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Athaya T, Li X, Hu H. A deep learning method to integrate extracelluar miRNA with mRNA for cancer studies. Bioinformatics 2024; 40:btae653. [PMID: 39495117 PMCID: PMC11565234 DOI: 10.1093/bioinformatics/btae653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 10/08/2024] [Accepted: 10/30/2024] [Indexed: 11/05/2024] Open
Abstract
MOTIVATION Extracellular miRNAs (exmiRs) and intracellular mRNAs both can serve as promising biomarkers and therapeutic targets for various diseases. However, exmiR expression data is often noisy, and obtaining intracellular mRNA expression data usually involves intrusive procedures. To gain valuable insights into disease mechanisms, it is thus essential to improve the quality of exmiR expression data and develop noninvasive methods for assessing intracellular mRNA expression. RESULTS We developed CrossPred, a deep-learning multi-encoder model for the cross-prediction of exmiRs and mRNAs. Utilizing contrastive learning, we created a shared embedding space to integrate exmiRs and mRNAs. This shared embedding was then used to predict intracellular mRNA expression from noisy exmiR data and to predict exmiR expression from intracellular mRNA data. We evaluated CrossPred on three types of cancers and assessed its effectiveness in predicting the expression levels of exmiRs and mRNAs. CrossPred outperformed the baseline encoder-decoder model, exmiR or mRNA-based models, and variational autoencoder models. Moreover, the integration of exmiR and mRNA data uncovered important exmiRs and mRNAs associated with cancer. Our study offers new insights into the bidirectional relationship between mRNAs and exmiRs. AVAILABILITY AND IMPLEMENTATION The datasets and tool are available at https://doi.org/10.5281/zenodo.13891508.
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Affiliation(s)
- Tasbiraha Athaya
- Department of Computer Science, University of Central Florida, 4000 Central Florida BLVD, Orlando, FL, 32816, United States
| | - Xiaoman Li
- Burnett School of Biomedical Sciences, University of Central Florida, 4000 Central Florida BLVD, Orlando, FL, 32816, United States
| | - Haiyan Hu
- Department of Computer Science, University of Central Florida, 4000 Central Florida BLVD, Orlando, FL, 32816, United States
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Zhang P, Li H, Gong H, Tian Y, Chen F, Li X, Xie C, Tu C, Qian S, Tan Y, Liu Q, Zhang B. c-Myc-XRCC2-FOS axis promotes the proliferation and the resistance to Doxorubicin of NSCLC. Biomed Pharmacother 2024; 179:117315. [PMID: 39153434 DOI: 10.1016/j.biopha.2024.117315] [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: 06/30/2024] [Revised: 08/09/2024] [Accepted: 08/14/2024] [Indexed: 08/19/2024] Open
Abstract
Lung cancer represents one of the most prevalent malignant neoplasms, commanding an alarming incidence and mortality rate globally. Non-small cell lung cancer (NSCLC), constituting approximately 80 %-90 % of all lung cancer cases, is the predominant pathological manifestation of this disease, with a disconcerting 5-year survival rate scarcely reaching 10 %. Extensive prior investigations have elucidated that the aberrant expression of X-ray repair cross-complementing gene 2 (XRCC2), a critical meiotic gene intricately involved in the DNA damage repair process, is intimately associated with tumorigenesis. Nevertheless, the precise roles and underlying mechanistic pathways of XRCC2 in NSCLC remain largely elusive. In the present study, we discerned an overexpression of XRCC2 within NSCLC patient tissues, particularly in high-grade samples, when juxtaposed with normal tissues. Targeted knockdown of XRCC2 notably impeded the proliferation of NSCLC both in vitro and in vivo. Comprehensive RNA sequencing and flow rescue assays unveiled that XRCC2 augments the proliferation of NSCLC cells through the down-regulation of FOS expression. Moreover, the c-Myc gene was definitively identified as an XRCC2 transcriptional factor by means of chromatin immunoprecipitation (ChIP) and luciferase reporter assays, whereby pharmacological attenuation of c-Myc expression, in conjunction with Doxorubicin, synergistically curtailed NSCLC cell growth both in vitro and in vivo. Collectively, our findings proffer critical insights into the novel c-Myc-XRCC2-FOS axis in promoting both proliferation and resistance to Doxorubicin in NSCLC cells, thereby extending a promising avenue for potential new diagnostic strategies and therapeutic interventions in NSCLC.
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Affiliation(s)
- Peihe Zhang
- Department of Hepatobiliary and Intestinal Surgery of Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013, China
| | - Hui Li
- Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Han Gong
- Department of Hepatobiliary and Intestinal Surgery of Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yuxuan Tian
- Department of Hepatobiliary and Intestinal Surgery of Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013, China
| | - Fuxin Chen
- Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013, China
| | - Xiang Li
- Department of Pathology, Xiangya Medical School, Central South University, Changsha, Hunan, China
| | - Chunbo Xie
- Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan, China
| | - Chaofeng Tu
- Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan, China
| | - Siyi Qian
- Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013, China
| | - Yueqiu Tan
- Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan, China; College of Life Sciences, Hunan Normal University, Changsha, China
| | - Qiang Liu
- Department of Hepatobiliary and Intestinal Surgery of Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
| | - Bin Zhang
- Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013, China.
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Yao H, Wu Y, Zhong Y, Huang C, Guo Z, Jin Y, Wang X. Role of c-Fos in DNA damage repair. J Cell Physiol 2024; 239:e31216. [PMID: 38327128 DOI: 10.1002/jcp.31216] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 01/17/2024] [Accepted: 01/27/2024] [Indexed: 02/09/2024]
Abstract
c-Fos, a member of the immediate early gene, serves as a widely used marker of neuronal activation induced by various types of brain damage. In addition, c-Fos is believed to play a regulatory role in DNA damage repair. This paper reviews the literature on c-Fos' involvement in the regulation of DNA damage repair and indicates that genes of the Fos family can be induced by various forms of DNA damage. In addition, cells lacking c-Fos have difficulties in DNA repair. c-Fos is involved in tumorigenesis and progression as a proto-oncogene that maintains cancer cell survival, which may also be related to DNA repair. c-Fos may impact the repair of DNA damage by regulating the expression of downstream proteins, including ATR, ERCC1, XPF, and others. Nonetheless, the underlying mechanisms necessitate further exploration.
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Affiliation(s)
- Haiyang Yao
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yilun Wu
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiming Zhong
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenxuan Huang
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zimo Guo
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yinpeng Jin
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xianli Wang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Ma YQ, Zhang M, Sun ZH, Tang HY, Wang Y, Liu JX, Zhang ZX, Wang C. Identification of anti-gastric cancer effects and molecular mechanisms of resveratrol: From network pharmacology and bioinformatics to experimental validation. World J Gastrointest Oncol 2024; 16:493-513. [PMID: 38425392 PMCID: PMC10900166 DOI: 10.4251/wjgo.v16.i2.493] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/05/2023] [Accepted: 01/12/2024] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most aggressive malignancies with limited therapeutic options and a poor prognosis. Resveratrol, a non-flavonoid polyphenolic compound found in a variety of Chinese medicinal materials, has shown excellent anti-GC effect. However, its exact mechanisms of action in GC have not been clarified. AIM To identify the effects of resveratrol on GC progression and explore the related molecular mechanisms. METHODS Action targets of resveratrol and GC-related targets were screened from public databases. The overlapping targets between the two were confirmed using a Venn diagram, and a "Resveratrol-Target-GC" network was constructed using Cytoscape software version 3.9.1. The protein-protein interaction (PPI) network was constructed using STRING database and core targets were identified by PPI network analysis. The Database for Annotation, Visualization and Integrated Discovery database was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A "Target-Pathway" network was created by using Cytoscape 3.9.1. The RNA and protein expression levels of core target genes were observed using the Cancer Genome Atlas and the Human Protein Atlas databases. DriverDBv3 and Timer2.0 databases were used for survival and immune infiltration analysis. Subsequently, the findings were further verified by molecular docking technology and in vitro experiments. RESULTS A total of 378 resveratrol action targets and 2154 GC disease targets were obtained from public databases, and 181 intersection targets between the two were screened by Venn diagram. The top 20 core targets were identified by PPI network analysis of the overlapping targets. GO function analysis mainly involved protein binding, identical protein binding, cytoplasm, nucleus, negative regulation of apoptotic process and response to xenobiotic stimulus. KEGG enrichment analysis suggested that the involved signaling pathways mainly included PI3K-AKT signaling pathway, MAPK signaling pathway, IL-17 signaling pathway, TNF signaling pathway, ErbB signaling pathway, etc. FBJ murine osteosarcoma viral oncogene homolog (FOS) and matrix metallopeptidase 9 (MMP9) were selected by differential expression analysis, and they were closely associated with immune infiltration. Molecular docking results showed that resveratrol docked well with these two targets. Resveratrol treatment arrested the cell cycle at the S phase, induced apoptosis, and weakened viability, migration and invasion in a dose-dependent manner. Furthermore, resveratrol could exhibit anti-GC effect by regulating FOS and MMP9 expression. CONCLUSION The anti-GC effects of resveratrol are related to the inhibition of cell proliferation, migration, invasion and induction of cell cycle arrest and apoptosis by targeting FOS and MMP9.
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Affiliation(s)
- Ying-Qian Ma
- Department of Oncology, Hebei General Hospital, Shijiazhuang 050051, Hebei Province, China
- School of Graduate Studies, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China
| | - Ming Zhang
- Department of Oncology, Hebei General Hospital, Shijiazhuang 050051, Hebei Province, China
| | - Zhen-Hua Sun
- Department of Oncology, Hebei General Hospital, Shijiazhuang 050051, Hebei Province, China
| | - Hong-Yue Tang
- Clinical Medical Research Center, Hebei General Hospital, Shijiazhuang 050051, Hebei Province, China
| | - Ying Wang
- School of Graduate Studies, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China
| | - Jiang-Xue Liu
- School of Graduate Studies, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China
| | - Zhan-Xue Zhang
- Department of Gastrointestinal Surgery, Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Chao Wang
- Clinical Medical Research Center, Hebei General Hospital, Shijiazhuang 050051, Hebei Province, China
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Liu YC, Wang JW, Li J, Guo Y, Han FJ, Lu WH, Wu Q. Mechanism of cryptotanshinone to improve endocrine and metabolic functions in the endometrium of PCOS rats. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117346. [PMID: 37879506 DOI: 10.1016/j.jep.2023.117346] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/21/2023] [Accepted: 10/22/2023] [Indexed: 10/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cryptotanshinone is the main bioactive component of Salvia miltiorrhiza, with various mechanisms of action, including antioxidant, anti-inflammatory, cardiovascular protection, neuroprotection, and hepatoprotection. Salvia miltiorrhiza is used clinically by gynecologists in China. AIM OF THE STUDY Polycystic ovary syndrome (PCOS) has a significant impact on women's quality of life, leading to infertility and reproductive disorders. Hence, this study aims to assess the pharmacological activity of cryptotanshinone in the treatment of PCOS and investigate its therapeutic mechanism. MATERIALS AND METHODS Human chorionic gonadotropin (HCG) combined with insulin is used to simulate a PCOS-like rat model and attempt to discover the abnormal changes that occur and the means by which the pathway acts in this model. RESULTS The transcriptome sequencing method is used to identify 292 differential genes that undergo significant changes, of which 219 were upregulated and 73 were downregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the signaling pathways reveals that differential expressed genes are significantly enriched in 23 typical pathways. Estrogen signaling pathways are screened in the cryptotanshinone and model groups, and significant differential changes in Fos, ALOX12, and AQP8 are found. This suggests that these signaling pathways and molecules may be the main signaling targets for regulating the differences in endometrial tissue. CONCLUSION These results indicate that cryptotanshinone has targets for regulating the proliferation of endometrial tissue via estrogen signaling pathways in PCOS-like rats, providing an experimental basis for the clinical application of cryptotanshinone in the treatment of PCOS.
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Affiliation(s)
- Yi-Chao Liu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China; Harbin Institute of Technology Hospital, Harbin Institute of Technology, Harbin, 150001, China.
| | - Jun-Wen Wang
- School of Medicine and Health, Harbin Institute of Technology, Harbin, 150001, China.
| | - Jia Li
- The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, No.26, Heping Road, Xiangfang District, Harbin, 150040, Heilongjiang Province, China.
| | - Ying Guo
- The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, No.26, Heping Road, Xiangfang District, Harbin, 150040, Heilongjiang Province, China.
| | - Feng-Juan Han
- The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, No.26, Heping Road, Xiangfang District, Harbin, 150040, Heilongjiang Province, China.
| | - Wei-Hong Lu
- School of Medicine and Health, Harbin Institute of Technology, Harbin, 150001, China.
| | - Qiong Wu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China; State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, 150001, China.
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Thakur K, Janjua D, Aggarwal N, Chhokar A, Yadav J, Tripathi T, Chaudhary A, Senrung A, Shrivastav A, Bharti AC. Physical interaction between STAT3 and AP1 in cervical carcinogenesis: Implications in HPV transcription control. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166817. [PMID: 37532113 DOI: 10.1016/j.bbadis.2023.166817] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/07/2023] [Accepted: 07/19/2023] [Indexed: 08/04/2023]
Abstract
The constitutive activation and aberrant expression of Signal Transducer and Activator of Transcription 3 (STAT3) plays a key role in initiation and progression of cervical cancer (CaCx). How STAT3 influences HPV transcription is poorly defined. In the present study, we probed direct and indirect interactions of STAT3 with HPV16/18 LCR. In silico assessment of cis-elements present on LCR revealed the presence of potential STAT3 binding motifs. However, experimental validation by ChIP-PCR could not confirm any specific STAT3 binding on HPV16 LCR. Protein-protein interaction (PPI) network analysis of STAT3 with other host transcription factors that bind LCR, highlighted the physical association of STAT3 with c-FOS and c-JUN. This was further confirmed in vitro by co-immunoprecipitation, where STAT3 co-immunoprecipitated with c-FOS and c-JUN in CaCx cells. The result was supported by immunocytochemical analysis and colocalization of STAT3 with c-FOS and c-JUN. Positive signals in proximity ligation assay validated physical interaction and colocalization of STAT3 with AP1. Colocalization of STAT3 with c-FOS and c-JUN increased upon IL-6 treatment and decreased post-Stattic treatment. Alteration of STAT3 expression affected the subcellular localization of c-FOS and c-JUN, along with the expression of viral oncoproteins (E6 and E7) in CaCx cells. High expression of c-JUN in tumor tissues correlated with poor prognosis in both HPV16 and HPV18 CaCx cohort whereas high expression of STAT3 correlated with poor prognosis in HPV18 CaCx lesions only. Overall, the data suggest an indirect interaction of STAT3 with HPV LCR via c-FOS and c-JUN and potentiate transcription of viral oncoproteins.
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Affiliation(s)
- Kulbhushan Thakur
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Divya Janjua
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Nikita Aggarwal
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Arun Chhokar
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India; Department of Zoology, Deshbandhu College, University of Delhi, Delhi, India
| | - Joni Yadav
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Apoorva Chaudhary
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Anna Senrung
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India
| | - Anuraag Shrivastav
- Department of Biology, The University of Winnipeg, 515 Portage Avenue, Winnipeg, Manitoba, Canada; Paul Albrechtsen Research Institute CCMB, 675 McDermot Ave, Winnipeg, Manitoba, Canada
| | - Alok Chandra Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), New Delhi, India.
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He Y, Ling Y, Zhang Z, Mertens RT, Cao Q, Xu X, Guo K, Shi Q, Zhang X, Huo L, Wang K, Guo H, Shen W, Shen M, Feng W, Xiao P. Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression. Redox Biol 2023; 65:102822. [PMID: 37494767 PMCID: PMC10388208 DOI: 10.1016/j.redox.2023.102822] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 07/28/2023] Open
Abstract
Ferroptosis has emerged to be a promising approach in cancer therapies; however, colorectal cancer (CRC) is relatively insensitive to ferroptosis. Exactly how the gut microenvironment impacts the ferroptotic sensitivity of CRC remains unknown. Herein, by performing metabolomics, we discovered that butyrate concentrations were significantly decreased in CRC patients. Butyrate supplementation sensitized CRC mice to ferroptosis induction, showing great in vivo translatability. Particularly, butyrate treatment reduced ferroptotic resistance of cancer stem cells. Mechanistically, butyrate inhibited xCT expression and xCT-dependent glutathione synthesis. Moreover, we identified c-Fos as a novel xCT suppressor, and further elucidated that butyrate induced c-Fos expression via disrupting class I HDAC activity. In CRC patients, butyrate negatively correlated with tumor xCT expression and positively correlated with c-Fos expression. Finally, butyrate was found to boost the pro-ferroptotic function of oxaliplatin (OXA). Immunohistochemistry data showed that OXA non-responders exhibited higher xCT expression compared to OXA responders. Hence, butyrate supplementation is a promising approach to break the ferroptosis resistance in CRC.
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Affiliation(s)
- Ying He
- Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, China
| | - Yuhang Ling
- Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, China
| | - Zhiyong Zhang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | | | - Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China; Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Xutao Xu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Ke Guo
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Qian Shi
- Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, China
| | - Xilin Zhang
- Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, China
| | - Lixia Huo
- Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, China
| | - Kan Wang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Huihui Guo
- Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, China
| | - Weiyun Shen
- Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, China
| | - Manlu Shen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Wenming Feng
- Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First People's Hospital of Huzhou, Huzhou, 313000, China.
| | - Peng Xiao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China; Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China; Institute of Immunology, Zhejiang University School of Medicine, 310058, Hangzhou, China; The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, 310058, China.
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Soghli N, Yousefi H, Naderi T, Fallah A, Moshksar A, Darbeheshti F, Vittori C, Delavar MR, Zare A, Rad HS, Kazemi A, Bitaraf A, Hussen BM, Taheri M, Jamali E. NRF2 signaling pathway: A comprehensive prognostic and gene expression profile analysis in breast cancer. Pathol Res Pract 2023; 243:154341. [PMID: 36739754 DOI: 10.1016/j.prp.2023.154341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/23/2023] [Accepted: 01/23/2023] [Indexed: 01/27/2023]
Abstract
Breast cancer is the most frequently diagnosed malignant tumor in women and a major public health concern. NRF2 axis is a cellular protector signaling pathway protecting both normal and cancer cells from oxidative damage. NRF2 is a transcription factor that binds to the gene promoters containing antioxidant response element-like sequences. In this report, differential expression of NRF2 signaling pathway elements, as well as the correlation of NRF2 pathway mRNAs with various clinicopathologic characteristics, including molecular subtypes, tumor grade, tumor stage, and methylation status, has been investigated in breast cancer using METABRIC and TCGA datasets. In the current report, our findings revealed the deregulation of several NRF2 signaling elements in breast cancer patients. Moreover, there were negative correlations between the methylation of NRF2 genes and mRNA expression. The expression of NRF2 genes significantly varied between different breast cancer subtypes. In conclusion, substantial deregulation of NRF2 signaling components suggests an important role of these genes in breast cancer. Because of the clear associations between mRNA expression and methylation status, DNA methylation could be one of the mechanisms that regulate the NRF2 pathway in breast cancer. Differential expression of Hippo genes among various breast cancer molecular subtypes suggests that NRF2 signaling may function differently in different subtypes of breast cancer. Our data also highlights an interesting link between NRF2 components' transcription and tumor grade/stage in breast cancer.
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Affiliation(s)
- Negin Soghli
- Babol University of Medical Sciences, Faculty of Dentistry, Babol, Iran
| | - Hassan Yousefi
- Louisiana State University Health Science Center (LSUHSC), Biochemistry & Molecular Biology, New Orleans, LA, USA; Stanley S. Scott Cancer Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Tohid Naderi
- Department of Laboratory Hematology and Blood Bank, School of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Aysan Fallah
- Department of hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amin Moshksar
- University of Texas Medical Branch (UTMB), Interventional Radiology, Galveston, TX, USA
| | - Farzaneh Darbeheshti
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Cecilia Vittori
- Stanley S. Scott Cancer Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Mahsa Rostamian Delavar
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Ali Zare
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Habib Sadeghi Rad
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Abtin Kazemi
- Fasa University of Medical Sciences, School of Medicine, Fasa, Iran
| | - Amirreza Bitaraf
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Mohammad Taheri
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Elena Jamali
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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9
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Hong X, Zhuang K, Xu N, Wang J, Liu Y, Tang S, Zhao J, Huang Z. An integrated analysis of prognostic mRNA signature in early- and progressive-stage gastric adenocarcinoma. Front Mol Biosci 2023; 9:1022056. [PMID: 36660425 PMCID: PMC9846543 DOI: 10.3389/fmolb.2022.1022056] [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: 08/18/2022] [Accepted: 11/28/2022] [Indexed: 01/06/2023] Open
Abstract
The pathogenesis and vital factors of early and progressive stages of stomach adenocarcinoma (STAD) have not been fully elucidated. In order to discover novel and potential targets to guide effective treatment strategies, a comprehensive bioinformatics study was performed, and the representative results were then validated by quantitative polymerase chain reaction (qPCR) and immunohistochemical (IMC) staining in clinical samples. A total of 4,627, 4,715, and 3,465 differentially expressed genes (DEGs) from overall-, early-, and progressive-stage STAD were identified, respectively. Prognostic models of 5-year OS were established for overall-, early-, and progressive-stage STAD, and ROC curves demonstrated AUC values for each model were 0.73, 0.87, and 0.92, respectively. Function analysis revealed that mRNAs of early-stage STAD were enriched in chemical stimulus-related pathways, whereas remarkable enrichment of mRNAs in progressive-stage STAD mainly lay in immune-related pathways. Both qPCR and IHC data confirmed the up-regulation of IGFBP1 in the early-stage and CHAF1A in progressive-stage STAD compared with their matched normal tissues, indicating that these two representative targets could be used to predict the prognostic status of the patients in these two distinct STAD stages, respectively. In addition, seven mRNAs (F2, GRID2, TF, APOB, KIF18B, INCENP, and GCG) could be potential novel biomarkers for STAD at different stages from this study. These results contributed to identifying STAD patients at high-risk, thus guiding targeted treatment with efficacy in these patients.
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Affiliation(s)
- Xiaoling Hong
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China,The Second School of Clinical Medicine, Guangdong Medical University, Zhanjiang, China
| | - Kai Zhuang
- Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China,School of Public Health, Guangdong Medical University, Dongguan, China
| | - Na Xu
- Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China
| | - Jiang Wang
- School of Biomedical Engineering, Guangdong Medical University, Zhanjiang, China
| | - Yong Liu
- Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China
| | - Siqi Tang
- Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China,The Second School of Clinical Medicine, Guangdong Medical University, Zhanjiang, China
| | - Junzhang Zhao
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, National Key Clinical Discipline, Guangzhou, China,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, China,*Correspondence: Junzhang Zhao, ; Zunnan Huang,
| | - Zunnan Huang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China,Marine Medical Research Institute of Guangdong Zhanjiang, Zhanjiang, China,*Correspondence: Junzhang Zhao, ; Zunnan Huang,
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10
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Identification of Kynurenic Acid-Induced Apoptotic Biomarkers in Gastric Cancer-Derived AGS Cells through Next-Generation Transcriptome Sequencing Analysis. Nutrients 2022; 15:nu15010193. [PMID: 36615849 PMCID: PMC9823332 DOI: 10.3390/nu15010193] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/23/2022] [Accepted: 12/26/2022] [Indexed: 01/04/2023] Open
Abstract
Understanding the triggers and therapeutic targets for gastric cancer, one of the most common cancers worldwide, can provide helpful information for the development of therapeutics. RNA sequencing technology can be utilized to identify complex disease targets and therapeutic applications. In the present study, we aimed to establish the pharmacological target of Kynurenic acid (KYNA) for gastric cancer AGS cells and to identify the biological network. RNA sequencing identified differentially expressed genes (DEGs) between KYNA-treated and untreated cells. A total of 278 genes were differentially expressed, of which 120 genes were up-regulated, and 158 genes were down-regulated. Gene ontology results confirmed that KYNA had effects such as a reduction in genes related to DNA replication and nucleosome organization on AGS cells. Protein-protein interaction was confirmed through STRING analysis, and it was confirmed that cancer cell growth and proliferation were inhibited through KEGG, Reactome, and Wiki pathway analysis, and various signaling pathways related to cancer cell death were induced. It was confirmed that KYNA treatment reduced the gene expression of cancer-causing AP-1 factors (Fos, Jun, ATF, and JDP) in AGS cell lines derived from gastric cancer. Overall, using next-generation transcriptome sequencing data and bioinformatics tools, we confirmed that KYNA had an apoptosis effect by inducing changes in various genes, including factor AP-1, in gastric cancer AGS cells. This study can identify pharmacological targets for gastric cancer treatment and provide a valuable resource for drug development.
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11
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Brennan A, Leech JT, Kad NM, Mason JM. Selective antagonism of cJun for cancer therapy. J Exp Clin Cancer Res 2020; 39:184. [PMID: 32917236 PMCID: PMC7488417 DOI: 10.1186/s13046-020-01686-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 08/20/2020] [Indexed: 01/10/2023] Open
Abstract
The activator protein-1 (AP-1) family of transcription factors modulate a diverse range of cellular signalling pathways into outputs which can be oncogenic or anti-oncogenic. The transcription of relevant genes is controlled by the cellular context, and in particular by the dimeric composition of AP-1. Here, we describe the evidence linking cJun in particular to a range of cancers. This includes correlative studies of protein levels in patient tumour samples and mechanistic understanding of the role of cJun in cancer cell models. This develops an understanding of cJun as a focal point of cancer-altered signalling which has the potential for therapeutic antagonism. Significant work has produced a range of small molecules and peptides which have been summarised here and categorised according to the binding surface they target within the cJun-DNA complex. We highlight the importance of selectively targeting a single AP-1 family member to antagonise known oncogenic function and avoid antagonism of anti-oncogenic function.
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Affiliation(s)
- Andrew Brennan
- Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
| | - James T Leech
- School of Biosciences, University of Kent, Canterbury, CT2 7NH, UK
| | - Neil M Kad
- School of Biosciences, University of Kent, Canterbury, CT2 7NH, UK
| | - Jody M Mason
- Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
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12
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Ebrahimi Ghahnavieh L, Tabatabaeian H, Ebrahimi Ghahnavieh Z, Honardoost MA, Azadeh M, Moazeni Bistgani M, Ghaedi K. Fluctuating expression of miR-584 in primary and high-grade gastric cancer. BMC Cancer 2020; 20:621. [PMID: 32615958 PMCID: PMC7345521 DOI: 10.1186/s12885-020-07116-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 06/25/2020] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer is the fifth most common cancer worldwide. Along with environmental factors, such as Helicobacter pylori (H. pylori) infection, genetic changes play important roles in gastric tumor formations. miR-584 is a less well-characterized microRNA (miRNA), with apparent activity in human cancers. However, miR-584 expression pattern in gastric cancer development has remained unclear. This study aims to analyze the expression of miR-584 in gastric cancer samples and investigates the associations between this miRNA and H. pylori infection and clinical characteristics. Methods The expression level of miR-584 was studied in primary gastric cancers versus healthy control gastric mucosa samples using the RT-qPCR method. The clinical data were analyzed statistically in terms of miR-584 expression. In silico studies were employed to study miR-584 more broadly in order to assess its expression and find new potential target genes. Results Both experimental and in silico studies showed up-regulation of miR-584 in patients with gastric cancer. This up-regulation seems to be induced by H. pylori infection since the infected samples showed increased levels of miR-584 expression. Deeper analyses revealed that miR-584 undergoes a dramatic down-regulation in late stages, invasive and lymph node-metastatic gastric tumors. Bioinformatics studies demonstrated that miR-584 has a substantial role in cancer pathways and has the potential to target STAT1 transcripts. Consistent with the inverse correlation between TCGA RNA-seq data of miR-584 and STAT1 transcripts, the qPCR analysis showed a significant negative correlation between these two RNAs in a set of clinical samples. Conclusion miR-584 undergoes up-regulation in the stage of primary tumor formation; however, becomes down-regulated upon the progression of gastric cancer. These findings suggest the potential of miR-584 as a diagnostic or prognostic biomarker in gastric cancer.
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Affiliation(s)
| | - Hossein Tabatabaeian
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran. .,Anahid Cancer Clinic, Isfahan Healthcare City, Isfahan, Iran.
| | - Zhaleh Ebrahimi Ghahnavieh
- Department of Medical Education, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad Amin Honardoost
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | | | - Mohamad Moazeni Bistgani
- Department of Surgery, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran. .,Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
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13
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Chen H, Ji L, Liu X, Zhong J. Correlation between the rs7101 and rs1063169 polymorphisms in the FOS noncoding region and susceptibility to and prognosis of colorectal cancer. Medicine (Baltimore) 2019; 98:e16131. [PMID: 31261535 PMCID: PMC6617440 DOI: 10.1097/md.0000000000016131] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 05/24/2019] [Accepted: 05/29/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The FOS gene is located on human chromosome 14q21-31 and encodes the nuclear oncoprotein c-Fos. This study analyzed the correlation between the FOS noncoding region rs7101 and rs1063169 polymorphisms and colorectal cancer susceptibility and prognosis. METHODS We analyzed the FOS genotypes in 432 colorectal cancer patients and 315 healthy subjects by PCR/Sanger sequencing. Survival was analyzed by Kaplan-Meier and Cox regression analysis. Western blot was used to detect the expression of c-Fos protein in cancer tissues and adjacent tissues in colorectal cancer patients with different genotypes. RESULTS The presence of a T allele at rs7101 and a T allele at rs1063169 in FOS carried a higher risk of colorectal cancer [adjusted odds ratio (OR) = 1.237, 95% confidence interval (95% CI) = 1.131-1.346, P ≤ .001 and adjusted OR = 1.218, 95% CI = 1.111-1.327, P ≤ .001, respectively]. c-Fos protein levels were significantly higher in variant cancer tissues than in normal mucosa tissues (P < .05), and c-Fos proteins levels were also higher in homozygous variant cancer tissues than in heterozygous variant cancer tissues. The 3-year survival rate of patients with wild-type FOS was higher than that of patients with variant FOS (P < .05). CONCLUSION The rs7101 and rs1063169 polymorphisms in the noncoding region of FOS are associated with the risk of developing colorectal cancer and the progression of colorectal cancer, which may be because the mutation enhances the expression of c-Fos protein to promote the incidence and development of colorectal cancer.
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Affiliation(s)
- Hongshu Chen
- Yidu Central Hospital of Weifang, Qingzhou, Shandong Province
| | - Lijuan Ji
- Yidu Central Hospital of Weifang, Qingzhou, Shandong Province
| | - Xiuzhen Liu
- Yidu Central Hospital of Weifang, Qingzhou, Shandong Province
| | - Jihong Zhong
- Department of Digestion, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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14
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Ghadami E, Nikbakhsh N, Fattahi S, Kosari‐Monfared M, Ranaee M, Taheri H, Amjadi‐Moheb F, Godazandeh G, Shafaei S, Nosrati A, Pilehchian Langroudi M, Samadani AA, Amirbozorgi G, Mirnia V, Akhavan‐Niaki H. Epigenetic alterations of CYLD promoter modulate its expression in gastric adenocarcinoma: A footprint of infections. J Cell Physiol 2019; 234:4115-4124. [DOI: 10.1002/jcp.27220] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Accepted: 07/16/2018] [Indexed: 12/14/2022]
Abstract
AbstractGastric cancer (GC) is one of the most common causes of cancer‐related death in the world, with multiple genetic and epigenetic alterations involved in disease development. CYLD tumor suppressor gene encodes a multifunctional deubiquitinase which negatively regulates various signaling pathways. Deregulation of this gene has been found in different types of cancer. This study aimed to evaluate for the first time the CpG island methylation pattern of CYLD gene promoter, and its expression level in gastric adenocarcinoma. CYLD messenger RNA expression and promoter methylation in 53 tumoral and their non‐neoplastic counterpart tissues were assessed using quantitative polymerase chain reaction and bisulfite sequencing. Also, we investigated the impacts of the infectious agents including Helicobacter pylori (H. pylori), EBV, and CMV on CYLD expression and promoter methylation in GC. Results showed that the expression level of CYLD was downregulated in GC, and was significantly associated with gender (female), patient’s age (<60), high grade, and no lymph‐node metastasis (p = 0.001, 0.002, 0.03, and 0.003, respectively). Among the 31 analyzed CpG sites located in about 600 bp region within the promoter, two CpG sites were hypermethylated in GC tissues. We also found a significant inverse association between DNA promoter methylation and CYLD expression (p = 0.02). Furthermore, a direct association between H. pylori, EBV, and CMV infections with hypermethylation and reduced CYLD expression was observed (p = 0.04, 0.03, and 0.03, respectively). Our findings indicate that CYLD is downregulated in GC. Infectious agents may influence CYLD expression.
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Affiliation(s)
- Elham Ghadami
- Department of Genetics, Faculty of Medicine Babol University of Medical Sciences Babol Iran
- Department of Genetics Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences Babol Iran
| | - Novin Nikbakhsh
- Department of Surgery Rouhani Hospital, Babol University of Medical Sciences Babol Iran
| | - Sadegh Fattahi
- Department of Genetics Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences Babol Iran
- Department of Molecular Biology North Research Center of Pasteur Institute Amol Iran
| | | | - Mohammad Ranaee
- Department of Pathology Rouhani Hospital, Babol University of Medical Sciences Babol Iran
| | - Hassan Taheri
- Department of Internal Medicine Rouhani Hospital, Babol University of Medical Sciences Babol Iran
| | - Fatemeh Amjadi‐Moheb
- Department of Genetics, Faculty of Medicine Babol University of Medical Sciences Babol Iran
| | - Gholamali Godazandeh
- Department of Thoracic Surgery Imam Khomeini Hospital, Mazandaran University of Medical Sciences Sari Iran
| | - Shahryar Shafaei
- Department of Pathology Rouhani Hospital, Babol University of Medical Sciences Babol Iran
| | - Anahita Nosrati
- Department of Pathology Imam Khomeini Hospital, Mazandaran University of Medical Sciences Sari Iran
| | | | - Ali Akbar Samadani
- Department of Genetics Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences Babol Iran
- Department of Genetics Gastrointestinal and Liver Diseases Research Center (GLDRC), Guilan University of Medical Sciences Rasht Iran
| | - Galia Amirbozorgi
- Department of Molecular Biology North Research Center of Pasteur Institute Amol Iran
| | - Vahideh Mirnia
- Faculty of Paramedicine Babol University of Medical Sciences Babol Iran
| | - Haleh Akhavan‐Niaki
- Department of Genetics, Faculty of Medicine Babol University of Medical Sciences Babol Iran
- Department of Genetics Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences Babol Iran
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15
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Zeng Y, Shen Z, Gu W, Wu M. Bioinformatics analysis to identify action targets in NCI-N87 gastric cancer cells exposed to quercetin. PHARMACEUTICAL BIOLOGY 2018; 56:393-398. [PMID: 30266078 PMCID: PMC6171422 DOI: 10.1080/13880209.2018.1493610] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 02/23/2018] [Accepted: 06/23/2018] [Indexed: 05/08/2023]
Abstract
CONTEXT Quercetin exerts antiproliferative effects on gastric cancer. However, its mechanisms of action on gastric cancer have not been comprehensively revealed. OBJECTIVE We investigated the mechanisms of action of quercetin against gastric cancer cells. MATERIALS AND METHODS Human NCI-N87 gastric cancer cells were treated with 15 μM quercetin or dimethyl sulfoxide (as a control) for 48 h. DNA isolated from cells was sequenced on a HiSeq 2500, and the data were used to identify differentially expressed genes (DEGs) between groups. Then, enrichment analyses were performed for DEGs and a protein-protein interaction (PPI) network was constructed. Finally, the transcription factors (TFs)-DEGs regulatory network was visualized by Cytoscape software. RESULTS A total of 121 DEGs were identified in the quercetin group. In the PPI network, Fos proto-oncogene (FOS, degree = 12), aryl hydrocarbon receptor (AHR, degree = 12), Jun proto-oncogene (JUN, degree = 11), and cytochrome P450 family 1 subfamily A member 1 (CYP1A1, degree = 11) with higher degrees highly interconnected with other proteins. Of the 5 TF-DEGs, early growth response 1 (EGR1), FOS like 1 (FOSL1), FOS, and JUN were upregulated, while AHR was downregulated. Moreover, FOSL1, JUN, and Wnt family member 7B (WNT7B) were enriched in the Wnt signaling pathway. DISCUSSION AND CONCLUSIONS CYP1A1 highly interconnected with AHR in the PPI network. Therefore, FOS, AHR, JUN, CYP1A1, EGR1, FOSL1, and WNT7B might be targets of quercetin in gastric cancer.
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Affiliation(s)
- Yun Zeng
- Department of Medical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Zhengjie Shen
- Department of Medical Oncology, Zhangjiagang First People’s Hospital, Zhangjiagang, Jiangsu, China
| | - Wenzhe Gu
- Department of Otorhinolaryngology, Zhangjiagang Hospital of Traditional Chinese Medicine, Zhangjiagang, Jiangsu, China
| | - Mianhua Wu
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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16
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Wang J, Chen Y, Chen Z, Xiang Z, Ding J, Han X. Microcystin-leucine arginine inhibits gonadotropin-releasing hormone synthesis in mice hypothalamus. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2018; 163:391-399. [PMID: 30064084 DOI: 10.1016/j.ecoenv.2018.07.094] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 07/20/2018] [Accepted: 07/24/2018] [Indexed: 06/08/2023]
Abstract
Microcystin-leucine arginine (MC-LR) causes serum testosterone declines and male reproductive disorders. However, the molecular mechanisms underlying the pathological changes are still unclear. In the present study, we aimed to investigate the toxic effects of MC-LR on gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus. Our results demonstrated that MC-LR could enter GnRH neurons and inhibit GnRH synthesis, resulting in the decrease of serum GnRH and testosterone levels. The inhibitory effects of MC-LR on GnRH synthesis were identified to be associated with activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB)/c-Fos signaling pathway. With miRNA microarray analyses, we found that miR-329-3p was down-regulated most dramatically in MC-LR-treated GT1-7 cells. We then further identified that miR-329-3p regulated PRKAR1A and PRKACB expression and thus influenced GnRH synthesis. This is the first study to explore the molecular mechanism underlying the inhibitory effects of MC-LR on GnRH synthesis in the hypothalamus. Our data have provided a new perspective in the development of diagnosis and treatment strategies for male infertility as a result of dysfunction of the hypothalamic-pituitary-gonadal axis.
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Affiliation(s)
- Jing Wang
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China
| | - Yabing Chen
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China
| | - Zhangpeng Chen
- State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Zou Xiang
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Jie Ding
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.
| | - Xiaodong Han
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.
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Liu S, Yao X, Zhang D, Sheng J, Wen X, Wang Q, Chen G, Li Z, Du Z, Zhang X. Analysis of Transcription Factor-Related Regulatory Networks Based on Bioinformatics Analysis and Validation in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1431396. [PMID: 30228980 PMCID: PMC6136478 DOI: 10.1155/2018/1431396] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 07/03/2018] [Accepted: 07/25/2018] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) accounts for a significant proportion of liver cancer, which has become the second most common cause of cancer-related mortality worldwide. To investigate the potential mechanisms of invasion and progression of HCC, bioinformatics analysis and validation by qRT-PCR were performed. We found 237 differentially expressed genes (DEGs) including EGR1, FOS, and FOSB, which were three cancer-related transcription factors. Subsequently, we constructed TF-gene network and miRNA-TF-mRNA network based on data obtained from mRNA and miRNA expression profiles for analysis of HCC. We found that 42 key genes from the TF-gene network including EGR1, FOS, and FOSB were most enriched in the p53 signaling pathway. The qRT-PCR data confirmed that mRNA levels of EGR1, FOS, and FOSB all were decreased in HCC tissues. In addition, we confirmed that the mRNA levels of CCNB1, CCNB2, and CHEK1, three key markers of the p53 signaling pathway, were all increased in HCC tissues by bioinformatics analysis and qRT-PCR validation. Therefore, we speculated that miR-181a-5p, which was upregulated in HCC tissues, could regulate FOS and EGR1 to promote the invasion and progression of HCC by p53 signaling pathway. Overall, the study provides support for the possible mechanisms of progression in HCC.
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Affiliation(s)
- Shui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, China
- Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, The Second Hospital of Jilin University, Changchun 130041, China
| | - Xiaoxiao Yao
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, China
- Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, The Second Hospital of Jilin University, Changchun 130041, China
| | - Dan Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, China
- Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, The Second Hospital of Jilin University, Changchun 130041, China
| | - Jiyao Sheng
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, China
- Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, The Second Hospital of Jilin University, Changchun 130041, China
| | - Xin Wen
- The Second Hospital of Jilin University, Changchun 130041, China
| | - Qingyu Wang
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun 130041, China
| | - Gaoyang Chen
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun 130041, China
| | - Zhaoyan Li
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun 130041, China
| | - Zhenwu Du
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun 130041, China
- Research Center of Second Clinical College, Jilin University, Changchun 130041, China
| | - Xuewen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, China
- Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, The Second Hospital of Jilin University, Changchun 130041, China
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18
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Liu ZG, Jiang G, Tang J, Wang H, Feng G, Chen F, Tu Z, Liu G, Zhao Y, Peng MJ, He ZW, Chen XY, Lindsay H, Xia YF, Li XN. c-Fos over-expression promotes radioresistance and predicts poor prognosis in malignant glioma. Oncotarget 2018; 7:65946-65956. [PMID: 27602752 PMCID: PMC5323205 DOI: 10.18632/oncotarget.11779] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 08/22/2016] [Indexed: 12/11/2022] Open
Abstract
c-Fos is a major component of activator protein (AP)-1 complex. It has been implicated in cell differentiation, proliferation, angiogenesis, invasion, and metastasis. To investigate the role of c-Fos in glioma radiosensitivity and to understand the underlying molecular mechanisms, we downregulated c-Fos gene expression by lentivirus-mediated shRNA in glioma cell lines and subsequently analyzed the radiosensitivity, DNA damage repair capacity, and cell cycle distribution. Finally, we explored its prognostic value in 41 malignant glioma patients by immunohistochemistry. Our results showed that silencing c-Fos sensitized glioma cells to radiation by increasing radiation-induced DNA double strand breaks (DSBs), disturbing the DNA damage repair process, promoting G2/M cell cycle arrest, and enhancing apoptosis. c-Fos protein overexpression correlated with poor prognosis in malignant glioma patients treated with standard therapy. Our findings provide new insights into the mechanism of radioresistance in malignant glioma and identify c-Fos as a potentially novel therapeutic target for malignant glioma patients.
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Affiliation(s)
- Zhi-Gang Liu
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| | - Guanmin Jiang
- Department of Clinical Laboratory, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| | - Jiao Tang
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| | - Hui Wang
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| | - Guokai Feng
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Furong Chen
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Ziwei Tu
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Guiyun Liu
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| | - Yu Zhao
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| | - Ming-Jing Peng
- Translational Medicine Center, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| | - Zheng-Wen He
- Department of Neurosurgery, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| | - Xiao-Yan Chen
- Department of Pathology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| | - Holly Lindsay
- Laboratory of Molecular Neuro-Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston TX, 77030, USA
| | - Yun-Fei Xia
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| | - Xiao-Nan Li
- Laboratory of Molecular Neuro-Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston TX, 77030, USA
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Trop-Steinberg S, Azar Y. AP-1 Expression and its Clinical Relevance in Immune Disorders and Cancer. Am J Med Sci 2017; 353:474-483. [PMID: 28502334 DOI: 10.1016/j.amjms.2017.01.019] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 01/26/2017] [Accepted: 01/30/2017] [Indexed: 02/07/2023]
Abstract
The inflammatory response is known to have a significant role in certain autoimmune diseases and malignancies. We review current knowledge regarding the functions of activator protein 1 (AP-1) as an important modulator in several immune disorders and carcinomas. AP-1 is overexpressed in rheumatoid arthritis and in long-term allogeneic hematopoietic stem cell transplantation survivors; however, decreased expression of AP-1 has been observed in psoriasis, systematic lupus erythematosus and in patients who do not survive after hematopoietic stem cell transplantation. AP-1 also is implicated in the control of various cancer cells. Higher levels of AP-1 components are present in breast and endometrial carcinomas, colorectal cancer and in acute myeloid leukemia, Hodgkin׳s lymphoma and anaplastic large cell lymphoma, with downregulation in ovarian and gastric carcinomas and in patients with chronic myelogenous leukemia. AP-1 may enable the development of helpful markers to identify early-stage disease or to predict severity.
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Affiliation(s)
| | - Yehudit Azar
- Bone Marrow Transplantation Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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20
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Pasovic L, Eidet JR, Olstad OK, Chen DF, Lyberg T, Utheim TP. Impact of Storage Temperature on the Expression of Cell Survival Genes in Cultured ARPE-19 Cells. Curr Eye Res 2016; 42:134-144. [PMID: 27259952 DOI: 10.3109/02713683.2016.1145236] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE The development of a suitable storage method for retinal pigment epithelium (RPE) is necessary in the establishment of future RPE replacement therapy, and storage temperature has proven to be pivotal for cell survival. ARPE-19, a widely used model for RPE, has been shown to yield the greatest number of viable cells when stored at 16°C compared to other storage temperatures. In this study, we analyze the gene expression profile of cultured ARPE-19 cells after seven days of storage at different temperatures in an effort to predict the gene-level consequences of storage of RPE transplants. MATERIALS AND METHODS ARPE-19 cells were cultured until confluence and then stored in minimum essential medium at 4°C, 16°C, and 37°C for seven days. The total RNA was isolated and the gene expression profile was determined using DNA microarrays. The Results were validated using qPCR. RESULTS Principal component and hierarchical clustering analyses show that the gene expression profiles of cell cultures stored at different temperatures cluster into separate groups. Cultures stored at 4°C cluster closest to the control cultures that were not stored and display the least change in gene expression after storage (157 differentially expressed genes). Cultures stored at 16°C and 37°C display a much larger change in differential gene expression (1787 and 1357 differentially expressed genes, respectively). At 16°C, the expression of several genes with proposed tumor suppressor functions was markedly increased. Changes in regulation of several known signaling pathways and of oxidative stress markers were discovered at both 16°C and 37°C, and activation of the angiogenesis marker vascular endothelial growth factor (VEGF) was discovered at 37°C. There was no evidence of the activation of inflammatory processes in stored cell cultures. CONCLUSION ARPE-19 cultures stored at 16°C show the greatest propensity to modulate their gene expression profile in a manner that supports cell survival during storage.
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Affiliation(s)
- Lara Pasovic
- a Department of Medical Biochemistry , Oslo University Hospital , Oslo , Norway.,b Faculty of Medicine, University of Oslo , Oslo , Norway
| | - Jon R Eidet
- c Department of Ophthalmology , Oslo University Hospital , Oslo , Norway
| | - Ole K Olstad
- a Department of Medical Biochemistry , Oslo University Hospital , Oslo , Norway
| | - Dong F Chen
- d Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology , Harvard Medical School , Boston , USA
| | - Torstein Lyberg
- a Department of Medical Biochemistry , Oslo University Hospital , Oslo , Norway
| | - Tor P Utheim
- a Department of Medical Biochemistry , Oslo University Hospital , Oslo , Norway.,e Department of Oral Biology, Faculty of Dentistry , University of Oslo , Oslo , Norway
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21
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Tumor Restrictive Suicide Gene Therapy for Glioma Controlled by the FOS Promoter. PLoS One 2015; 10:e0143112. [PMID: 26571389 PMCID: PMC4646428 DOI: 10.1371/journal.pone.0143112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 11/01/2015] [Indexed: 01/11/2023] Open
Abstract
Effective suicide gene delivery and expression are crucial to achieving successful effects in gene therapy. An ideal tumor-specific promoter expresses therapeutic genes in tumor cells with minimal normal tissue expression. We compared the activity of the FOS (FBJ murine osteosarcoma viral oncogene homolog) promoter with five alternative tumor-specific promoters in glioma cells and non-malignant astrocytes. The FOS promoter caused significantly higher transcriptional activity in glioma cell lines than all alternative promoters with the exception of CMV. The FOS promoter showed 13.9%, 32.4%, and 70.8% of the transcriptional activity of CMV in three glioma cell lines (U87, U251, and U373). Importantly, however, the FOS promoter showed only 1.6% of the transcriptional activity of CMV in normal astrocytes. We also tested the biologic activity of recombinant adenovirus containing the suicide gene herpes simplex virus thymidine kinase (HSV-tk) driven by the FOS promoter, including selective killing efficacy in vitro and tumor inhibition rate in vivo. Adenoviral-mediated delivery of the HSV-tk gene controlled by the FOS promoter conferred a cytotoxic effect on human glioma cells in vitro and in vivo. This study suggests that use of the FOS-tk adenovirus system is a promising strategy for glioma-specific gene therapy but still much left for improvement.
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22
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Expression of c-fos was associated with clinicopathologic characteristics and prognosis in pancreatic cancer. PLoS One 2015; 10:e0120332. [PMID: 25789763 PMCID: PMC4366380 DOI: 10.1371/journal.pone.0120332] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 01/30/2015] [Indexed: 01/28/2023] Open
Abstract
It has long been regarded that pancreatic cancer (PC) is a life-threatening malignant tumor. Thus, much attention has been paid for factors, especially relative molecules, predictive for prognosis of PC. However, c-fos expression in PC was less investigated. In addition, its association with clinicopathologic variables and prognosis remains unknown. In the present study, expression of c-fos was detected by tissue microarray-based immunohistochemical staining in cancer and adjacent tissues from 333 patients with PC. The staining results were correlated with clinicopathologic parameters and overall survival. Furthermore, prognostic significance of c-fos in subsets of PC was also evaluated. It was shown that low expression of c-fos was more often in cancer than in adjacent tissues of PC (P<0.001). Besides, high cancerous c-fos expression was significantly associated with tumor site and T stage, whereas peri-neural invasion was of a borderline significant relevance. Log-rank test revealed that high expression of c-fos in cancer tissues was a significant marker of poor overall survival, accompanied by some conventional clinicopathologic variables, such as sex, grade, peri-neural invasion, T and N stages. More importantly, cancerous c-fos expression was identified as an independent prognosticator in multivariate analysis. Finally, the prognostic implication of c-fos expression was proven in four subsets of patients with PC. These data suggested that c-fos expression was of relationships with progression and dismal prognosis of PC.
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23
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Regression analysis of combined gene expression regulation in acute myeloid leukemia. PLoS Comput Biol 2014; 10:e1003908. [PMID: 25340776 PMCID: PMC4207489 DOI: 10.1371/journal.pcbi.1003908] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 09/13/2014] [Indexed: 12/04/2022] Open
Abstract
Gene expression is a combinatorial function of genetic/epigenetic factors such as copy number variation (CNV), DNA methylation (DM), transcription factors (TF) occupancy, and microRNA (miRNA) post-transcriptional regulation. At the maturity of microarray/sequencing technologies, large amounts of data measuring the genome-wide signals of those factors became available from Encyclopedia of DNA Elements (ENCODE) and The Cancer Genome Atlas (TCGA). However, there is a lack of an integrative model to take full advantage of these rich yet heterogeneous data. To this end, we developed RACER (Regression Analysis of Combined Expression Regulation), which fits the mRNA expression as response using as explanatory variables, the TF data from ENCODE, and CNV, DM, miRNA expression signals from TCGA. Briefly, RACER first infers the sample-specific regulatory activities by TFs and miRNAs, which are then used as inputs to infer specific TF/miRNA-gene interactions. Such a two-stage regression framework circumvents a common difficulty in integrating ENCODE data measured in generic cell-line with the sample-specific TCGA measurements. As a case study, we integrated Acute Myeloid Leukemia (AML) data from TCGA and the related TF binding data measured in K562 from ENCODE. As a proof-of-concept, we first verified our model formalism by 10-fold cross-validation on predicting gene expression. We next evaluated RACER on recovering known regulatory interactions, and demonstrated its superior statistical power over existing methods in detecting known miRNA/TF targets. Additionally, we developed a feature selection procedure, which identified 18 regulators, whose activities clustered consistently with cytogenetic risk groups. One of the selected regulators is miR-548p, whose inferred targets were significantly enriched for leukemia-related pathway, implicating its novel role in AML pathogenesis. Moreover, survival analysis using the inferred activities identified C-Fos as a potential AML prognostic marker. Together, we provided a novel framework that successfully integrated the TCGA and ENCODE data in revealing AML-specific regulatory program at global level. Recent studies from The Cancer Genome Atlas (TCGA) showed that most Acute Myeloid Leukemia (AML) patients lack DNA mutations, which can potentially explain the tumorigenesis, and motivated a systematic approach to elucidate aberrant molecular signatures at the transcriptional and epigenetic levels. Using recently available data from two large consortia namely Encyclopedia of DNA Elements and TCGA, we developed a novel computational model to infer the regulatory activities of the expression regulators and their target genes in AML samples. Our analysis revealed 18 regulators whose dysregulation contributed significantly to explaining the global mRNA expression changes. Encouragingly, the inferred activities of these regulatory features followed a consistent pattern with cytogenetic phenotypes of the AML patients. Among these regulators, we identified microRNA hsa-miR-548p, whose regulatory relationships with leukemia-related genes including YY1 suggest its novel role in AML pathogenesis. Additionally, we discovered that the inferred activities of transcription factor C-Fos can be used as a prognostic marker to characterize survival rate of the AML patients. Together, we demonstrated an effective model that can integrate useful information from a large amount of heterogeneous data to dissect regulatory effects. Furthermore, the novel biological findings from this study may be constructive to future experimental research in AML.
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24
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Sioletic S, Czaplinski J, Hu L, Fletcher JA, Fletcher CDM, Wagner AJ, Loda M, Demetri GD, Sicinska ET, Snyder EL. c-Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas. J Pathol 2014; 234:190-202. [PMID: 24852265 DOI: 10.1002/path.4379] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 05/12/2014] [Accepted: 05/18/2014] [Indexed: 12/26/2022]
Abstract
Genomic amplification of the c-Jun proto-oncogene has been identified in ∼30% of dedifferentiated liposarcomas (DDLPS), but the functional contribution of c-Jun to the progression of DDLPS remains poorly understood. In previous work we showed that knock-down of c-Jun by RNA interference impaired the in vitro proliferation and in vivo growth of a DDLPS cell line (LP6) with genomic amplification of the c-Jun locus. Here, we used gene expression analysis and functional studies in a broad panel of cell lines to further define the role of c-Jun in DDLPS and other soft tissue sarcomas. We show that c-Jun knock-down impairs transition through the G1 phase of the cell cycle in multiple DDLPS cell lines. We also found that high levels of c-Jun expression are both necessary and sufficient to promote DDLPS cell migration and invasion in vitro. Our data suggest that high levels of c-Jun enhance motility in part by driving the expression of ENPP2/Autotaxin. c-Jun over-expression has minimal effects on in vitro proliferation but substantially enhances the in vivo growth of weakly tumourigenic DDLPS cell lines. Finally, we provide evidence that c-Jun genomic amplification and over-expression may have similar functional consequences in other types of soft tissue sarcoma. Our data suggest a model in which relatively low levels of c-Jun are sufficient for in vitro proliferation, but high levels of c-Jun enhance invasiveness and capacity for in vivo tumour growth. These observations provide an explanation for the selective advantage provided by c-Jun genomic amplification in vivo and suggest that sarcomas with elevated c-Jun levels are likely to have a particularly high malignant potential. Data from exon array and RNA-Seq experiments have been deposited in the GEO database (Accession No. GSE57531).
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Affiliation(s)
- Stefano Sioletic
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA, USA
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25
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Identifying gastric cancer related genes using the shortest path algorithm and protein-protein interaction network. BIOMED RESEARCH INTERNATIONAL 2014; 2014:371397. [PMID: 24729971 PMCID: PMC3963223 DOI: 10.1155/2014/371397] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 02/03/2014] [Indexed: 01/07/2023]
Abstract
Gastric cancer, as one of the leading causes of cancer related deaths worldwide, causes about 800,000 deaths per year. Up to now, the mechanism underlying this disease is still not totally uncovered. Identification of related genes of this disease is an important step which can help to understand the mechanism underlying this disease, thereby designing effective treatments. In this study, some novel gastric cancer related genes were discovered based on the knowledge of known gastric cancer related ones. These genes were searched by applying the shortest path algorithm in protein-protein interaction network. The analysis results suggest that some of them are indeed involved in the biological process of gastric cancer, which indicates that they are the actual gastric cancer related genes with high probability. It is hopeful that the findings in this study may help promote the study of this disease and the methods can provide new insights to study various diseases.
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26
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Oliveira-Ferrer L, Rößler K, Haustein V, Schröder C, Wicklein D, Maltseva D, Khaustova N, Samatov T, Tonevitsky A, Mahner S, Jänicke F, Schumacher U, Milde-Langosch K. c-FOS suppresses ovarian cancer progression by changing adhesion. Br J Cancer 2013; 110:753-63. [PMID: 24322891 PMCID: PMC3915133 DOI: 10.1038/bjc.2013.774] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 11/07/2013] [Accepted: 11/13/2013] [Indexed: 01/11/2023] Open
Abstract
Background: C-Fos was initially described as oncogene, but was associated with favourable prognosis in ovarian cancer (OvCa) patients. The molecular and functional aspects underlying this effect are still unknown. Methods: Using stable transfectants of SKOV3 and OVCAR8 cells, proliferation, migration, invasion and apoptotic potential of c-FOS-overexpressing clones and controls were compared. Adherence to components of the extracellular matrix was analysed in static assays, and adhesion to E-selectin, endothelial and mesothelial cells in dynamic flow assays. The effect of c-FOS in vivo was studied after intraperitoneal injection of SKOV3 clones into SCID mice, and changes in gene expression were determined by microarray analysis. Results: Tumour growth after injection into SCID mice was strongly delayed by c-FOS overexpression, with reduction of lung metastases and circulating tumour cells. In vitro, c-FOS had only weak influence on proliferation and migration, but was strongly pro-apoptotic. Adhesion to components of the extracellular matrix (collagen I, IV) and to E-selectin, endothelial and mesothelial cells was significantly reduced in c-FOS-overexpressing OvCa cells. This corresponds to deregulation of adhesion proteins and glycosylation enzymes in microarray analysis. Conclusion: In addition to its known pro-apoptotic effect, c-FOS might influence OvCa progression by changing the adhesion of OvCa cells to peritoneal surfaces.
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Affiliation(s)
- L Oliveira-Ferrer
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany
| | - K Rößler
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany
| | - V Haustein
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany
| | - C Schröder
- Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany
| | - D Wicklein
- Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany
| | - D Maltseva
- SRC Bioclinicum, Ugreshskaya Street 2/85, Moscow 115088, Russia
| | - N Khaustova
- SRC Bioclinicum, Ugreshskaya Street 2/85, Moscow 115088, Russia
| | - T Samatov
- SRC Bioclinicum, Ugreshskaya Street 2/85, Moscow 115088, Russia
| | - A Tonevitsky
- Institute of General Pathology and Pathophysiology, Baltijskaya Street 8, Moscow 125315, Russia
| | - S Mahner
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany
| | - F Jänicke
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany
| | - U Schumacher
- Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany
| | - K Milde-Langosch
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany
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27
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Zhang S, Zhang M, Goldstein S, Li Y, Ge J, He B, Ruiz G. The effect of c-fos on acute myocardial infarction and the significance of metoprolol intervention in a rat model. Cell Biochem Biophys 2013; 65:249-55. [PMID: 23054911 DOI: 10.1007/s12013-012-9428-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Over-expression of c-fos may play a role in some diseases. Research pertaining to the expression of c-fos in acute myocardial ınfarction (AMI) is rare, and the detailed role of c-fos in AMI has not been reported. Therefore, the purpose of this project was to elucidate the detailed effect of c-fos on AMI rats and evaluate the effect of a metoprolol intervention. An AMI rat model was established for the purposes of this study. The expression of c-fos in AMI was evaluated via immunohistochemical analysis and in situ hybridization. Simultaneously, we investigated the effect of c-fos on AMI rats via medicinal treatment with c-fos monoclonal antibody, isoproterenol, and metoprolol. Positive c-Fos protein expression and c-fos mRNA expression in cardiomyocytes were increased at 1, 3, 7, and 10 days after ligation in AMI rats compared with a sham-operated group. Peak expression occurred at 3 days after ligation. The weight percentage fraction of infarct size was decreased in rats treated with c-fos monoclonal antibody compared with the control normal saline treatment group. The weight percentage fraction of infarction size was increased after c-fos was increased via the administration of isoproterenol. c-Fos protein expression and the infarct size in rats treated with metoprolol were also decreased compared with the control normal saline treatment group. The results showed that c-fos expression rapidly increased after coronary ligation; c-fos plays an important role in myocardial lesions and is likely to be involved in the pathogenesis of AMI as well. Metoprolol can inhibit the expression of c-fos and has a positive therapeutic effect on rats after AMI; the involvement effect of metoprolol on myocardial infarction might be correlated with its effect on the inhibition of c-fos.
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Affiliation(s)
- Song Zhang
- Department of Cardiovascular Diseases, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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28
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Healy S, Khan P, Davie JR. Immediate early response genes and cell transformation. Pharmacol Ther 2013; 137:64-77. [DOI: 10.1016/j.pharmthera.2012.09.001] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Accepted: 09/06/2012] [Indexed: 01/20/2023]
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29
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Pandey MK, Liu G, Cooper TK, Mulder KM. Knockdown of c-Fos suppresses the growth of human colon carcinoma cells in athymic mice. Int J Cancer 2012; 130:213-22. [PMID: 21344377 PMCID: PMC3163111 DOI: 10.1002/ijc.25997] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2010] [Accepted: 01/26/2011] [Indexed: 01/07/2023]
Abstract
Here we have investigated whether inhibition of c-Fos expression in RKO human colon carcinoma cells (HCCCs) would result in reduced TGFβ1 expression and suppression of tumor growth in athymic mice. We stably transfected RKO cells with c-Fos small interfering RNA (siRNA) or with the corresponding control siRNA. Using these stable cell lines, we demonstrated that siRNA-c-Fos significantly suppressed both AP-1 binding, promoter reporter activity at the proximal AP-1 site in the TGFβ1 promoter, and TGFβ1 production. Further, we established colon cancer xenografts with each of RKO-siRNA-EV, RKO-siRNA-Ctrl and RKO-siRNA-c-Fos cells. By 24 days, the tumor size of RKO-siRNA-c-Fos xenografts was 40% that of either RKO-EV or RKO-siRNA-Ctrl. Immunohistochemistry (IHC) of tumor xenografts demonstrated that siRNA-c-Fos significantly blocked c-Fos expression, and consequently expression of TGFβ1. However, expression of TGFβ2 and TGFβ3 were unaffected. Overall, our results demonstrate that blockade of TGFβ1 production by siRNA-c-Fos effectively suppressed tumor growth in vivo.
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Affiliation(s)
- Manoj K. Pandey
- Department of Biochemistry and Molecular Biology, Penn State Hershey College of Medicine, Hershey, PA, 17033
| | - Guangming Liu
- Department of Biochemistry and Molecular Biology, Penn State Hershey College of Medicine, Hershey, PA, 17033
| | - Timothy K. Cooper
- Department of Comparative Medicine and Pathology, Penn State Hershey College of Medicine, Hershey, PA, 17033
| | - Kathleen M. Mulder
- Department of Biochemistry and Molecular Biology, Penn State Hershey College of Medicine, Hershey, PA, 17033
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Zhou L, Zhang JS, Yu JC, Cui QC, Zhou WX, Kang WM, Ma ZQ. Negative association of c-fos expression as a favorable prognostic indicator in gastric cancer. Arch Med Res 2010; 41:201-6. [PMID: 20682178 DOI: 10.1016/j.arcmed.2010.04.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2009] [Accepted: 04/12/2010] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIMS The onco-protein c-fos was previously linked to favorable prognosis of gastric cancer (GC) without further validations. The present study was designed to address the issue based on a cohort of Chinese patients. METHODS Expression of c-fos was determined by immunohistochemical staining in specimens from 58 patients with GC who underwent surgical resection. The relationships between c-fos expression and clinicopathological and prognostic variables were further evaluated. RESULTS Expression of c-fos in tumor epithelia was observed in 39 (67.2%) patients. The protein was also positively expressed in lymphocytes within tumors and para-tumor epithelia. Tumors with positive expression of c-fos in tumor epithelia had a smaller size and marginally earlier T stage in all patients and/or those who underwent curative resection. Univariate analysis showed that patients with positive c-fos expression in tumor epithelia had significantly prolonged overall and tumor-free survival. Cox regression analysis revealed that c-fos expression in tumor epithelia was an independent or potential independent indicator of improved prognosis in different subgroups of patients. Expression of c-fos in para-tumor epithelia and intra-tumor lymphocytes was not associated with clinicopathological variables and long-term outcomes in patients. CONCLUSIONS Our data demonstrated that c-fos expression was negatively associated with tumor progression and was predictive for favorable survival in patients with GC.
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Affiliation(s)
- Li Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
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Luo J, Zhu Y, Yang G, Gong L, Wang B, Liu H. Loss of Reprimo and S100A2 expression in human gastric adenocarcinoma. Diagn Cytopathol 2010; 39:752-7. [PMID: 20949468 DOI: 10.1002/dc.21461] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Accepted: 05/01/2010] [Indexed: 11/09/2022]
Abstract
Reprimo and S100A2 are two newly identified candidate tumor-suppressor genes, which play an important role in the regulation of p53-dependent cell cycle. In this study, we examined the expressions of Reprimo and S100A2 in surgical specimens of gastric adenocarcinoma and correlated these results with pathological and clinical parameters. Tissues were obtained from 100 gastric adenocarcinoma patients that underwent curative gastrectomy. Reprimo and S100A2 expressions were evaluated by immunohistochemical analysis. Loss of Reprimo and S100A2 expressions occurred in 65 and 52% of the patients, respectively. Loss of Reprimo expression was significantly correlated with the depth of tumor invasion (P = 0.000), lymphatic vessel invasion (P = 0.006), and lymph node metastasis (P = 0.000). Loss of S100A2 expression was significantly associated with histological type (P = 0.009), depth of invasion (P = 0.033), lymphatic vessel invasion (P = 0.01), and lymph node metastasis (P = 0.001). In addition, there was a significant positive association between the expressions of Reprimo and S100A2 (P < 0.01). The results suggest that loss of Reprimo and S100A2 expressions occurs frequently in gastric adenocarcinomas. The expressions of Reprimo and S100A2 may be potential biomarkers for gastric adenocarcinomas detection.
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Affiliation(s)
- Jun Luo
- Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
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Activating protein-1 family of transcription factors in the human placenta complicated by preeclampsia with and without fetal growth restriction. Placenta 2010; 31:919-27. [PMID: 20800894 DOI: 10.1016/j.placenta.2010.08.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2010] [Revised: 07/28/2010] [Accepted: 08/04/2010] [Indexed: 01/30/2023]
Abstract
Preeclampsia (PE) is a serious disorder of human pregnancy, it is often associated with fetal growth restriction (FGR) which is a failure of the fetus to reach its own growth potential. Activator protein-1 (AP-1) is a family of transcription factors inducible in response to a variety of extracellular stimuli and functions. AP-1 plays a complex role in the regulation of different fundamental cellular processes, including cell proliferation, survival, death and transformation. We investigate the expression pattern of AP-1 transcription factors in normal placentas during gestation and in placentas from PE without and with FGR using semiquantitative RT-PCR and immunohistochemistry techniques. The most interesting data concern the alterations of protein expression patterns of c-fos, Jun D and c-jun in normal gestation as well as in PE and PE-FGR pathologies. In addition, alterations but not significant changes are detected in mRNA expressions for these transcription factors. We strongly suggest that c-fos is implicated in regulating invasiveness mechanism of extravillous trophoblast in normal gestation as well as in PE placentas. In addition, we suggest that the opposite modulation of Jun D and c-jun in PE and PE-FGR supports the recent hypothesis that PE and PE-FGR could be considered two pathologies with different origin (maternal and placental) each of which has a different molecular pattern of expression.
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Abstract
Cooperation among transcription factors is central for their ability to execute specific transcriptional programmes. The AP1 complex exemplifies a network of transcription factors that function in unison under normal circumstances and during the course of tumour development and progression. This Perspective summarizes our current understanding of the changes in members of the AP1 complex and the role of ATF2 as part of this complex in tumorigenesis.
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Affiliation(s)
- Pablo Lopez-Bergami
- Instituto de Biologia y Medicina Experimental, Vuelta de Obligado 2490, Buenos Aires1428, Argentina,
| | - Eric Lau
- Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, CA 92037, USA,
| | - Ze'ev Ronai
- Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, CA 92037, USA
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Feng MY, Wang K, Shi QT, Yu XW, Geng JS. Gene expression profiling in TWIST-depleted gastric cancer cells. Anat Rec (Hoboken) 2009; 292:262-70. [PMID: 19051271 DOI: 10.1002/ar.20802] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
TWIST is an important transcription factor during embryonic development and has recently been found to promote the epithelial-mesenchymal transition (EMT) phenomenon seen during the initial steps of tumor metastasis. To further investigate the potential targets and interacting genes of TWIST in human gastric cancer, we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion. Moreover, TWIST-depleted HGC-27 cells showed a reversal of the morphologic and molecular changes associated with EMT. These results provide evidence that TWIST regulates the expression of several genes involved in the differentiation, adhesion, and proliferation of gastric cancer cells. The role of TWIST in the development of certain types of gastric cancer is discussed.
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Affiliation(s)
- Mei-Yan Feng
- The Pathology Department, Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
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C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma. Br J Cancer 2008; 99:1269-75. [PMID: 18854825 PMCID: PMC2570515 DOI: 10.1038/sj.bjc.6604650] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Members of the Fos protein family dimerise with Jun proteins to form the AP-1 transcription factor complex. They have a central function in proliferation and differentiation of normal tissue as well as in oncogenic transformation and tumour progression. We analysed the expression of c-Fos, FosB, Fra-1 and Fra-2 to investigate the function of Fos transcription factors in ovarian cancer. A total of 101 patients were included in the study. Expression of Fos proteins was determined by western blot analysis, quantified by densitometry and verified by immunohistochemistry. Reduced c-Fos expression was independently associated with unfavourable progression-free survival (20.6, 31.6 and 51.2 months for patients with low, moderate and high c-Fos expression; P=0.003) as well as overall survival (23.8, 46.0 and 55.5 months for low, moderate and high c-Fos levels; P=0.003). No correlations were observed for FosB, Fra-1 and Fra-2. We conclude that loss of c-Fos expression is associated with tumour progression in ovarian carcinoma and that c-Fos may be a prognostic factor. These results are in contrast to the classic concept of c-Fos as an oncogene, but are supported by the recently discovered tumour-suppressing and proapoptotic function of c-Fos in various cancer types.
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