and including more than 70 histological and molecular subtypes with different pathological and clinical development characteristics. Method: We identified prognostic biomarkers of sarcomas by integrating clinical information and RNA-seq data from TCGA and GEO databases. In addition, results obtained from cell cycle, cell migration, and invasion assays were used to assess the capacity for Tanespimycin to inhibit the proliferation and metastasis of sarcoma. Results: Sarcoma samples (N = 536) were divided into four pathological subtypes including DL (dedifferentiated liposarcoma), LMS (leiomyosarcoma), UPS (undifferentiated pleomorphic sarcomas), and MFS (myxofibrosarcoma). RNA-seq expression profile data from the TCGA dataset were used to analyze differentially expressed genes (DEGs) within metastatic and non-metastatic samples of these four sarcoma pathological subtypes with DEGs defined as metastatic-related signatures (MRS). Prognostic analysis of MRS identified a group of genes significantly associated with prognosis in three pathological subtypes: DL, LMS, and UPS. ISG15, NUP50, PTTG1, SERPINE1, and TSR1 were found to be more likely associated with adverse prognosis. We also identified Tanespimycin as a drug exerting inhibitory effects on metastatic LMS subtype and therefore can serve a potential treatment for this type of sarcoma. Conclusions: These results provide new insights into the pathogenesis, diagnosis, treatment, and prognosis of sarcomas and provide new directions for further study of sarcoma.
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Affiliation(s)
- Ya-Ling Li
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China.,National Health Commission Key Laboratory of Immunodermatology (China Medical University), Shenyang, China.,Key Laboratory of Immunodermatology, Ministry of Education, Shenyang, China
| | - Ya-Li Gao
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China.,National Health Commission Key Laboratory of Immunodermatology (China Medical University), Shenyang, China.,Key Laboratory of Immunodermatology, Ministry of Education, Shenyang, China
| | - Xue-Li Niu
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China.,National Health Commission Key Laboratory of Immunodermatology (China Medical University), Shenyang, China.,Key Laboratory of Immunodermatology, Ministry of Education, Shenyang, China
| | - Yu-Tong Wu
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China.,National Health Commission Key Laboratory of Immunodermatology (China Medical University), Shenyang, China.,Key Laboratory of Immunodermatology, Ministry of Education, Shenyang, China
| | - Yi-Mei Du
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China.,National Health Commission Key Laboratory of Immunodermatology (China Medical University), Shenyang, China.,Key Laboratory of Immunodermatology, Ministry of Education, Shenyang, China
| | - Ming-Sui Tang
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China.,National Health Commission Key Laboratory of Immunodermatology (China Medical University), Shenyang, China.,Key Laboratory of Immunodermatology, Ministry of Education, Shenyang, China
| | - Jing-Yi Li
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China.,National Health Commission Key Laboratory of Immunodermatology (China Medical University), Shenyang, China.,Key Laboratory of Immunodermatology, Ministry of Education, Shenyang, China
| | - Xiu-Hao Guan
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China.,National Health Commission Key Laboratory of Immunodermatology (China Medical University), Shenyang, China.,Key Laboratory of Immunodermatology, Ministry of Education, Shenyang, China
| | - Bing Song
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China.,School of Dentistry, Cardiff University, Cardiff, United Kingdom
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23
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Chen JY, Sun Y, Qiao N, Ge YY, Li JH, Lin Y, Yao SL. Co-expression Network Analysis Identifies Fourteen Hub Genes Associated with Prognosis in Clear Cell Renal Cell Carcinoma. Curr Med Sci 2020; 40:773-785. [PMID: 32862390 DOI: 10.1007/s11596-020-2245-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 06/03/2020] [Indexed: 12/14/2022]
Abstract
Renal cancer is a common genitourinary malignance, of which clear cell renal cell carcinoma (ccRCC) has high aggressiveness and leads to most cancer-related deaths. Identification of sensitive and reliable biomarkers for predicting tumorigenesis and progression has great significance in guiding the diagnosis and treatment of ccRCC. Here, we identified 2397 common differentially expressed genes (DEGs) using paired normal and tumor ccRCC tissues from GSE53757 and The Cancer Genome Atlas (TCGA). Then, we performed weighted gene co-expression network analysis and protein-protein interaction network analysis, 17 candidate hub genes were identified. These candidate hub genes were further validated in GSE36895 and Oncomine database and 14 real hub genes were identified. All the hub genes were up-regulated and significantly positively correlated with pathological stage and histologic grade of ccRCC. Survival analysis showed that the higher expression level of each hub gene tended to predict a worse clinical outcome. ROC analysis showed that all the hub genes can accurately distinguish between tumor and normal samples, and between early stage and advanced stage ccRCC. Moreover, all the hub genes were positively associated with distant metastasis, lymph node infiltration, tumor recurrence and the expression of MKi67, suggesting these genes might promote tumor proliferation, invasion and metastasis. Furthermore, the functional annotation demonstrated that most genes were enriched in cell-cycle related biological function. In summary, our study identified 14 potential biomarkers for predicting tumorigenesis and progression, which might contribute to early diagnosis, prognosis prediction and therapeutic intervention.
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Affiliation(s)
- Jia-Yi Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yan Sun
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Nan Qiao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yang-Yang Ge
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jian-Hua Li
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yun Lin
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Shang-Long Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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24
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Grzechowiak I, Graś J, Szymańska D, Biernacka M, Guglas K, Poter P, Mackiewicz A, Kolenda T. The Oncogenic Roles of PTTG1 and PTTG2 Genes and Pseudogene PTTG3P in Head and Neck Squamous Cell Carcinomas. Diagnostics (Basel) 2020; 10:diagnostics10080606. [PMID: 32824814 PMCID: PMC7459614 DOI: 10.3390/diagnostics10080606] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 12/17/2022] Open
Abstract
Background: Head and neck squamous cell carcinomas are a group of heterogeneous diseases that occur in the mouth, pharynx and larynx and are characterized by poor prognosis. A low overall survival rate leads to a need to develop biomarkers for early head and neck squamous cell carcinomas detection, accurate prognosis and appropriate selection of therapy. Therefore, in this paper, we investigate the biological role of the PTTG3P pseudogene and associated genes PTTG1 and PTTG2 and their potential use as biomarkers. Methods: Based on TCGA data and the UALCAN database, PTTG3P, PTTG1 and PTTG2 expression profiles and clinicopathological features with TP53 gene status as well as expression levels of correlated genes were analyzed in patients’ tissue samples. The selected genes were classified according to their biological function using the PANTHER tool. Gene Set Enrichment Analysis software was used for functional enrichment analysis. All statistical analyses were performed using GraphPad Prism 5. Results: In head and neck squamous cell carcinomas, significant up-regulation of the PTTG3P pseudogene, PTTG1 and PTTG2 genes’ expression between normal and cancer samples were observed. Moreover, the expression of PTTG3P, PTTG1 and PTTG2 depends on the type of mutation in TP53 gene, and they correlate with genes from p53 pathway. PTTG3P expression was significantly correlated with PTTG1 as well as PTTG2, as was PTTG1 expression with PTTG2. Significant differences between expression levels of PTTG3P, PTTG1 and PTTG2 in head and neck squamous cell carcinomas patients were also observed in clinicopathological contexts. The contexts taken into consideration included: T-stage for PTTG3P; grade for PTTG3, PTTG1 and PTTG2; perineural invasion and lymph node neck dissection for PTTG1 and HPV p16 status for PTTG3P, PTTG1 and PTTG2. A significantly longer disease-free survival for patients with low expressions of PTTG3P and PTTG2, as compared to high expression groups, was also observed. Gene Set Enrichment Analysis indicated that the PTTG3 high-expressing group of patients have the most deregulated genes connected with DNA repair, oxidative phosphorylation and peroxisome pathways. For PTTG1, altered genes are from DNA repair groups, Myc targets, E2F targets and oxidative phosphorylation pathways, while for PTTG2, changes in E2F targets, G2M checkpoints and oxidative phosphorylation pathways are indicated. Conclusions: PTTG3P and PTTG2 can be used as a prognostic biomarker in head and neck squamous cell carcinomas diagnostics. Moreover, patients with high expressions of PTTG3P, PTTG1 or PTTG2 have worse outcomes due to upregulation of oncogenic pathways and more aggressive phenotypes.
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Affiliation(s)
- Inga Grzechowiak
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland; (I.G.); (J.G.); (D.S.); (M.B.); (A.M.)
| | - Justyna Graś
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland; (I.G.); (J.G.); (D.S.); (M.B.); (A.M.)
| | - Dominika Szymańska
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland; (I.G.); (J.G.); (D.S.); (M.B.); (A.M.)
| | - Martyna Biernacka
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland; (I.G.); (J.G.); (D.S.); (M.B.); (A.M.)
| | - Kacper Guglas
- Laboratory of Cancer Genetics, 15 Garbary Street, 61-866 Poznan, Poland;
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, 61 Zwirki i Wigury Street, 02-091 Warsaw, Poland
| | - Paulina Poter
- Department of Oncologic Pathology and Prophylaxis, Poznan University of Medical Sciences, Greater Poland Cancer Center, 15 Garbary Street, 61-866 Poznan, Poland;
- Department of Pathology, Pomeranian Medical University, 1 Unii Lubelskiej Street, 71-242 Szczecin, Poland
| | - Andrzej Mackiewicz
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland; (I.G.); (J.G.); (D.S.); (M.B.); (A.M.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary Street, 61-866 Poznan, Poland
| | - Tomasz Kolenda
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland; (I.G.); (J.G.); (D.S.); (M.B.); (A.M.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary Street, 61-866 Poznan, Poland
- Correspondence:
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25
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Suppression of PTTG1 inhibits cell angiogenesis, migration and invasion in glioma cells. Med Oncol 2020; 37:73. [PMID: 32725378 DOI: 10.1007/s12032-020-01398-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 07/16/2020] [Indexed: 02/07/2023]
Abstract
Pituitary tumor-transforming gene 1 (PTTG1) has been identified as an oncogene and is overexpressed in many tumor types. However, the role of PTTG1 in glioblastoma (GBM) has not been well characterized, especially in relation to angiogenesis, migration, and invasion. In the present study, our results showed that the expression of PTTG1 was significantly higher in patients with GBM. Bioinformatic analysis showed that angiogenesis and the cell migration-related process were increased in patients with high PTTG1 expression levels; meanwhile, PTTG1 was positively correlated with marker genes of angiogenesis, migration and the evasion of apoptosis. In vitro assays showed that PTTG1 knockdown dramatically suppressed angiogenesis, migration and invasion, and increased the apoptosis of GBM cells. Moreover, our results also showed that silencing PTTG1 suppressed the activity of the TGF-β/PI3K-AKT-mTOR pathway, which induced tumor deterioration in multiple organs. Overall, our findings indicate that PTTG1 is a glioma malignant factor that promotes angiogenesis, migration, invasion, and the evasion of apoptosis, and these roles may be related to the TGF-β/PI3K-AKT-mTOR pathway. Thus, the targeted inhibition of PTTG1 might be a novel therapeutic strategy and a potential diagnostic biomarker for GBM-targeted therapies.
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26
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Jing L, Feng L, Zhou Z, Shi S, Deng R, Wang Z, Zhang Y, Ren Z, Liu Y. TNNT2 as a potential biomarker for the progression and prognosis of colorectal cancer. Oncol Rep 2020; 44:628-636. [PMID: 32627044 PMCID: PMC7336514 DOI: 10.3892/or.2020.7637] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 02/26/2020] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. At present, there are limited effective biomarkers of CRC. The present study aimed to identify potential signatures associated with the tumorigenesis and prognosis of CRC using publicly available databases, and further validate the identified biomarkers in CRC cell lines. Identification of differentially expressed mRNAs between CRC and paracancerous samples was conducted based on data from The Cancer Genome Atlas (TCGA; 471 tumor samples and 41 normal samples). Survival analysis was performed to explore the prognostic value of troponin 2 (TNNT2) in the TCGA training set, which was further validated in an external dataset, GSE17531. Functional enrichment analysis was conducted to determine the possible biological functions using GSEA 3.0. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were utilized to detect the mRNA and protein expression levels of TNNT2 between CRC and normal colorectal cells. Immunohistochemistry was performed to detect the protein expression of TNNT2 in CRC and normal tissues. TNNT2 was significantly upregulated in CRC samples compared with adjacent normal samples in the TCGA dataset. Increased expression of TNNT2 was associated with inferior prognosis in the TCGA training dataset and GSE17531 validation dataset. Functional enrichment analysis revealed that the ErbB signaling pathway and glycerophospholipid metabolism pathway were significantly activated in the TNNT2 high expression group. Overexpression of TNNT2 mRNA and TNNT2 protein in CRC tumor cells was confirmed by RT-qPCR and western blotting, respectively. Immunohistochemistry indicated increased protein expression levels of TNNT2 in CRC tissues in comparison with normal tissues. TNNT2 was associated with the tumorigenesis and prognosis of CRC, which may be useful for novel biomarker identification and targeted therapeutic strategy development.
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Affiliation(s)
- Li Jing
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Li Feng
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Zhiguo Zhou
- Department of Radiotherapy, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Shuai Shi
- Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Ruoying Deng
- Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Zhicong Wang
- Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yi Zhang
- Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Zhixue Ren
- The Seven People's Hospital of Hebei Province, Dingzhou, Hebei 073000, P.R. China
| | - Yibing Liu
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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27
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Zhu M, Dang Y, Yang Z, Liu Y, Zhang L, Xu Y, Zhou W, Ji G. Comprehensive RNA Sequencing in Adenoma-Cancer Transition Identified Predictive Biomarkers and Therapeutic Targets of Human CRC. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 20:25-33. [PMID: 32145677 PMCID: PMC7057163 DOI: 10.1016/j.omtn.2020.01.031] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 11/13/2019] [Accepted: 01/23/2020] [Indexed: 12/12/2022]
Abstract
Specific molecular biomarkers for predicting the transition from colorectal adenoma to cancer have been identified, however, circular RNA (circRNA)-related signatures remain to be clarified. We carried out high-throughput RNA sequencing to determine the expression profiles of circRNAs, microRNAs (miRNAs), and mRNAs in human colorectal cancer (CRC), adenoma, and adjacent normal tissues. We identified 84 circRNAs, 41 miRNAs, and 398 mRNAs that were commonly differentially expressed in CRC and adenoma tissues compared with normal tissues. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) analyses identified numerous cancer-related hub genes that might serve as potential therapeutic targets in CRC. Competing endogenous RNA (ceRNA) networks, including three circRNAs, three miRNAs, and 28 mRNAs were constructed, suggesting their potential role in cancer progression. Representative differentially expressed RNAs were validated by the Cancer Genome Atlas (TCGA) database and real-time PCR experiments. Receiver operating characteristic (ROC) curve analysis identified three circRNAs (hsa_circ_0049487, hsa_circ_0066875, and hsa_circ_0007444) as possible novel biomarkers predicting the transition from colonic adenoma to cancer. Overall, our findings may provide novel perspectives to clarify the mechanisms of the transition from premalignant adenoma to cancer and identify specific circRNA-related signatures with possible applications for the early diagnosis of and as potential therapeutic targets in CRC.
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Affiliation(s)
- Mingzhe Zhu
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yanqi Dang
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Zhenhua Yang
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Digestive Endoscopy Department, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yang Liu
- Department of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Li Zhang
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yangxian Xu
- Department of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Wenjun Zhou
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
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28
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Fraune C, Yehorov S, Luebke AM, Steurer S, Hube-Magg C, Büscheck F, Höflmayer D, Tsourlakis MC, Clauditz TS, Simon R, Sauter G, Weidemann S, Dum D, Kind S, Minner S, Schlomm T, Huland H, Heinzer H, Graefen M, Burandt E. Upregulation of PTTG1 is associated with poor prognosis in prostate cancer. Pathol Int 2020; 70:441-451. [PMID: 32314536 DOI: 10.1111/pin.12938] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/18/2020] [Accepted: 04/01/2020] [Indexed: 12/18/2022]
Abstract
Pituitary tumor-transforming gene 1 (PTTG1) is a regulator of chromosome stability. PTTG1 overexpression had been associated with tumor aggressiveness in several cancer types. To examine its prognostic utility in prostate cancer, a tissue microarray including 12 427 tumors with clinical and molecular data was analyzed by immunohistochemistry. PTTG1 immunostaining was largely absent in normal prostate epithelial cells. In cancers, staining was considered weak in 5.4%, moderate in 5.6% and strong in 0.8%. Strong staining was linked to advanced pT stage, high classical and quantitative Gleason grade, high Ki67-labeling index (all P < 0.0001) and lymph node metastasis (P = 0.0083). The prognostic impact of PTTG1 expression was independent of established preoperative and postoperative prognostic features. Comparison with molecular features revealed that PTTG1 upregulation was associated with nine of 12 common genomic deletions (P < 0.05), p53 alterations and high androgen receptor levels (P < 0.001 each), but was unrelated to the TMPRSS2:ERG fusion status. In conclusion, these data identify PTTG1 as a strong and independent prognostic feature in prostate cancer. PTTG1 measurement, either alone or in combination with other biomarkers might be instrumental for determining prostate cancer aggressiveness.
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Affiliation(s)
- Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Serhiy Yehorov
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Simon Kind
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorsten Schlomm
- Department of Urology, University Medical Center Charité-Berlin, Berlin, Germany
| | - Hartwig Huland
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans Heinzer
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Markus Graefen
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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29
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Liu J, Wan Y, Li S, Qiu H, Jiang Y, Ma X, Zhou S, Cheng W. Identification of aberrantly methylated differentially expressed genes and associated pathways in endometrial cancer using integrated bioinformatic analysis. Cancer Med 2020; 9:3522-3536. [PMID: 32170852 PMCID: PMC7221444 DOI: 10.1002/cam4.2956] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 01/21/2020] [Accepted: 02/19/2020] [Indexed: 12/14/2022] Open
Abstract
Endometrial cancer (EC) is a fatal female reproductive tumor. Bioinformatic tools are increasingly developed to screen out molecular targets related to EC. In this study, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE17025 and http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE40032 were obtained from Gene Expression Omnibus (GEO). “limma” package and Venn diagram tool were used to identify hub genes. FunRich was used for functional analysis. Retrieval of Interacting Genes Database (STRING) was used to analyze protein‐protein interaction (PPI) complex. Cancer Genome Atlas (TCGA), GEPIA, immunohistochemistry staining, and ROC curve analysis were carried out for validation. Univariate and multivariate regression analyses were performed to predict the risk score. Compound muscle action potential (CMap) was used to find potential drugs. GSEA was also done. We retrieved seven oncogenes which were upregulated and hypomethylated and 12 tumor suppressor genes (TSGs) which were downregulated and hypermethylated. The upregulated and hypomethylated genes were strikingly enriched in term “immune response” while the downregulated and hypermethylated genes were mainly focused on term “aromatic compound catabolic process.” TCGA and GEPIA were used to screen out EDNRB, CDO1, NDN, PLCD1, ROR2, ESPL1, PRAME, and PTTG1. Among them, ESPL1 and ROR2 were identified by Cox regression analysis and were used to construct prognostic risk model. The result showed that ESPL1 was a negative independent prognostic factor. Cmap identified aminoglutethimide, luteolin, sulfadimethoxine, and maprotiline had correlation with EC. GSEA results showed that “hedgehog signaling pathway” was enriched. This research inferred potential aberrantly methylated DEGs and dysregulated pathways may participate in EC development and firstly reported eight hub genes, including EDNRB, CDO1, NDN, PLCD1, ROR2, ESPL1, PRAME, and PTTG1 that could be used to predict EC prognosis. Aminoglutethimide and luteolin may be used to fight against EC.
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Affiliation(s)
- JinHui Liu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - YiCong Wan
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Siyue Li
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - HuaiDe Qiu
- Center of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yi Jiang
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoling Ma
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - ShuLin Zhou
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - WenJun Cheng
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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30
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Ding X, Duan H, Luo H. Identification of Core Gene Expression Signature and Key Pathways in Colorectal Cancer. Front Genet 2020; 11:45. [PMID: 32153633 PMCID: PMC7046836 DOI: 10.3389/fgene.2020.00045] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 01/15/2020] [Indexed: 12/17/2022] Open
Abstract
Objective Colorectal cancer (CRC) is considered the most prevalent malignant tumor that contributes to high cancer-related mortality. However, the signaling pathways involved in CRC and CRC-driven genes are largely unknown. We sought to discover a novel biomarker in CRC. Materials and Methods All clinical CRC samples (n = 20) were from Renmin Hospital of Wuhan University. We first selected MAD2L1 by integrated bioinformatics analysis of a GSE dataset. Next, the expression of MAD2L1 in tissues and cell lines was verified by quantitative real-time PCR. The effects of MAD2L1 on cell growth, proliferation, the cell cycle, and apoptosis were examined by in vitro assays. Results We identified 683 shared DEGs (420 upregulated and 263 downregulated), and the top twenty genes (CDK1, CCNA2, TOP2A, PLK1, MAD2L1, AURKA, BUB1B, UBE2C, TPX2, RRM2, KIF11, NCAPG, MELK, NUSAP1, MCM4, RFC4, PTTG1, CHEK1, CEP55, DTL) were selected by integrated analysis. These hub genes were significantly overexpressed in CRC samples and were positively correlated. Our data revealed that the expression of MAD2L1 in CRC tissues is higher than that in normal tissues. MAD2L1 knockdown significantly suppressed CRC cell growth by impairing cell cycle progression and inducing cell apoptosis. Conclusion MAD2L1, as a novel oncogenic gene, plays a role in regulating cancer cell growth and apoptosis and could be used as a new biomarker for diagnosis and therapy in CRC.
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Affiliation(s)
- Xiang Ding
- Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan, China
| | - Houyu Duan
- Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan, China
| | - Hesheng Luo
- Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan, China
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31
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Li X, Zhang Q, Zhao L, Jiang L, Qi A, Wei Q, Song X, Wang L, Zhang L, Zhao Y, Lv X, Wei M, Zhao L. A Combined four-mRNA Signature Associated with Lymphatic Metastasis for Prognosis of Colorectal Cancer. J Cancer 2020; 11:2139-2149. [PMID: 32127941 PMCID: PMC7052913 DOI: 10.7150/jca.38796] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 01/04/2020] [Indexed: 12/17/2022] Open
Abstract
Background: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Lymph node metastasis (LNM) is a common mode of metastasis of CRC. However, the combined mRNA biomarkers associated with LNM of CRC that can effectively predict CRC prognosis have not been reported yet. Methods: To identify biomarkers that are associated with LNM, we collected data from the The Cancer Genome Atlas (TCGA) database. The edgeR package was searched to seek LNM-related genes by comparisons between cancer samples and normal colorectal tissues and between LNM and non-LNM (NLNM) of CRC. Univariate and multivariate regression analysis of genes in the intersection to build gene signature associated with independent prognosis of CRC, and then verified by Kaplan-Meier curve and log-rank test, receiver operating characteristic (ROC) curve was used to determine the efficiency of survival prediction of our four-mRNA signature. Finally, the potential molecular mechanisms and properties of these gene signature were also explored with functional and pathway enrichment analysis. Results: 329 mRNAs were up-regulated in CRC tissues with LNM, and 8461 mRNAs were up-regulated in CRC tissues, the intersection is 100 mRNAs. After univariate and multivariate Cox regression analysis of 100 mRNAs, a novel four LNM related mRNAs (EPHA8, KRT85, GABRA3, and CLPSL1) were screened as independent prognostic indicators of CRC. Surprisingly, the four-mRNA signature can predict the prognosis of CRC patients independently of clinical factors andthe area under the curve (AUC) of the ROC is 0.730. The novel four-mRNA signature was used to identify high and low-risk groups. Stratified analysis indicated the risk score based on four-mRNA signature was an independent prognostic indicator for female, T3+T4, N1+N2 ,stage III+IV and patients with no new tumor event. Functional annotation of this risk model in high-risk patients revealed that pathways associated with neuroactive ligand-receptor interaction, estrogen signaling pathway, and steroid hormone biosynthesis. Conclusions: By conducting TCGA data mining, our study demonstrated that a four-mRNA signature associated with LNM can be used as a combined biomarker for independent prognosis of CRC.
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Affiliation(s)
- Xueping Li
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Qiang Zhang
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Lan Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Longyang Jiang
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Aoshuang Qi
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Qian Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Xinyue Song
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Lin Wang
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Liwen Zhang
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Yanyun Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Xuemei Lv
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
| | - Lin Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China.,Liaoning Engineering Technology Research Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, Liaoning, China
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32
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Guo H, Cai J, Wang X, Wang B, Wang F, Li X, Qu X, Kong X, Gao Y, Wu H, Sun X, Xia Q, Kong X. Prognostic values of a novel multi-mRNA signature for predicting relapse of cholangiocarcinoma. Int J Biol Sci 2020; 16:869-881. [PMID: 32071556 PMCID: PMC7019144 DOI: 10.7150/ijbs.38846] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 11/05/2019] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an epithelial cancer and has high death and recurrence rates, current methods cannot satisfy the need for predicting cancer relapse effectively. So, we aimed at conducting a multi-mRNA signature to improve the relapse prediction of CCA. We analyzed mRNA expression profiling in large CCA cohorts from the Gene Expression Omnibus (GEO) database (GSE76297, GSE32879, GSE26566, GSE31370, and GSE45001) and The Cancer Genome Atlas (TCGA) database. The Least absolute shrinkage and selection operator (LASSO) regression model was used to establish a 7-mRNA-based signature that was significantly related to the recurrence-free survival (RFS) in two test series. Based on the 7-mRNA signature, the cohort TCGA patients could be divided into high-risk or low-risk subgroups with significantly different RFS [p < 0.001, hazard ratio (HR): 48.886, 95% confidence interval (CI): 6.226-3.837E+02]. Simultaneously, the prognostic value of the 7-mRNA signature was confirmed in clinical samples of Ren Ji hospital (p < 0.001, HR: 4.558, 95% CI: 1.829-11.357). Further analysis including multivariable and sub-group analyses revealed that the 7-mRNA signature was an independent prognostic value for recurrence of patients with CCA. In conclusion, our results might provide an efficient tool for relapse prediction and were beneficial to individualized management for CCA patients.
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Affiliation(s)
- Han Guo
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Cai
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xuan Wang
- Institute of Clinical Immunology, Department of Liver Diseases, Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Bingrui Wang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fang Wang
- Institute of Clinical Immunology, Department of Liver Diseases, Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Xiang Li
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoye Qu
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xianming Kong
- Central Laboratory, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yueqiu Gao
- Institute of Clinical Immunology, Department of Liver Diseases, Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Hailong Wu
- Shanghai Key Laboratory for Molecular Imaging, Collaborative Research Center, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Xuehua Sun
- Institute of Clinical Immunology, Department of Liver Diseases, Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoni Kong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Institute of Clinical Immunology, Department of Liver Diseases, Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
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33
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Kong J, Wang T, Zhang Z, Yang X, Shen S, Wang W. Five Core Genes Related to the Progression and Prognosis of Hepatocellular Carcinoma Identified by Analysis of a Coexpression Network. DNA Cell Biol 2019; 38:1564-1576. [PMID: 31633379 DOI: 10.1089/dna.2019.4932] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The molecular mechanism of tumorigenesis of the prevalent cancer hepatocellular carcinoma (HCC) is unclear. In this study, through weighted gene coexpression network analysis, a coexpression network was constructed by selecting the top 25% most variant genes in the dataset GSE62232. The average linkage hierarchical clustering identified 24 modules, and among them, the pink module associated with prognosis of HCC was screened. Five gene candidates (PCNA, RFC4, PTTG1, H2AFZ, and RRM1) with a common network in the module were screened after the protein-protein interaction network complex was combined with the coexpression network. After progression and survival analysis, all candidates were identified as real core genes. According to the Human Protein Atlas and the Oncomine database, these genes were dysregulated in HCC samples. The receiver operating characteristic curve proved that the expression levels of the core genes had high diagnostic efficacy. The results of gene set enrichment analysis and functional enrichment analysis demonstrated the importance of the cell cycle-related pathways in HCC progression and prognosis. In conclusion, the five real core genes and cell cycle-related pathways identified in this study could greatly improve the knowledge about HCC progression and contribute to HCC treatment.
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Affiliation(s)
- Junjie Kong
- Department of Liver Surgery, Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, P.R. China
| | - Tao Wang
- Department of Liver Surgery, Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, P.R. China
| | - Zifei Zhang
- Department of Liver Surgery, Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, P.R. China
| | - Xianwei Yang
- Department of Liver Surgery, Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, P.R. China
| | - Shu Shen
- Department of Liver Surgery, Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, P.R. China
| | - Wentao Wang
- Department of Liver Surgery, Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, P.R. China
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34
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Tang H, Wu Z, Zhang Y, Xia T, Liu D, Cai J, Ye Q. Identification and Function Analysis of a Five-Long Noncoding RNA Prognostic Signature for Endometrial Cancer Patients. DNA Cell Biol 2019; 38:1480-1498. [PMID: 31539276 DOI: 10.1089/dna.2019.4944] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
This study aimed to construct a long noncoding RNA (lncRNA)-based prognostic signature to improve the survival prediction for endometrial cancer (EC) patients and guide individualized treatments. mRNA and miRNA sequencing and clinical data of 526 patients with EC (randomized to training or validation set, n = 263) were collected from The Cancer Genome Atlas database. Differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and differentially expressed miRNAs (DEMs) were identified between 263 EC samples and 33 normal controls. Univariate and multivariate Cox regression analyses identified five DELs (LINC00475, LINC01352, MIR503HG, KCNMB2-AS1, and LINC01143) that were overall survival related. The Kaplan-Meier curve showed that the risk score model established by these five DELs can significantly distinguish the survival ratio of patients at high risk from those at low risk. The receiver operating characteristic curve indicated that this risk score exhibited good survival prediction performance, with the area under the curve of 0.978. In addition, this risk score was independent of other clinical factors. Stratification analysis based on two independent prognostic clinical factors (histologic grade and recurrence status) demonstrated that the high-risk score was still a poor prognostic factor for patients with histologic grade 3, recurrence or nonrecurrence status. In nomogram model, the risk score was one of the main contributions to survival rates, and its Harrell's concordance index was higher than the other two independent clinical factors, although all lower than the combined. Furthermore, mechanism analyses showed that these lncRNAs functioned by coexpressing with DEGs (i.e., LINC00475-PTGDR, LINC01352/MIR503HG-BACH2, KCNMB2-AS1-PCSK9, LINC01143-NUF2/PTTG1) or as a competing endogenous RNA of DEMs to regulate DEGs (LINC00475-miR-4728-PTGDR, MIR503HG-miR-3170-BACH2). In conclusion, our novel risk score system may be a promising prognostic biomarker to guide personalized treatment for EC patients and it can add prognostic value for current clinical system.
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Affiliation(s)
- Hong Tang
- Department of Gynecology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhixi Wu
- Department of Obstetrics and Gynecology, Dongguan People's Hospital (Affiliated Dongguan Hospital, Southern Medical University), Dongguan, China
| | - Yuan Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Tingting Xia
- Center for Reproductive Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Dong Liu
- Department of Gynecology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jiarong Cai
- Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Qingjian Ye
- Department of Gynecology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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35
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Zhu B, Gao M, Zhang L, Wang J, Wang L, Qin LL, Kang XX, Zhao ZG. Association of PTTG1 polymorphism rs1895320, rs2910200 and rs6882742 with non-functioning pituitary adenomas in Chinese Han population: a case-control study. Metab Brain Dis 2019; 34:841-846. [PMID: 30607824 DOI: 10.1007/s11011-018-0364-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 12/04/2018] [Indexed: 11/26/2022]
Abstract
Due to absence of clinical manifestations of hormonal hyper secretion, the treatment of Nonfunctioning pituitary adenoma (NFPA) was always delayed. PTTG1 was reported to be overexpressed in most of pituitary tumors, however, the polymorphism of PTTG1 rs1895320, rs2910200 and rs6882742 with NFPA were still not fully elucidated in NFPA. Thus, a hospital based case control study which included 79 patients and 142 healthy control participants were conducted. DNA was extracted from peripheral blood samples and genotyped by Mass Array methods. In addition, a meta-analysis of rs2910200 was also employed to further testify the conclusion. Significant difference were observed between patients and healthy controls under rs2910200 locus between allelic genotype (p = 0.0219). However, no other significant difference was observed in rs1895329 and rs6882742. In addition, a logistic regression analysis showed that the dominant model of rs2910200 were closely correlated with the NFPA susceptibility (OR = 1.951, 95% CI:1.075-3.542, p = 0.028). While no significant difference was observed in the rs1895320 and rs6882742 under dominant model, recessive model and additive model The meta-analysis results showed that the dominant model and heterozygote model can significantly increase the risk of PA (p = 0.007, OR = 1.57, 95% CI:1.14-2.18; p = 0.009, OR = 1.57, 95% CI:1.12-2.19). Whereas no significant difference were observed under the homozygous model and recessive model. In conclusion, the polymorphism of PTTG1 rs2910200 dominant model and T allelic might increase the risk of NFPA.
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Affiliation(s)
- Bin Zhu
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - Ming Gao
- Laboratory Department, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - Lei Zhang
- Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100050, China
| | - Juan Wang
- Education research evaluation center, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Lei Wang
- Department of endocrinology, Third affiliated hospital of Beijing university of Chinese medicine, Beijing, 100029, China
| | - Ling Ling Qin
- Technology Department, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xi Xiong Kang
- Laboratory Department, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - Zhi Gang Zhao
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
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36
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Hu ZG, Zheng CW, Su HZ, Zeng YL, Lin CJ, Guo ZY, Zhong FD, Yuan GD, He SQ. MicroRNA-329-mediated PTTG1 downregulation inactivates the MAPK signaling pathway to suppress cell proliferation and tumor growth in cholangiocarcinoma. J Cell Biochem 2019; 120:9964-9978. [PMID: 30582202 DOI: 10.1002/jcb.28279] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 11/19/2018] [Indexed: 12/14/2022]
Abstract
Cholangiocarcinoma (CCA) is a severe malignancy usually producing a poor prognosis and high mortality rate. MicroRNAs (miRNAs) have been reported in association with CCA; however, the role miR-329 plays in the CCA condition still remains unclear. Therefore, this study was conducted to explore the underlying mechanism of which miR-329 is influencing the progression of CCA. This work studied the differential analysis of the expression chips of CCA obtained from the Gene Expression Omnibus database. Next, to determine both the expression and role of pituitary tumor transforming gene-1 (PTTG1) in CCA, the miRNAs regulating PTTG1 were predicted. In the CCA cells that had been intervened with miR-329 upregulation or inhibition, along with PTTG1 silencing, expression of miR-329, PTTG1, p-p38/p38, p-ERK5/ERK5, proliferating cell nuclear antigen (PCNA), Cyclin D1, Bcl-2-associated X protein (Bax), B-cell CLL/lymphoma 2 (Bcl-2), and caspase-3 were determined. The effects of both miR-329 and PTTG1 on cell proliferation, cell-cycle distribution, and apoptosis were also assayed. The miR-329 was likely to affect the CCA development through regulation of the PTTG1-mediated mitogen-activated protein kinase (MAPK) signaling pathway. The miR-329 targeted PTTG1, leading to inactivation of the MAPK signaling pathway. Upregulation of miR-329 and silencing of PTTG1 inhibited the CCA cell proliferation, induced cell-cycle arrest, and subsequently promoted apoptosis with elevations in Bax, cleaved caspase-3, and total caspase-3, but showed declines in PCNA, Cyclin D1, and Bcl-2. Moreover, miR-329 was also found to suppress the tumor growth by downregulation of PTTG1. To summarize, miR-329 inhibited the expression of PTTG1 to inactivate the MAPK signaling pathway, thus suppressing the CCA progression, thereby providing a therapeutic basis for the CCA treatment.
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Affiliation(s)
- Zhi-Gao Hu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, People's Republic of China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Chao-Wen Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Hui-Zhao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Yong-Lian Zeng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Cheng-Jie Lin
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, People's Republic of China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Zhen-Ya Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Fu-Di Zhong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Guan-Dou Yuan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Song-Qing He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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