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Ganguly S, Arora I, Tollefsbol TO. Impact of Stilbenes as Epigenetic Modulators of Breast Cancer Risk and Associated Biomarkers. Int J Mol Sci 2021; 22:ijms221810033. [PMID: 34576196 PMCID: PMC8472542 DOI: 10.3390/ijms221810033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 09/12/2021] [Accepted: 09/13/2021] [Indexed: 12/12/2022] Open
Abstract
With the recent advancement of genetic screening for testing susceptibility to mammary oncogenesis in women, the relevance of the gene−environment interaction has become progressively apparent in the context of aberrant gene expressions. Fetal exposure to external stressors, hormones, and nutrients, along with the inherited genome, impact its traits, including cancer susceptibility. Currently, there is increasing interest in the role of epigenetic biomarkers such as genomic methylation signatures, plasma microRNAs, and alterations in cell-signaling pathways in the diagnosis and primary prevention of breast cancer, as well as its prognosis. Polyphenols like natural stilbenes have been shown to be effective in chemoprevention by exerting cytotoxic effects that can stall cell proliferation. Besides possessing antioxidant properties against the DNA-damaging effects of reactive oxygen species, stilbenes have also been observed to modulate cell-signaling pathways. With the increasing trend of early-life screening for hereditary breast cancer risks, the potency of different phytochemicals in harnessing the epigenetic biomarkers of breast cancer risk demand more investigation. This review will explore means of exploiting the abilities of stilbenes in altering the underlying factors that influence breast cancer risk, as well as the appearance of associated biomarkers.
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Affiliation(s)
- Sebanti Ganguly
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (S.G.); (I.A.)
| | - Itika Arora
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (S.G.); (I.A.)
| | - Trygve O. Tollefsbol
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (S.G.); (I.A.)
- Integrative Center for Aging Research, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Cell Senescence Culture Facility, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence: ; Tel.: +1-205-934-4573
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Nguyen HT, Kacimi SEO, Nguyen TL, Suman KH, Lemus-Martin R, Saleem H, Do DN. MiR-21 in the Cancers of the Digestive System and Its Potential Role as a Diagnostic, Predictive, and Therapeutic Biomarker. BIOLOGY 2021; 10:biology10050417. [PMID: 34066762 PMCID: PMC8151274 DOI: 10.3390/biology10050417] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/27/2021] [Accepted: 05/03/2021] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs. They can regulate the expression of their target genes, and thus, their dysregulation significantly contributes to the development of cancer. Growing evidence suggests that miRNAs could be used as cancer biomarkers. As an oncogenic miRNA, the roles of miR-21 as a diagnostic and prognostic biomarker, and its therapeutic applications have been extensively studied. In this review, the roles of miR-21 are first demonstrated via its different molecular networks. Then, a comprehensive review on the potential targets and the current applications as a diagnostic and prognostic cancer biomarker and the therapeutic roles of miR-21 in six different cancers in the digestive system is provided. Lastly, a brief discussion on the challenges for the use of miR-21 as a therapeutic tool for these cancers is added.
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Affiliation(s)
- Ha Thi Nguyen
- Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam;
- Faculty of Medicine, Duy Tan University, Danang 550000, Vietnam
| | | | - Truc Ly Nguyen
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea;
| | - Kamrul Hassan Suman
- Department of Fisheries Biology & Aquatic Environment, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur 1706, Bangladesh;
| | | | - Humaira Saleem
- Jamil–ur–Rahman Center for Genome Research, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;
| | - Duy Ngoc Do
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS B2N5E3, Canada
- Correspondence: ; Tel.: +1-819-571-5310
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Li F, Li H, Hou Y. Identification and analysis of survival-associated ceRNA triplets in prostate adenocarcinoma. Oncol Lett 2019; 18:4040-4047. [PMID: 31579415 PMCID: PMC6757318 DOI: 10.3892/ol.2019.10752] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Accepted: 06/13/2019] [Indexed: 12/19/2022] Open
Abstract
Prostate adenocarcinoma (PRAD) is one of the most common causes of cancer-associated mortality worldwide. Recent evidence has emphasized the role of competitive endogenous RNAs (ceRNA) in prostate cancer. However, the current understanding of the roles that ceRNAs play in survival-associated PRAD remains in its infancy. In the present study, a PRAD-specific ceRNA network was constructed by integrating long non-coding RNA (lncRNA)-microRNA (miRNA)-gene interactions using experimental and computational methods, as well as expression correlations from The Cancer Genome Atlas database. The topological features of the ceRNA network were then analyzed and the PRAD-risk lncRNAs were compared with non-risk lncRNAs within this network. It was revealed that PRAD-risk lncRNAs had a higher degree, closeness and betweenness centrality, but also had the shortest path length. Finally, 42 significant PRAD-survival-associated triplets were identified. Notably, these triplets may form a compacted subnetwork composed of only 25 nodes (5 miRNAs, 4 lncRNAs and 16 genes) and 32 edges, indicating that some nodes were involved in many triplets. Among this subnetwork, mir-21 indicated the highest degree centrality and was demonstrated to exert its oncogenic effects in prostate tumors by downregulating transforming growth factor β receptor 2 (TGFBR2). Two triplets (MIR22HG_hsa-mir-21_TGFBR2 and MIR22HG_hsa-mir-21_BCL2) were finally identified; not only were they significantly associated with PRAD survival but they also had the highest average degree in the identified subnetwork. The results from the present study provide further insights into the understanding of the potential roles and interactions of ceRNA triplets and potential prognosis markers for PRAD.
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Affiliation(s)
- Fan Li
- Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Hai Li
- Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yi Hou
- Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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4
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Chatterjee M, Sengupta S. Emerging roles of long non-coding RNAs in cancer. J Biosci 2019; 44:22. [PMID: 30837373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Cancer is a physiological condition that has both the endogenous and exogenous influences on its progression. It originates from unusual cell growth, where the cells undergo massive genetic alterations, bypass the signaling machinery and compromise its genetic cohesion. Literature has well narrated the DNA damage studies including driver mutations that interfere with the treatment strategies. However, with evolving medical excellence, recent day studies are trying to unveil the contribution of RNAs in the progression of tumor malignancies. A number of non-coding RNAs have been identified as an active component in cancer genomics. This article aims to review the role of long non-coding RNAs in the spectra of cancers and its prognostic value as the biomarkers in molecular targeting with clinical utility and therapeutic beneficence.
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Affiliation(s)
- Manjima Chatterjee
- School of BioSciences and Technology, VIT University, Vellore 632 014, India
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Alaei S, Sadeghi B, Najafi A, Masoudi-Nejad A. LncRNA and mRNA integration network reconstruction reveals novel key regulators in esophageal squamous-cell carcinoma. Genomics 2018; 111:76-89. [PMID: 29317304 DOI: 10.1016/j.ygeno.2018.01.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 01/05/2018] [Accepted: 01/05/2018] [Indexed: 12/19/2022]
Abstract
Many experimental and computational studies have identified key protein coding genes in initiation and progression of esophageal squamous cell carcinoma (ESCC). However, the number of researches that tried to reveal the role of long non-coding RNAs (lncRNAs) in ESCC has been limited. LncRNAs are one of the important regulators of cancers which are transcribed dominantly in the genome and in various conditions. The main goal of this study was to use a systems biology approach to predict novel lncRNAs as well as protein coding genes associated with ESCC and assess their prognostic values. By using microarray expression data for mRNAs and lncRNAs from a large number of ESCC patients, we utilized "Weighted Gene Co-expression Network Analysis" (WGCNA) method to make a big coding-non-coding gene co-expression network, and discovered important functional modules. Gene set enrichment and pathway analysis revealed major biological processes and pathways involved in these modules. After selecting some protein coding genes involved in biological processes and pathways related to cancer, we used "LncTar", a computational tool to predict potential interactions between these genes and lncRNAs. By combining interaction results with Pearson correlations, we introduced some novel lncRNAs with putative key regulatory roles in the network. Survival analysis with Kaplan-Meier estimator and Log-rank test statistic confirmed that most of the introduced genes are associated with poor prognosis in ESCC. Overall, our study reveals novel protein coding genes and lncRNAs associated with ESCC, along with their predicted interactions. Based on the promising results of survival analysis, these genes can be used as good estimators of patients' survival, or even can be analyzed further as new potential signatures or targets for the therapy of ESCC disease.
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Affiliation(s)
- Shervin Alaei
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Balal Sadeghi
- Food Hygiene and Public Health Department, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Ali Najafi
- Molecular Biology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ali Masoudi-Nejad
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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Wang JB, Liu FH, Chen JH, Ge HT, Mu LY, Bao HB, Lin ZG. Identifying survival-associated modules from the dysregulated triplet network in glioblastoma multiforme. J Cancer Res Clin Oncol 2017; 143:661-671. [PMID: 28168356 DOI: 10.1007/s00432-016-2332-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 12/23/2016] [Indexed: 12/25/2022]
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) can act as competitive endogenous RNAs (ceRNAs) to compete with mRNAs for binding miroRNAs (miRNAs). The dysregulated triplets, composed by mRNAs, lncRNAs, and miRNAs, contributed to the development and progression of diseases, such as cancer. However, the roles played by triplet biomarkers are not fully understand in glioblastoma multiforme (GBM) patient survival. OBJECTIVES Here, we constructed a differential triplet interaction network (TriNet) between GBM and normal tissues and identified GBM survival related triplets. METHODS Four significantly dysregulated modules, enriched differentially expressed molecules, were identified by integrating affinity propagation method and hypergeometric method. Furthermore, knockdown of TP73-AS1 was implemented by siRNA and the expression of RFX1 was examined in U87 cells by qRT-PCR. The apoptosis of U87 cells was investigated using MTT assay and Acridine orange/Ethidium bromide (AO/EB) assay. RESULTS We randomly split GBM samples into training and testing sets, and found that these four modules can robustly and significantly distinguish low- and high-survival patients in both two sets. By manually curated literatures for triplets mediated by core interactions, we found that members involved tumor invasion, proliferation, and migration. The dysregulated triplets may cause the poor survival of GBM patients. We finally experimentally verified that knockdown of TP73-AS1, an lncRNA of one triplet, could not only reduce the expression of RFX1, an mRNA of this triplet, but also induce apoptosis in U87 cells. CONCLUSIONS These results can provide further insights to understand the functions of triplet biomarkers that associated with GBM prognosis.
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Affiliation(s)
- Jia-Bin Wang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Feng-Hua Liu
- Department of Blood Transfusion, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Jian-Hang Chen
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Hai-Tao Ge
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Lu-Yan Mu
- Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Hong-Bo Bao
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, 150001, Heilongjiang, People's Republic of China
- Heilongjiang Academy of Medical Sciences, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Zhi-Guo Lin
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China.
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8
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Sun YL, Liu F, Liu F, Zhao XH. Protein and gene expression characteristics of heterogeneous nuclear ribonucleoprotein H1 in esophageal squamous cell carcinoma. World J Gastroenterol 2016; 22:7322-7331. [PMID: 27621578 PMCID: PMC4997634 DOI: 10.3748/wjg.v22.i32.7322] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/16/2016] [Accepted: 06/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the expression characteristics of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) mRNA and protein in cell lines and tissues of esophageal squamous cell carcinoma (ESCC).
METHODS Western blotting was used to assess the expression of HNRNPH1 protein in seven ESCC cell lines and 30 paired fresh tissue specimens. The subcellular localization of HNRNPH1 was determined by immunofluorescence in ESCC cells. The RNA sequencing data from 87 patients with ESCC were obtained from the cancer genome atlas (TCGA), and the expression and clinical characteristics analysis of different transcript variants of HNRNPH1 were evaluated in this dataset. In addition, immunohistochemistry was carried out to detect the expression of HNRNPH1 protein in 125 patients.
RESULTS The expression of HNRNPH1 protein varied across different ESCC cell lines. It was exclusively restricted to the nucleus of the ESCC cells. There are two transcript variants of the HNRNPH1 gene. Variant 1 was constitutively expressed, and its expression did not change during tumorigenesis. In contrast, levels of variant 2 were low in non-tumorous tissues and were dramatically increased in ESCC (P = 0.0026). The high levels of variant 2 were associated with poorer differentiated tumors (P = 0.0287). Furthermore, in paired fresh tissue specimens, HNRNPH1 protein was overexpressed in 73.3% (22/30) of neoplastic tissues. HNRNPH1 was significantly upregulated in ESCC, with strong staining in 43.2% (54/125) of tumor tissues and 22.4% (28/125) of matched non-cancerous tissues (P = 0.0005). Positive HNRNPH1 expression was significantly associated with poor tumor differentiation degree (P = 0.0337).
CONCLUSION The different alternative transcript variants of HNRNPH1 exhibited different expression changes during tumorigenesis. Its mRNA and protein were overexpressed in ESCC and associated with poorer differentiation of tumor cells. These findings highlight the potential of HNRNPH1 in the therapy and diagnosis of ESCC.
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MESH Headings
- Adult
- Aged
- Alternative Splicing
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Cell Line, Tumor
- Cell Proliferation
- Esophageal Neoplasms/genetics
- Esophageal Neoplasms/metabolism
- Esophageal Neoplasms/pathology
- Esophageal Squamous Cell Carcinoma
- Female
- Gene Expression Regulation, Neoplastic
- Heterogeneous-Nuclear Ribonucleoprotein Group F-H/genetics
- Heterogeneous-Nuclear Ribonucleoprotein Group F-H/metabolism
- Humans
- Male
- Middle Aged
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Up-Regulation
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Flippot R, Malouf GG, Su X, Mouawad R, Spano JP, Khayat D. Cancer subtypes classification using long non-coding RNA. Oncotarget 2016; 7:54082-54093. [PMID: 27340923 PMCID: PMC5288243 DOI: 10.18632/oncotarget.10213] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 05/30/2016] [Indexed: 12/16/2022] Open
Abstract
Inter-tumor heterogeneity might explain divergent clinical evolution of cancers bearing similar pathological features. In the last decade, genomic has highly improved tumor subtypes classification through the identification of oncogenic or tumor suppressor drivers. In addition, epigenetics and long non-coding RNAs (lncRNAs) are emerging as new fields for investigation, which might also account for tumor heterogeneity. There is growing evidence that modifications of lncRNA expression profiles are involved in cancer progression through epigenetic regulation, activation of pro-oncogenic pathways and crosstalks with other RNA subtypes. Consequently, the study of lncRNA expression profile will be a key factor in the future for charting cancer subtype classifications as well as defining prognostic and progression biomarkers. Herein we discuss the interest of lncRNA as potent prognostic and predictive biomarkers, and provide a glimpse on the impact of emerging cancer subtypes classification based on lncRNAs.
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Affiliation(s)
- Ronan Flippot
- Groupe Hospitalier Pitié-Salpêtrière, Department of Medical Oncology, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France
| | - Gabriel G. Malouf
- Groupe Hospitalier Pitié-Salpêtrière, Department of Medical Oncology, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France
| | - Xiaoping Su
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Roger Mouawad
- Groupe Hospitalier Pitié-Salpêtrière, Department of Medical Oncology, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France
| | - Jean-Philippe Spano
- Groupe Hospitalier Pitié-Salpêtrière, Department of Medical Oncology, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France
| | - David Khayat
- Groupe Hospitalier Pitié-Salpêtrière, Department of Medical Oncology, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France
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Zhang D, Hou XL, Wu B, Li DD. Long non-coding RNAs in esophageal cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:2744-2753. [DOI: 10.11569/wcjd.v23.i17.2744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are RNA transcripts which are longer than 200 nucleotides and have no protein-coding capacity. Studies have shown that lncRNAs can regulate gene expression at multiple levels and play roles in cell proliferation, differentiation, metabolism, and apoptosis. Abnormal expression of lncRNAs has close relationships to tumor development, invasion, metastasis and prognosis. Esophageal cancer is one of the most deadly gastrointestinal cancers, and lncRNAs play important roles in the pathogenesis of esophageal cancer. In this paper, we review the current progress in research on lncRNAs in esophageal cancer, hoping to provide new ideas and strategies for early diagnosis, treatment and prognostic evaluation of esophageal cancer.
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Nie J, Ge X, Geng Y, Cao H, Zhu W, Jiao Y, Wu J, Zhou J, Cao J. miR-34a inhibits the migration and invasion of esophageal squamous cell carcinoma by targeting Yin Yang-1. Oncol Rep 2015; 34:311-7. [PMID: 25954903 DOI: 10.3892/or.2015.3962] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 04/16/2015] [Indexed: 01/15/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC), one of the most common gastrointestinal tumors, is known for its high mortality rate. microRNAs (miRNAs) have been reported to play important regulatory roles in cancer metastasis and progression. miR-34a has been demonstrated to be associated with the development of and metastasis in certain types of cancer via various target genes, but its function and targets in ESCC are unknown. The aim of this study was to examine whether the expression of miR-34a was significantly decreased in ESCC tissues, compared with normal esophageal tissues using RT-PCR and western blot analysis. The results showed that miR-34a overexpression increased apoptosis and decreased clonogenic formation, but inhibited invasion and migration in ESCC cells by suppressing MMP-2 and -9 expression. Yin Yang-1 (YY1), a widely distributed transcription factor that belongs to the GLI-Kruppel class of zinc finger proteins, was found to be a direct target of miR-34a in ESCC cell lines. Rescue experiments indicated that the suppressive effect of miR-34a on invasion and migration was mediated by activating YY1 expression. Results of the present study showed that miR-34a is associated with ESCC migration and provides a potential therapeutic and diagnostic target for ESCC.
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Affiliation(s)
- Jihua Nie
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Xin Ge
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Yangyang Geng
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Han Cao
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Wei Zhu
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Yang Jiao
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Jinchang Wu
- The Core Laboratory of Suzhou Cancer Center and Department of Radiotherapy of Suzhou Municipal Hospital, Suzhou, Jiangsu 215001, P.R. China
| | - Jundong Zhou
- The Core Laboratory of Suzhou Cancer Center and Department of Radiotherapy of Suzhou Municipal Hospital, Suzhou, Jiangsu 215001, P.R. China
| | - Jianping Cao
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
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12
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Zaidi AH, Saldin LT, Kelly LA, Bergal L, Londono R, Kosovec JE, Komatsu Y, Kasi PM, Shetty AA, Keane TJ, Thakkar SJ, Huleihel L, Landreneau RJ, Badylak SF, Jobe BA. MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model. PLoS One 2015; 10:e0122375. [PMID: 25826212 PMCID: PMC4380408 DOI: 10.1371/journal.pone.0122375] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 02/15/2015] [Indexed: 02/06/2023] Open
Abstract
Objective To establish a miRNA signature for metastasis in an animal model of esophageal adenocarcinoma (EAC). Background The incidence of esophageal adenocarcinoma (EAC) has dramatically increased and esophageal cancer is now the sixth leading cause of cancer deaths worldwide. Mortality rates remain high among patients with advanced stage disease and esophagectomy is associated with high complication rates. Hence, early identification of potentially metastatic disease would better guide treatment strategies. Methods The modified Levrat’s surgery was performed to induce EAC in Sprague-Dawley rats. Primary EAC and distant metastatic sites were confirmed via histology and immunofluorescence. miRNA profiling was performed on primary tumors with or without metastasis. A unique subset of miRNAs expressed in primary tumors and metastases was identified with Ingenuity Pathway Analysis (IPA) along with upstream and downstream targets. miRNA-linked gene expression analysis was performed on a secondary cohort of metastasis positive (n=5) and metastasis negative (n=28) primary tumors. Results The epithelial origin of distant metastasis was established by IF using villin (VIL1) and mucin 5AC (MUC5AC) antibodies. miRNome analysis identified four down-regulated miRNAs in metastasis positive primary tumors compared to metastasis negative tumors: miR-92a-3p (p=0.0001), miR-141-3p (p=0.0022), miR-451-1a (p=0.0181) and miR133a-3p (p=0.0304). Six target genes identified in the top scoring networks by IPA were validated as significantly, differentially expressed in metastasis positive primary tumors: Ago2, Akt1, Kras, Bcl2L11, CDKN1B and Zeb2. Conclusion In vivo metastasis was confirmed in the modified Levrat’s model. Analysis of the primary tumor identified a distinctive miRNA signature for primary tumors that metastasized.
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Affiliation(s)
- Ali H. Zaidi
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Lindsey T. Saldin
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Lori A. Kelly
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Linda Bergal
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Ricardo Londono
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Juliann E. Kosovec
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Yoshihiro Komatsu
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Pashtoon M. Kasi
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Amit A. Shetty
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Timothy J. Keane
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Shyam J. Thakkar
- Division of Gastroenterology, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Luai Huleihel
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Rodney J. Landreneau
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
| | - Stephen F. Badylak
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Blair A. Jobe
- Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, United States of America
- * E-mail:
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