1
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Chen J, Xing QC. Advancements and challenges in esophageal carcinoma prognostic models: A comprehensive review and future directions. World J Gastrointest Oncol 2025; 17:101379. [PMID: 39958560 PMCID: PMC11755996 DOI: 10.4251/wjgo.v17.i2.101379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/04/2024] [Accepted: 11/22/2024] [Indexed: 01/18/2025] Open
Abstract
In this article, we comment on the article published by Yu et al. By employing LASSO regression and Cox proportional hazard models, the article identified nine significant variables affecting survival, including body mass index, Karnofsky performance status, and tumor-node-metastasis staging. We firmly concur with Yu et al regarding the vital significance of clinical prediction models (CPMs), including logistic regression and Cox regression for assessment in esophageal carcinoma (EC). However, the nomogram's limitations and the complexities of integrating genetic factors pose challenges. The integration of immunological data with advanced statistics offers new research directions. High-throughput sequencing and big data, facilitated by machine learning, have revolutionized cancer research but require substantial computational resources. The future of CPMs in EC depends on leveraging these technologies to improve predictive accuracy and clinical application, addressing the need for larger datasets, patient-reported outcomes, and regular updates for clinical relevance.
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Affiliation(s)
- Jia Chen
- Department of Clinical Pharmacy, Xiangtan Central Hospital, Xiangtan 411100, Hunan Province, China
| | - Qi-Chang Xing
- Department of Clinical Pharmacy, Xiangtan Central Hospital, Xiangtan 411100, Hunan Province, China
- The Affiliated Hospital, Hunan University, Changsha 410082, Hunan Province, China
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2
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Zhang X, Liu J, Zuo C, Peng X, Xie J, Shu Y, Ao D, Zhang Y, Ye Q, Cai J. Role of SIK1 in tumors: Emerging players and therapeutic potentials (Review). Oncol Rep 2024; 52:169. [PMID: 39422046 PMCID: PMC11544583 DOI: 10.3892/or.2024.8828] [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: 08/23/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024] Open
Abstract
Salt‑induced kinase 1 (SIK1) is a serine/threonine protein kinase that is a member of the AMP‑activated protein kinase family. SIK is catalytically activated through its phosphorylation by the upstream kinase LKB1. SIK1 has been reported to be associated with numerous types of cancer. The present review summarizes the structure, regulatory factors and inhibitors of SIK1, and also describes how SIK1 is a signal regulatory factor that fulfills connecting roles in various signal regulatory pathways. Furthermore, the anti‑inflammatory effects of SIK1 during the early stage of tumor occurrence and its different regulatory effects following tumor occurrence, are summarized, and through collating the tumor signal regulatory mechanisms in which SIK1 participates, it has been demonstrated that SIK1 acts as a necessary node in cancer signal transduction. In conclusion, SIK1 is discussed independent of the SIKs family, its research results and recent progress in oncology are summarized in detail with a focus on SIK1, and its potential as a therapeutic target is highlighted, underscoring the need for SIK1‑targeted regulatory strategies in future cancer therapy.
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Affiliation(s)
- Xinran Zhang
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Jing Liu
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Chenyang Zuo
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Xiaochun Peng
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Jinyuan Xie
- Department of Joint Surgery and Sports Medicine, Jingmen Central Hospital, Jingmen, Hubei 448000, P.R. China
| | - Ya Shu
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Dongxu Ao
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Yang Zhang
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Qingqing Ye
- Department of Breast Surgery, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Jun Cai
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
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3
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Feng S, Wei F, Shi H, Chen S, Wang B, Huang D, Luo L. Roles of salt‑inducible kinases in cancer (Review). Int J Oncol 2023; 63:118. [PMID: 37654200 PMCID: PMC10546379 DOI: 10.3892/ijo.2023.5566] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 08/01/2023] [Indexed: 09/02/2023] Open
Abstract
Salt inducible kinases (SIKs) with three subtypes SIK1, SIK2 and SIK3, belong to the AMP‑activated protein kinase family. They are expressed ubiquitously in humans. Under normal circumstances, SIK1 regulates adrenocortical function in response to high salt or adrenocorticotropic hormone stimulation, SIK2 is involved in cell metabolism, controlling insulin signaling and gluconeogenesis and SIK3 coordinates with the mTOR complex, promoting cancer. The dysregulation of SIKs has been widely detected in various types of cancers. Based on most of the existing studies, SIK1 is mostly considered a tumor inhibitor, SIK2 and SIK3 are usually associated with tumor promotion. However, the functions of SIKs have shown contradictory in certain tumors, suggesting that SIKs cannot be simply classified as oncogenes or tumor suppressor genes. The present review provided a comprehensive summary of the roles of SIKs in the initiation and progression of different cancers, aiming to elucidate their clinical value and discuss potential strategies for targeting SIKs in cancer therapy.
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Affiliation(s)
- Shenghui Feng
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Fangyi Wei
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Haoran Shi
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shen Chen
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Bangqi Wang
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Deqiang Huang
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Lingyu Luo
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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4
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Sun JY, Ni MM. Long non-coding RNA HEIH: a novel tumor activator in multiple cancers. Cancer Cell Int 2021; 21:558. [PMID: 34689775 PMCID: PMC8543845 DOI: 10.1186/s12935-021-02272-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/16/2021] [Indexed: 12/27/2022] Open
Abstract
The last decade has witnessed the altered expression levels of long non-coding RNA HEIH in different types of cancer. More than half of the HEIH studies in cancer have been published within the last two years. To our knowledge, this is the first review to discuss very recent developments and insights into HEIH contribution to carcinogenesis. The functional role, molecular mechanism, and clinical significance of HEIH in human cancers are described in detail. The expression of HEIH is elevated in a broad spectrum of cancers, and its disorder contributes to cell proliferation, migration, invasion, and drug resistance of cancer cells through different underlying mechanisms. In addition, the high expression of HEIH is significantly associated with advanced tumor stage, tumor size and decreased overall survival, suggesting HEIH may function as a prognostic biomarker and potential therapeutic target for human cancers.
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Affiliation(s)
- Jie-Yu Sun
- Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Ming-Ming Ni
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, 72 Guangzhou Rd., Nanjing, 210008, People's Republic of China.
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Wang D, Zhang S, Zhang H, Lin S. Omics study of harmful algal blooms in China: Current status, challenges, and future perspectives. HARMFUL ALGAE 2021; 107:102079. [PMID: 34456014 DOI: 10.1016/j.hal.2021.102079] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 06/24/2021] [Accepted: 06/30/2021] [Indexed: 06/13/2023]
Abstract
In the past two decades, the frequency, scale, and scope of harmful algal blooms (HABs) have increased significantly in the coastal waters of China. HABs have become a major ecological and environmental problem in China that seriously threatens the structure and function of marine ecosystems, the sustainable development of mariculture, and the health of human beings. Much effort has been devoted to studying HABs in China, and great achievements have been made in understanding the oceanographic and ecological mechanisms of HABs as well as the biology and physiological ecology of HAB-causing species. Furthermore, state-of-the-art omics technologies, such as transcriptomics and proteomics, have been used to elucidate the physiological responses of HAB-causing species to environmental changes, the biosynthesis of paralytic shellfish toxin, and the mechanisms underlying the formation of HABs. This review summarizes omics studies of HABs in China over the past few years and discusses challenges and future perspectives of HAB research.
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Affiliation(s)
- Dazhi Wang
- State Key Laboratory of Marine Environmental Science/College of the Environment and Ecology, Xiamen University, Xiamen 361102, China; Key Laboratory of Marine Ecology & Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.
| | - Shufeng Zhang
- State Key Laboratory of Marine Environmental Science/College of the Environment and Ecology, Xiamen University, Xiamen 361102, China; Key Laboratory of Marine Ecology & Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.
| | - Hao Zhang
- CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.
| | - Senjie Lin
- State Key Laboratory of Marine Environmental Science/College of Ocean and Earth Science, Xiamen University, Xiamen 361102, China.
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6
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MYC DNA Methylation in Prostate Tumor Tissue Is Associated with Gleason Score. Genes (Basel) 2020; 12:genes12010012. [PMID: 33374332 PMCID: PMC7823928 DOI: 10.3390/genes12010012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/20/2020] [Accepted: 12/11/2020] [Indexed: 12/29/2022] Open
Abstract
Increasing evidence suggests a role of epigenetic mechanisms at chromosome 8q24, an important cancer genetic susceptibility region, in prostate cancer. We investigated whether MYC DNA methylation at 8q24 (six CpG sites from exon 3 to the 3′ UTR) in prostate tumor was associated with tumor aggressiveness (based on Gleason score, GS), and we incorporated RNA expression data to investigate the function. We accessed radical prostatectomy tissue for 50 Caucasian and 50 African American prostate cancer patients at the University of Maryland Medical Center, selecting an equal number of GS 6 and GS 7 cases per group. MYC DNA methylation was lower in tumor than paired normal prostate tissue for all six CpG sites (median difference: −14.74 to −0.20 percentage points), and we observed similar results for two nearby sites in The Cancer Genome Atlas (p < 0.0001). We observed significantly lower methylation for more aggressive (GS 7) than less aggressive (GS 6) tumors for three exon 3 sites (for CpG 212 (chr8:128753145), GS 6 median = 89.7%; GS 7 median = 85.8%; p-value = 9.4 × 10−4). MYC DNA methylation was not associated with MYC expression, but was inversely associated with PRNCR1 expression after multiple comparison adjustment (q-value = 0.04). Findings suggest that prostate tumor MYC exon 3 hypomethylation is associated with increased aggressiveness.
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7
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Vafadar A, Shabaninejad Z, Movahedpour A, Mohammadi S, Fathullahzadeh S, Mirzaei HR, Namdar A, Savardashtaki A, Mirzaei H. Long Non-Coding RNAs As Epigenetic Regulators in Cancer. Curr Pharm Des 2020; 25:3563-3577. [PMID: 31470781 DOI: 10.2174/1381612825666190830161528] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Accepted: 08/21/2019] [Indexed: 02/08/2023]
Abstract
Long noncoding RNAs (lncRNAs) constitute large portions of the mammalian transcriptome which appeared as a fundamental player, regulating various cellular mechanisms. LncRNAs do not encode proteins, have mRNA-like transcripts and frequently processed similar to the mRNAs. Many investigations have determined that lncRNAs interact with DNA, RNA molecules or proteins and play a significant regulatory function in several biological processes, such as genomic imprinting, epigenetic regulation, cell cycle regulation, apoptosis, and differentiation. LncRNAs can modulate gene expression on three levels: chromatin remodeling, transcription, and post-transcriptional processing. The majority of the identified lncRNAs seem to be transcribed by the RNA polymerase II. Recent evidence has illustrated that dysregulation of lncRNAs can lead to many human diseases, in particular, cancer. The aberrant expression of lncRNAs in malignancies contributes to the dysregulation of proliferation and differentiation process. Consequently, lncRNAs can be useful to the diagnosis, treatment, and prognosis, and have been characterized as potential cancer markers as well. In this review, we highlighted the role and molecular mechanisms of lncRNAs and their correlation with some of the cancers.
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Affiliation(s)
- Asma Vafadar
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Shabaninejad
- Department of Nanotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.,Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Movahedpour
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.,Student research committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soheila Mohammadi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sima Fathullahzadeh
- Medical Biotechnology Research Center, Ashkezar Branch, Islamic Azad University, Ashkezar, Yazd, Iran
| | - Hamid R Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Afshin Namdar
- Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.,Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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8
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Gu Y, Lin X, Kapoor A, Chow MJ, Jiang Y, Zhao K, Tang D. The Oncogenic Potential of the Centromeric Border Protein FAM84B of the 8q24.21 Gene Desert. Genes (Basel) 2020; 11:genes11030312. [PMID: 32183428 PMCID: PMC7140883 DOI: 10.3390/genes11030312] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 03/09/2020] [Accepted: 03/13/2020] [Indexed: 12/14/2022] Open
Abstract
FAM84B is a risk gene in breast and prostate cancers. Its upregulation is associated with poor prognosis of prostate cancer, breast cancer, and esophageal squamous cell carcinoma. FAM84B facilitates cancer cell proliferation and invasion in vitro, and xenograft growth in vivo. The FAM84B and Myc genes border a 1.2 Mb gene desert at 8q24.21. Co-amplification of both occurs in 20 cancer types. Mice deficient of a 430 Kb fragment within the 1.2 Mb gene desert have downregulated FAM84B and Myc expressions concurrent with reduced breast cancer growth. Intriguingly, Myc works in partnership with other oncogenes, including Ras. FAM84B shares similarities with the H-Ras-like suppressor (HRASLS) family over their typical LRAT (lecithin:retinal acyltransferase) domain. This domain contains a catalytic triad, H23, H35, and C113, which constitutes the phospholipase A1/2 and O-acyltransferase activities of HRASLS1-5. These enzymatic activities underlie their suppression of Ras. FAM84B conserves H23 and H35 but not C113 with both histidine residues residing within a highly conserved motif that FAM84B shares with HRASLS1-5. Deletion of this motif abolishes FAM84B oncogenic activities. These properties suggest a collaboration of FAM84B with Myc, consistent with the role of the gene desert in strengthening Myc functions. Here, we will discuss recent research on FAM84B-derived oncogenic potential.
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Affiliation(s)
- Yan Gu
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada; (Y.G.); (X.L.); (M.J.C.); (Y.J.); (K.Z.)
- Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada;
- The Research Institute of St Joe’s Hamilton, St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada
| | - Xiaozeng Lin
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada; (Y.G.); (X.L.); (M.J.C.); (Y.J.); (K.Z.)
- Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada;
- The Research Institute of St Joe’s Hamilton, St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada
| | - Anil Kapoor
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada; (Y.G.); (X.L.); (M.J.C.); (Y.J.); (K.Z.)
- Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada;
- Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Mathilda Jing Chow
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada; (Y.G.); (X.L.); (M.J.C.); (Y.J.); (K.Z.)
- Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada;
- The Research Institute of St Joe’s Hamilton, St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada
| | - Yanzhi Jiang
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada; (Y.G.); (X.L.); (M.J.C.); (Y.J.); (K.Z.)
- Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada;
- The Research Institute of St Joe’s Hamilton, St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada
| | - Kuncheng Zhao
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada; (Y.G.); (X.L.); (M.J.C.); (Y.J.); (K.Z.)
- Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada;
- The Research Institute of St Joe’s Hamilton, St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada
| | - Damu Tang
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada; (Y.G.); (X.L.); (M.J.C.); (Y.J.); (K.Z.)
- Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada;
- The Research Institute of St Joe’s Hamilton, St Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada
- Correspondence: ; Tel.: +(905)-522-1155 (ext. 35168)
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Shang Z, Yu J, Sun L, Tian J, Zhu S, Zhang B, Dong Q, Jiang N, Flores-Morales A, Chang C, Niu Y. LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex. Nucleic Acids Res 2019; 47:4211-4225. [PMID: 30773595 PMCID: PMC6486551 DOI: 10.1093/nar/gkz108] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 01/14/2019] [Accepted: 02/12/2019] [Indexed: 12/14/2022] Open
Abstract
In PTEN-deficient prostate cancers, AKT signaling may be activated upon suppression of androgen receptor signaling. Activation of AKT as well as NF-κB signaling involves a key regulatory protein complex containing PHLPP, FKBP51 and IKKα. Here, we report a critical role of lncRNA PCAT1 in regulating the PHLPP/FKBP51/IKKα complex and progression of castration-resistant prostate cancer (CRPC). Using database queries, bioinformatic analyses, as well as RIP and RNA pull-down assays, we discovered and validated that the lncRNA-PCAT1 perturbs the PHLPP/FKBP51/IKKα complex and activates AKT and NF-κB signaling. Expression of lncRNA-PCAT1 is positively linked to CRPC progression. PCAT1 binds directly to FKBP51, displacing PHLPP from the PHLPP/FKBP51/IKKα complex, leading to activation of AKT and NF-κB signaling. Targeting PCAT1 restores PHLPP binding to FKBP1 leading to suppression of AKT signaling. Preclinical study in a mouse model of CRPC suggests therapeutic potential by targeting lncRNA PCAT1 to suppress CRPC progression. Together, the newly identified PCAT1/FKBP51/IKKα complex provides mechanistic insight in the interplay between AKT, NF-κB and AR signaling in CRPC, and the preclinical studies suggest that a novel role for PCAT1 as a therapeutic target.
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Affiliation(s)
- Zhiqun Shang
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Jianpeng Yu
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Libin Sun
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin 300211, China.,Department of Urology, First Affiliated Hospital, Shanxi Medical University, Shanxi 030001, China
| | - Jing Tian
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Shimiao Zhu
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Boya Zhang
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Qian Dong
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Ning Jiang
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Amilcar Flores-Morales
- Department of Health Science, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Chawnshang Chang
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin 300211, China.,Department of Pathology and Urology, University of Rochester, Rochester, NY 14620, USA
| | - Yuanjie Niu
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin 300211, China
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10
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Guo JL, Tang T, Li JH, Yang YH, Zhang L, Quan Y. LncRNA HEIH Enhances Paclitaxel-Tolerance of Endometrial Cancer Cells via Activation of MAPK Signaling Pathway. Pathol Oncol Res 2019; 26:1757-1766. [PMID: 31650338 DOI: 10.1007/s12253-019-00718-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 08/13/2019] [Indexed: 02/08/2023]
Abstract
This study aimed to investigate the function of lncRNA HEIH on promoting endometrial cancer cells' tolerance of paclitaxel (PTX). LncRNA HEIH expression was measured by QRT-PCR in endometrial cancer tissues, human healthy tissues and cell lines. The PTX-resistant endometrial cancer cells (Ishikawa-RE and HHUA-RE) were intermittently exposed to increase concentrations of PTX and were constructed as evidenced by MTT assay. Besides, the specific siRNA of HEIH (siHEIH) and pcDNA3.1-HEIH plasmid transfection were utilized to alter the expression of HEIH in the cells and investigate the effects of HEIH on resistance to PTX in endometrial cancer cells. Moreover, MTT, colony formation and apoptosis analysis were taken advantage to evaluate cell viability and proliferation when treated with PTX. Then, differential genes in PTX-resistant and HEIH-knock-down PTX-resistant endometrial cancer cells were screened out by microarray analysis. Finally, gene-set enrichment analysis was used to predict the promising signaling pathway of HEIH and western blotting analysis were performed to verify the relevant genes expression of MAPK signaling pathway. LncRNA HEIH, the dysregulation of which involved in production of drug-resistance, was overexpressed in PTX-resistant endometrial cancer cells. Up-regulating HEIH would activate MAPK pathway, promote chemo-resistance of endometrial cancer cells and enhance cell proliferation and viability, whereas silencing HEIH depressed the MAPK signaling pathway, contributed to restoring chemo-sensitivity to PTX and repressed cell physiological process. Down-regulating lncRNA HEIH expression reversed the PTX-resistance of endometrial cancer cells through MAPK signaling pathway.
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Affiliation(s)
- Jun-Liang Guo
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, No.20 Section 3, Renmin South Road, Chengdu City, 610041, Sichuan, People's Republic of China
| | - Tian Tang
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, No.20 Section 3, Renmin South Road, Chengdu City, 610041, Sichuan, People's Republic of China
| | - Jin-Hong Li
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, No.20 Section 3, Renmin South Road, Chengdu City, 610041, Sichuan, People's Republic of China
| | - Yi-Hong Yang
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, No.20 Section 3, Renmin South Road, Chengdu City, 610041, Sichuan, People's Republic of China
| | - Long Zhang
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, No.20 Section 3, Renmin South Road, Chengdu City, 610041, Sichuan, People's Republic of China
| | - Yi Quan
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, No.20 Section 3, Renmin South Road, Chengdu City, 610041, Sichuan, People's Republic of China.
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11
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LncRNA HEIH regulates cell proliferation and apoptosis through miR-4458/SOCS1 axis in triple-negative breast cancer. Hum Cell 2019; 32:522-528. [DOI: 10.1007/s13577-019-00273-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 08/05/2019] [Indexed: 12/24/2022]
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12
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Höflmayer D, Willich C, Hube-Magg C, Simon R, Lang D, Neubauer E, Jacobsen F, Hinsch A, Luebke AM, Tsourlakis MC, Huland H, Graefen M, Haese A, Heinzer H, Minner S, Büscheck F, Sauter G, Schlomm T, Steurer S, Clauditz TS, Burandt E, Wilczak W, Bernreuther C. SNW1 is a prognostic biomarker in prostate cancer. Diagn Pathol 2019; 14:33. [PMID: 31043167 PMCID: PMC6495565 DOI: 10.1186/s13000-019-0810-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 04/11/2019] [Indexed: 12/16/2022] Open
Abstract
Background SNW1 is a nuclear receptor co-activator involved in splicing and transcription control, including androgen receptor signaling. Overexpression of SNW1 has been linked to adverse prognosis in different cancer types, but studies on the role of SNW1 in prostate cancer are lacking. Methods Using immunohistochemistry, we analyzed SNW1 expression in 10,310 prostate cancers in a tissue microarray (TMA) with attached clinical and molecular data. Results The comparison with normal prostate tissue revealed an up regulation of SNW1 in a subset of cancer samples. SNW1 staining was considered weak in 31.5%, moderate in 37.7% and strong in 14% of cancers. Strong SNW1 expression was markedly more frequent in prostate cancers harboring the TMPRSS2:ERG fusion (24%) than in ERG negative cancers (7%, p < 0.0001). Significant associations with Gleason grade, stage, nodal status and early biochemical recurrence were observed in the ERG negative and positive subset. Multivariable modeling revealed that the prognostic value of SNW1 up regulation was independent from the established preoperative histopathological and clinical parameters. Conclusion These results demonstrate that SNW1 overexpression is an independent prognostic marker in prostate cancer with potential clinical utility. Electronic supplementary material The online version of this article (10.1186/s13000-019-0810-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Carla Willich
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany.
| | - Dagmar Lang
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Emily Neubauer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Marie Christina Tsourlakis
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Hartwig Huland
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Markus Graefen
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Alexander Haese
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Hans Heinzer
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Thorsten Schlomm
- Department of Urology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, D-10117, Berlin, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
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13
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Lin HY, Callan CY, Fang Z, Tung HY, Park JY. Interactions of PVT1 and CASC11 on Prostate Cancer Risk in African Americans. Cancer Epidemiol Biomarkers Prev 2019; 28:1067-1075. [PMID: 30914434 DOI: 10.1158/1055-9965.epi-18-1092] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 01/09/2019] [Accepted: 03/21/2019] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND African American (AA) men have a higher risk of developing prostate cancer than white men. SNPs are known to play an important role in developing prostate cancer. The impact of PVT1 and its neighborhood genes (CASC11 and MYC) on prostate cancer risk are getting more attention recently. The interactions among these three genes associated with prostate cancer risk are understudied, especially for AA men. The objective of this study is to investigate SNP-SNP interactions in the CASC11-MYC-PVT1 region associated with prostate cancer risk in AA men. METHODS We evaluated 205 SNPs using the 2,253 prostate cancer patients and 2,423 controls and applied multiphase (discovery-validation) design. In addition to SNP individual effects, SNP-SNP interactions were evaluated using the SNP Interaction Pattern Identifier, which assesses 45 patterns. RESULTS Three SNPs (rs9642880, rs16902359, and rs12680047) and 79 SNP-SNP pairs were significantly associated with prostate cancer risk. These two SNPs (rs16902359 and rs9642880) in CASC11 interacted frequently with other SNPs with 56 and 9 pairs, respectively. We identified the novel interaction of CASC11-PVT1, which is the most common gene interaction (70%) in the top 79 pairs. Several top SNP interactions have a moderate to large effect size (OR, 0.27-0.68) and have a higher prediction power to prostate cancer risk than SNP individual effects. CONCLUSIONS Novel SNP-SNP interactions in the CASC11-MYC-PVT1 region have a larger impact than SNP individual effects on prostate cancer risk in AA men. IMPACT This gene-gene interaction between CASC11 and PVT1 can provide valuable information to reveal potential biological mechanisms of prostate cancer development.
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Affiliation(s)
- Hui-Yi Lin
- Biostatistics Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
| | - Catherine Y Callan
- Biostatistics Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Zhide Fang
- Biostatistics Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Heng-Yuan Tung
- Biostatistics Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Jong Y Park
- Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, Florida
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14
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Schroeder C, Grell J, Hube-Magg C, Kluth M, Lang D, Simon R, Höflmayer D, Minner S, Burandt E, Clauditz TS, Büscheck F, Jacobsen F, Huland H, Graefen M, Schlomm T, Sauter G, Steurer S. Aberrant expression of the microtubule-associated protein tau is an independent prognostic feature in prostate cancer. BMC Cancer 2019; 19:193. [PMID: 30823906 PMCID: PMC6397474 DOI: 10.1186/s12885-019-5390-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 02/20/2019] [Indexed: 12/30/2022] Open
Abstract
Background Microtubule-associated protein Tau (MAPT) overexpression has been linked to poor prognosis and decreased response to taxane-based therapies in several cancer types, but its relevance in prostate cancer is unknown. Methods In this study, MAPT expression was analyzed by immunohistochemistry on a tissue microarray containing 17,747 prostate cancers. Results MAPT was absent in normal prostate epithelial cells but detectable in 1004 (8.2%) of 12,313 interpretable cancers. Its expression was associated with advanced tumor stage, high Gleason grade, positive lymph nodes, and early biochemical recurrence (p < 0.0001 each). For example, MAPT was found in 3.6% of 2072 Gleason ≤3 + 3 cancers but in 14.4% of 704 Gleason ≥4 + 4 cancers. High-level MAPT staining was also linked to TMPRSS2:ERG fusions (p < 0.0001). MAPT staining was seen in 15.2 and 16% of cancers with TMPRSS2:ERG fusion detected by immunohistochemistry and fluorescence in-situ hybridization, but in only 3.5 and 3.9% of cancers without ERG staining or ERG rearrangements. Moreover, an association was found between MAPT expression and PTEN deletions, with 19% MAPT positivity in 948 PTEN deleted cancers but only 7% MAPT positivity in 3895 tumors with normal PTEN copy numbers (p < 0.0001). Multivariate analysis revealed that the prognostic value of MAPT was independent from established parameters. Conventional large section analyses showed intratumoral MAPT heterogeneity in all three analyzed cancers. Conclusions The results of our study identify MAPT, as a moderate prognostic marker in prostate cancer, whose clinical impact, however, may be limited due to the rarity and heterogeneity of its expression. Electronic supplementary material The online version of this article (10.1186/s12885-019-5390-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Cornelia Schroeder
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Jan Grell
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Dagmar Lang
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany.
| | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Hartwig Huland
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Markus Graefen
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Thorsten Schlomm
- Department of Urology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, D-10117, Berlin, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany
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15
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MicroRNA-1205, encoded on chromosome 8q24, targets EGLN3 to induce cell growth and contributes to risk of castration-resistant prostate cancer. Oncogene 2019; 38:4820-4834. [PMID: 30808975 PMCID: PMC6565506 DOI: 10.1038/s41388-019-0760-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 01/06/2019] [Accepted: 02/12/2019] [Indexed: 12/27/2022]
Abstract
The chromosome 8q24.21 locus, which contains the proto-oncogene c-MYC, long non-coding RNA PVT1, and microRNAs (miRs), is the most commonly amplified region in human prostate cancer. A long-range interaction of genetic variants with c-MYC or long non-coding PVT1 at this locus contributes to the genetic risk of prostate cancer. At this locus is a cluster of genes for six miRs (miR-1204, −1205, −1206, −1207–3p, −1207–5p, and −1208), but their functional role remains elusive. Here, the copy numbers and expressions of miRs-1204~1208 were investigated using quantitative PCR for prostate cancer cell lines and primary tumors. The data revealed that copy numbers and expression of miR-1205 were increased in both castration-resistant prostate cancer cell lines and in primary tumors. In castration-resistant prostate cancer specimens, the copy number at the miR-1205 locus correlated with expression of miR-1205. Furthermore, functional analysis with an miR-1205 mimic, an miR-1205 inhibitor, and CRISPR/Cas9 knockout revealed that, in human prostate cancer cells, miR-1205 promoted cell proliferation and cell cycle progression and inhibited hydrogen peroxide-induced apoptosis. In these cells, miR-1205 downregulated expression of the Egl-9 family hypoxia inducible factor 3 (EGLN3) gene and targeted a site in its 3’-untranslated region to downregulate its transcriptional activity. Thus, by targeting EGLN3, miR-1205 has an oncogenic role and may contribute to the genetic risk of castration-resistant prostate cancer.
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16
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Zheng X, Zhao K, Liu T, Liu L, Zhou C, Xu M. Long noncoding RNA PVT1 promotes laryngeal squamous cell carcinoma development by acting as a molecular sponge to regulate miR-519d-3p. J Cell Biochem 2018; 120:3911-3921. [PMID: 30304557 DOI: 10.1002/jcb.27673] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/21/2018] [Indexed: 12/30/2022]
Abstract
OBJECTIVE This study was designed to investigate the effects and mechanism of long noncoding RNA (lncRNA) PVT1 on cell migration, proliferation, and apoptosis of laryngeal squamous cell carcinoma (LSCC). METHODS We screened lncRNAs expression profiles in four pair LSCC and matched noncancerous tissues by microarray assay. The messenger RNA levels of PVT1 in tissues and cells were evaluated by quantitative real-time polymerase chain reaction analysis. StarBase website was used to predict the target miRNAs for PVT1. And the interaction between PVT1 and target miRNA-519d-3p in LSCC cells was analyzed using dual-luciferase reporter assay. MTT assay was used to investigate the cell viability. Cell counting assay was used to explore the cell proliferation. Annexin-V propidium iodide flow cytometry was used to examine the cell apoptosis, and transwell assay was used to investigate the effects of lncRNA PVT1 on cell migration. RESULTS PVT1 was significantly overexpressed in human LSCC tissues and several LSCC cell lines. Upregulation of lncRNA PVT1 markedly facilitated proliferation suppressed apoptosis and promoted cell migration in LSCC cells. We further demonstrated that silencing PVT1 strikingly suppressed proliferation, promoted apoptosis, and reduced migration in LSCC cells. Further bioinformatic analysis and dual-luciferase reporter assay revealed that PVT1 could function as an oncogenic transcript partly through sponging miR-519d-3p. Besides, mechanistic investigations indicated that PVT1 could promote cell and migration through interacting with miR-519d-3p. CONCLUSION LncRNA PVT1 is consistently overexpressed in human LSCC, and overexpression of lncRNA PVT1 contributes to the proliferation and migration of LSCC through inhibiting miR-519d-3p expression.
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Affiliation(s)
- Xiling Zheng
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Kang Zhao
- Department of Otorhinolaryngology Head and Neck Surgery, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Tao Liu
- Department of General Surgery, Yan'an University Affiliated Hospital, Yan'an, Shaanxi, China
| | - Lei Liu
- Department of General Surgery, Yan'an University Affiliated Hospital, Yan'an, Shaanxi, China
| | - Changming Zhou
- Department of Otorhinolaryngology Head and Neck Surgery, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Min Xu
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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17
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Dias A, Kote-Jarai Z, Mikropoulos C, Eeles R. Prostate Cancer Germline Variations and Implications for Screening and Treatment. Cold Spring Harb Perspect Med 2018; 8:a030379. [PMID: 29101112 PMCID: PMC6120689 DOI: 10.1101/cshperspect.a030379] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Prostate cancer (PCa) is a highly heritable disease, and rapid evolution of sequencing technologies has enabled marked progression of our understanding of its genetic inheritance. A complex polygenic model that involves common low-penetrance susceptibility alleles causing individually small but cumulatively significant risk and rarer genetic variants causing greater risk represent the current most accepted model. Through genome-wide association studies, more than 100 single-nucleotide polymorphisms (SNPs) associated with PCa risk have been identified. Consistent reports have identified germline mutations in the genes BRCA1, BRCA2, MMR, HOXB13, CHEK2, and NBS1 as conferring moderate risks, with some leading to a more aggressive disease behavior. Considering this knowledge, several research strategies have been developed to determine whether targeted prostate screening using genetic information can overcome the limitations of population-based prostate-specific antigen (PSA) screening. Germline DNA-repair mutations are more frequent in men with metastatic disease than previously thought, and these patients have a more favorable response to therapy with poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors. Genomic information is a practical tool that has the potential to enable the concept of precision medicine to become a reality in all steps of PCa patient care.
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Affiliation(s)
- Alexander Dias
- The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom
- The Institute of Cancer Research and Royal Marsden National Health Service (NHS) Foundation Trust, Academic Urology Unit and The Oncogenetics Team, London SW3 6JJ, United Kingdom
| | - Zsofia Kote-Jarai
- The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom
| | | | - Ros Eeles
- The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom
- The Institute of Cancer Research and Royal Marsden National Health Service (NHS) Foundation Trust, Academic Urology Unit and The Oncogenetics Team, London SW3 6JJ, United Kingdom
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18
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Bawa PS, Ravi S, Paul S, Chaudhary B, Srinivasan S. A novel molecular mechanism for a long non-coding RNA PCAT92 implicated in prostate cancer. Oncotarget 2018; 9:32419-32434. [PMID: 30197753 PMCID: PMC6126693 DOI: 10.18632/oncotarget.25940] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 07/18/2018] [Indexed: 11/25/2022] Open
Abstract
The role of many lncRNAs in cancer remains elusive including that for a Prostate Cancer Associated Transcript 92 (PCAT92). PCAT92 shares the locus on chromosome 13 with ABCC4 gene, known to be implicated in prostate cancer. It has been shown that PCAT92 and ABCC4 are up-regulated in prostate cancer samples from multiple transcriptome datasets. Among the prostate cancer cell-lines LNCaP showed maximum overexpression of PCAT92 compared to control cell-line RWPE-1. We have shown that knockdown of PCAT92 in LNCaP cells reduces cell viability and proliferation and down-regulates ABCC4 transcript/protein expression. The shared region between PCAT92 and ABCC4 has a binding site for an oncogenic transcription factor (ZIC2) which is also upregulated in the majority of datasets studied here. ZIC2 binding to the predicted ABCC4 promoter has been confirmed using pull-down assay. Interestingly, under PCAT92 knockdown condition, there is a reduction in the ZIC2 binding to ABCC4 promoter indicating the potential involvement of PCAT92 in the recruitment of ZIC2. We have identified distinct regions on PCAT92 with potential to bind to ZIC2 non-DNA binding Zinc-finger domain and potential for triplex formation near ABCC4 promoter region, which have been experimentally validated. Together, these observations and localization in the nucleus suggests that PCAT92 may play a role in prostate cancer by increasing the local concentration of ZIC2 by forming RNA-DNA triplex near ABCC4 promoter thus helping in recruitment of ZIC2 for ABCC4 regulation.
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Affiliation(s)
- Pushpinder Singh Bawa
- Institute of Bioinformatics and Applied Biotechnology, Biotech Park, Electronic City Phase I, Bangalore, India.,Manipal University, Manipal, Karnataka, India
| | - Samathmika Ravi
- Institute of Bioinformatics and Applied Biotechnology, Biotech Park, Electronic City Phase I, Bangalore, India
| | - Swagatika Paul
- Institute of Bioinformatics and Applied Biotechnology, Biotech Park, Electronic City Phase I, Bangalore, India
| | - Bibha Chaudhary
- Institute of Bioinformatics and Applied Biotechnology, Biotech Park, Electronic City Phase I, Bangalore, India
| | - Subhashini Srinivasan
- Institute of Bioinformatics and Applied Biotechnology, Biotech Park, Electronic City Phase I, Bangalore, India
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19
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Wan B, Wu HY, Lv DJ, Zhou XM, Zhong LR, Lei B, Zhang SB, Mao XM. Downregulation of lncRNA PVT1 expression inhibits proliferation and migration by regulating p38 expression in prostate cancer. Oncol Lett 2018; 16:5160-5166. [PMID: 30250582 PMCID: PMC6144883 DOI: 10.3892/ol.2018.9305] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Accepted: 06/26/2018] [Indexed: 12/22/2022] Open
Abstract
Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) has been reported to be overexpressed in prostate cancer cells and associated with tumorigenesis in various types of cancer. However, the biological function of lncRNA PVT1 remains largely unknown. The aim of the present study was to investigate the effect of lncRNA PVT1 expression on the proliferation and migration of prostate cancer cells. Stably transfected prostate cancer cells with downregulated expression of lncRNA PVT1 were constructed by an efficient siRNA fragment, followed by confirmation by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Proliferation was assessed using CCK-8, colony formation and xenograft assays, and cell migration was evaluated using a wound healing assay. The PathScan® Intracellular Signaling Array kit was utilized to explore the underlying molecular mechanisms of lncRNA PVT1 expression in prostate cancer cells. RT-qPCR results confirmed that the lncRNA PVT1 expression level was successfully knocked down in prostate cancer cells. When lncRNA PVT1 expression was downregulated in prostate cancer cells, proliferation and migration were significantly inhibited, compared with the control lncRNA PVT1 group. Furthermore, PVT1 knockdown decreased the phosphorylation of p38 in DU145 cells. Therefore, the present study demonstrated that lncRNA PVT1 downregulation inhibits the proliferation and migration of prostate cancer cells, and is associated with p38 phosphorylation.
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Affiliation(s)
- Bo Wan
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Hua-Yan Wu
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Dao-Jun Lv
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xu-Min Zhou
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Li-Ren Zhong
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Bin Lei
- Department of Urology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Shou-Bo Zhang
- Center for Reproductive Medicine, The Guangdong Armed Police Hospital, The Guangzhou Medical University, Guangzhou, Guangdong 510507, P.R. China
| | - Xiang-Ming Mao
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.,Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
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20
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Yang L, Xie N, Huang J, Huang H, Xu S, Wang Z, Cai J. SIK1-LNC represses the proliferative, migrative, and invasive abilities of lung cancer cells. Onco Targets Ther 2018; 11:4197-4206. [PMID: 30050311 PMCID: PMC6056170 DOI: 10.2147/ott.s165278] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Discussions regarding the correlations between long non-coding RNAs (lncRNAs) and cancers have dominated research in recent years. SIK1-LNC, a type of lncRNA and adjacent to salt-inducible kinases 1 (SIK1), has been found aberrantly expressed in lung cancer. However, its functional role in lung cancer remains largely unknown. Purpose In this study, we aimed to explore the association between SIK1-LNC expression and SIK1 in lung cancer cells and further identify the impact of SIK1-LNC on the proliferation, migration invasion of lung cancer cells. Patients and methods Of the 30 patients with non-small-cell lung carcinoma from Zhongnan Hospital of Wuhan University, RT-qPCR was performed to detect SIK1 and SIK1-LNC expressions in patients’ samples. Overexpression and knockdown experiments were conducted to analyze the SIK1 and SIK1-LNC expressions in lung cancer cell lines. CCK-8, Brdu, scratch wound-healing, and Transwell assays were respectively employed to evaluate the proliferative, migrative, and invasive abilities of lung cancer cells. Results Both SIK1-LNC and SIK1 expression levels were evidently downregulated in 30 lung cancer tissues. SIK1-LNC expression was bound up with clinicopathologic features, including lymph node metastasis and distant metastasis. SIK1 expression showed a positive tendency with SIK1-LNC expression in lung cancer cells. SIK1-LNC exerted a significant repression on cell proliferatiive, miogrative and invasive abilities of lung cancer cells. Conclusion Our findings suggested that SIK1-LNC may act as a novel biomarker and therapeutic target for lung cancer.
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Affiliation(s)
- Liu Yang
- Department of Cancer Biotherapy Center, Hubei Cancer Hospital, Wuhan 430079, Hubei, People's Republic of China
| | - Nianlin Xie
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, Shaanxi, People's Republic of China
| | - Jingyu Huang
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, People's Republic of China
| | - Hu Huang
- Department of Oncology, The 161th Hospital of PLA, Wuhan, Hubei 430010, People's Republic of China,
| | - Shaogan Xu
- Department of Thoracic Surgery, The 161th Hospital of PLA, Wuhan, Hubei 430010, People's Republic of China
| | - Zhigang Wang
- Department of Oncology, The 161th Hospital of PLA, Wuhan, Hubei 430010, People's Republic of China,
| | - Jun Cai
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei, People's Republic of China,
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21
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Majewska M, Lipka A, Paukszto L, Jastrzebski JP, Gowkielewicz M, Jozwik M, Majewski MK. Preliminary RNA-Seq Analysis of Long Non-Coding RNAs Expressed in Human Term Placenta. Int J Mol Sci 2018; 19:ijms19071894. [PMID: 29954144 PMCID: PMC6073670 DOI: 10.3390/ijms19071894] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 06/24/2018] [Indexed: 12/20/2022] Open
Abstract
Development of particular structures and proper functioning of the placenta are under the influence of sophisticated pathways, controlled by the expression of substantial genes that are additionally regulated by long non-coding RNAs (lncRNAs). To date, the expression profile of lncRNA in human term placenta has not been fully established. This study was conducted to characterize the lncRNA expression profile in human term placenta and to verify whether there are differences in the transcriptomic profile between the sex of the fetus and pregnancy multiplicity. RNA-Seq data were used to profile, quantify, and classify lncRNAs in human term placenta. The applied methodology enabled detection of the expression of 4463 isoforms from 2899 annotated lncRNA loci, plus 990 putative lncRNA transcripts from 607 intergenic regions. Those placentally expressed lncRNAs displayed features such as shorter transcript length, longer exon length, fewer exons, and lower expression levels compared to messenger RNAs (mRNAs). Among all placental transcripts, 175,268 were classified as mRNAs and 15,819 as lncRNAs, and 56,727 variants were discovered within unannotated regions. Five differentially expressed lncRNAs (HAND2-AS1, XIST, RP1-97J1.2, AC010084.1, TTTY15) were identified by a sex-bias comparison. Splicing events were detected within 37 genes and 4 lncRNA loci. Functional analysis of cis-related potential targets for lncRNAs identified 2021 enriched genes. It is presumed that the obtained data will expand the current knowledge of lncRNAs in placenta and human non-coding catalogs, making them more contemporary and specific.
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Affiliation(s)
- Marta Majewska
- Department of Human Physiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland.
| | - Aleksandra Lipka
- Department of Gynecology and Obstetrics, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-045 Olsztyn, Poland.
| | - Lukasz Paukszto
- Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland.
| | - Jan Pawel Jastrzebski
- Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland.
| | - Marek Gowkielewicz
- Department of Gynecology and Obstetrics, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-045 Olsztyn, Poland.
| | - Marcin Jozwik
- Department of Gynecology and Obstetrics, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-045 Olsztyn, Poland.
| | - Mariusz Krzysztof Majewski
- Department of Human Physiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland.
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22
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daSilva LF, Beckedorff FC, Ayupe AC, Amaral MS, Mesel V, Videira A, Reis EM, Setubal JC, Verjovski-Almeida S. Chromatin Landscape Distinguishes the Genomic Loci of Hundreds of Androgen-Receptor-Associated LincRNAs From the Loci of Non-associated LincRNAs. Front Genet 2018; 9:132. [PMID: 29875794 PMCID: PMC5985396 DOI: 10.3389/fgene.2018.00132] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 04/03/2018] [Indexed: 11/30/2022] Open
Abstract
Cell signaling events triggered by androgen hormone in prostate cells is dependent on activation of the androgen receptor (AR) transcription factor. Androgen hormone binding to AR promotes its displacement from the cytoplasm to the nucleus and AR binding to DNA motifs, thus inducing activatory and inhibitory transcriptional programs through a complex regulatory mechanism not yet fully understood. In this work, we performed RNA-seq deep-sequencing of LNCaP prostate cancer cells and found over 7000 expressed long intergenic non-coding RNAs (lincRNAs), of which ∼4000 are novel lincRNAs, and 258 lincRNAs have their expression activated by androgen. Immunoprecipitation of AR, followed by large-scale sequencing of co-immunoprecipitated RNAs (RIP-Seq) has identified in the LNCaP cell line a total of 619 lincRNAs that were significantly enriched (FDR < 10%, DESeq2) in the anti-Androgen Receptor (antiAR) fraction in relation to the control fraction (non-specific IgG), and we named them Androgen-Receptor-Associated lincRNAs (ARA-lincRNAs). A genome-wide analysis showed that protein-coding gene neighbors to ARA-lincRNAs had a significantly higher androgen-induced change in expression than protein-coding genes neighboring lincRNAs not associated to AR. To find relevant epigenetic signatures enriched at the ARA-lincRNAs’ transcription start sites (TSSs) we used a machine learning approach and identified that the ARA-lincRNA genomic loci in LNCaP cells are significantly enriched with epigenetic marks that are characteristic of in cis enhancer RNA regulators, and that the H3K27ac mark of active enhancers is conspicuously enriched at the TSS of ARA-lincRNAs adjacent to androgen-activated protein-coding genes. In addition, LNCaP topologically associating domains (TADs) that comprise chromatin regions with ARA-lincRNAs exhibit transcription factor contents, epigenetic marks and gene transcriptional activities that are significantly different from TADs not containing ARA-lincRNAs. This work highlights the possible involvement of hundreds of lincRNAs working in synergy with the AR on the genome-wide androgen-induced gene regulatory program in prostate cells.
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Affiliation(s)
- Lucas F daSilva
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.,Laboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, Brazil
| | - Felipe C Beckedorff
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.,Laboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, Brazil
| | - Ana C Ayupe
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Murilo S Amaral
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.,Laboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, Brazil
| | - Vinícius Mesel
- Laboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, Brazil
| | - Alexandre Videira
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.,Laboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, Brazil
| | - Eduardo M Reis
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - João C Setubal
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.,Biocomplexity Institute of Virginia Tech, Blacksburg, VA, United States
| | - Sergio Verjovski-Almeida
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.,Laboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo, Brazil
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23
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Zhou DD, Liu XF, Lu CW, Pant OP, Liu XD. Long non-coding RNA PVT1: Emerging biomarker in digestive system cancer. Cell Prolif 2017; 50. [PMID: 29027279 DOI: 10.1111/cpr.12398] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 09/22/2017] [Indexed: 12/19/2022] Open
Abstract
The digestive system cancers are leading cause of cancer-related death worldwide, and have high risks of morbidity and mortality. More and more long non-coding RNAs (lncRNAs) have been studied to be abnormally expressed in cancers and play a key role in the process of digestive system tumour progression. Plasmacytoma variant translocation 1 (PVT1) seems fairly novel. Since 1984, PVT1 was identified to be an activator of MYC in mice. Its role in human tumour initiation and progression has long been a subject of interest. The expression of PVT1 is elevated in digestive system cancers and correlates with poor prognosis. In this review, we illustrate the various functions of PVT1 during the different stages in the complex process of digestive system tumours (including oesophageal cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma and pancreatic cancer). The growing evidence shows the involvement of PVT1 in both proliferation and differentiation process in addition to its involvement in epithelial to mesenchymal transition (EMT). These findings lead us to conclude that PVT1 promotes proliferation, survival, invasion, metastasis and drug resistance in digestive system cancer cells. We will also discuss PVT1's potential in diagnosis and treatment target of digestive system cancer. There was a great probability PVT1 could be a novel biomarker in screening tumours, prognosis biomarkers and future targeted therapy to improve the survival rate in cancer patients.
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Affiliation(s)
- Dan-Dan Zhou
- Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun, China.,Department of Radiology, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiu-Fen Liu
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Cheng-Wei Lu
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Om Prakash Pant
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiao-Dong Liu
- Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun, China
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24
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An androgen reduced transcript of LncRNA GAS5 promoted prostate cancer proliferation. PLoS One 2017; 12:e0182305. [PMID: 28771526 PMCID: PMC5542543 DOI: 10.1371/journal.pone.0182305] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 07/16/2017] [Indexed: 02/04/2023] Open
Abstract
Prostate cancer (PCa) becomes a leading cause of death in males nowadays. Recent reports showed that androgen-responsive long non-coding RNAs played important roles in tumorigenesis and progression of PCa. In this study, we focused on a special transcript of GAS5 (ENST00000456293.5, GAS5-007), which was reported as a tumor suppressor. Here, we demonstrated GAS5-007 was reduced by androgen treatment and inhibited by AR. Next, we explored the expression level of GAS, finding the expression of it in PCa tissue was higher than normal tissue in both public databases and human tissue samples. Functional analysis of GAS5 showed it was related to regulating translational elongation, protein biosynthesis, and transcription. Moreover, we observed GAS5-007 knockdown inhibited the proliferation, cell cycle and promoted cell apoptosis of PCa. We also constructed a GAS5-miRNA network to explain the different roles of different GAS5 transcripts in PCa. This study provides novel insights to identify potential diagnostic biomarker and therapy target for prostate cancer in clinical treatment.
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25
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江 海, 李 平, 张 梅, 张 锋, 苏 丽. RNA-Seq技术及其在胃肠肿瘤研究中的应用现状. Shijie Huaren Xiaohua Zazhi 2017; 25:1564-1571. [DOI: 10.11569/wcjd.v25.i17.1564] [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
转录组是特定的细胞或组织在特定的时间或状态下转录出来的RNA集合, 转录组研究能够从整体水平研究基因功能以及基因结构, 并能很好的显示处于表达状态的基因数量和活跃程度. 作为转录组学新一代高通量测序技术之一, RNA-Seq技术能够更为快速、准确地为人们提供更多的生物体转录信息, 在生物医学研究中已经得到广泛应用. 随着全球胃肠肿瘤发病率的逐年提高, RNA-Seq技术在胃肠肿瘤研究领域进行全转录组测序分析的应用越来越多, 并取得了一些新的进展. 本文将就RNA-Seq技术原理、优势及其在胃肠肿瘤研究中的具体应用进行论述.
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26
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Structural variants caused by Alu insertions are associated with risks for many human diseases. Proc Natl Acad Sci U S A 2017; 114:E3984-E3992. [PMID: 28465436 DOI: 10.1073/pnas.1704117114] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Interspersed repeat sequences comprise much of our DNA, although their functional effects are poorly understood. The most commonly occurring repeat is the Alu short interspersed element. New Alu insertions occur in human populations, and have been responsible for several instances of genetic disease. In this study, we sought to determine if there are instances of polymorphic Alu insertion variants that function in a common variant, common disease paradigm. We cataloged 809 polymorphic Alu elements mapping to 1,159 loci implicated in disease risk by genome-wide association study (GWAS) (P < 10-8). We found that Alu insertion variants occur disproportionately at GWAS loci (P = 0.013). Moreover, we identified 44 of these Alu elements in linkage disequilibrium (r2 > 0.7) with the trait-associated SNP. This figure represents a >20-fold increase in the number of polymorphic Alu elements associated with human phenotypes. This work provides a broader perspective on how structural variants in repetitive DNAs may contribute to human disease.
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27
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Novel Nine-Exon AR Transcripts (Exon 1/Exon 1b/Exons 2-8) in Normal and Cancerous Breast and Prostate Cells. Int J Mol Sci 2016; 18:ijms18010040. [PMID: 28035996 PMCID: PMC5297675 DOI: 10.3390/ijms18010040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 12/08/2016] [Accepted: 12/20/2016] [Indexed: 12/12/2022] Open
Abstract
Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2-8 but differ in exon 1 with the canonical exon 1 in isoform 1 and the variant exon 1b in isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b. Moreover, we identified AR transcripts in both normal and cancerous breast and prostate cells that contained either exon 1b or 1b/TAG spliced between the canonical exon 1 and exon 2, generating nine-exon AR transcripts that we have named isoforms 3a and 3b. The proteins encoded by these new AR variants could regulate androgen-responsive reporters in breast and prostate cancer cells under androgen-depleted conditions. Analysis of type 3 AR-GFP fusion proteins showed partial nuclear localization in PC3 cells under androgen-depleted conditions, supporting androgen-independent activation of the AR. Type 3 AR proteins inhibited androgen-induced growth of LNCaP cells. Microarray analysis identified a small set of type 3a AR target genes in LNCaP cells, including genes known to modulate growth and proliferation of prostate cancer (PCGEM1, PEG3, EPHA3, and EFNB2) or other types of human cancers (TOX3, ST8SIA4, and SLITRK3), and genes that are diagnostic/prognostic biomarkers of prostate cancer (GRINA3, and BCHE).
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28
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Zhuang C, Li J, Liu Y, Chen M, Yuan J, Fu X, Zhan Y, Liu L, Lin J, Zhou Q, Xu W, Zhao G, Cai Z, Huang W. Tetracycline-inducible shRNA targeting long non-coding RNA PVT1 inhibits cell growth and induces apoptosis in bladder cancer cells. Oncotarget 2015; 6:41194-203. [PMID: 26517688 PMCID: PMC4747399 DOI: 10.18632/oncotarget.5880] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 09/28/2015] [Indexed: 02/05/2023] Open
Abstract
Recent studies show that long non-coding RNAs (lncRNAs) may be significant functional regulators in tumor development, including bladder cancer. Here, we found that PVT1 was upregulated in bladder cancer tissues and cells. Further experiments revealed that PVT1 promoted cell proliferation and suppressed cell apoptosis. Furthermore we also used the emerging technology, synthetic biology, to create tetracycline-inducible small hairpin RNA (shRNA) vectors which silenced PVT1 in a dosage-dependent manner to inhibit the progression of bladder cancer. In conclusion, data suggest that PVT1 could be an oncogene and may be a therapeutic target in bladder cancer. Synthetic "tetracycline-on" switch system can be used to quantitatively control the expression of PVT1 in bladder cancer in response to different concentration of doxycycline to suppress the progression of bladder cancer.
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Affiliation(s)
- Chengle Zhuang
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
- Shantou University Medical College, Shantou 515041, Guangdong Province, People's Republic of China
| | - Jianfa Li
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
- Shantou University Medical College, Shantou 515041, Guangdong Province, People's Republic of China
| | - Yuchen Liu
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
| | - Mingwei Chen
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
- Anhui Medical University, Hefei 230601, Anhui Province, People's Republic of China
| | - Jiancheng Yuan
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
| | - Xing Fu
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
| | - Yonghao Zhan
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
| | - Li Liu
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
| | - Junhao Lin
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
| | - Qing Zhou
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
| | - Wen Xu
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
| | - Guoping Zhao
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Centerat Shanghai, Shanghai 200000, Shanghai, People's Republic of China
| | - Zhiming Cai
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
| | - Weiren Huang
- Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, Shenzhen 518039, Guangdong Province, People's Republic of China
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29
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Kontos CK, Adamopoulos PG, Scorilas A. Prognostic and predictive biomarkers in prostate cancer. Expert Rev Mol Diagn 2015; 15:1567-76. [PMID: 26548550 DOI: 10.1586/14737159.2015.1110022] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Prostate cancer (PCa) is one of the leading causes of cancer death among males, especially in more developed countries. Diagnosis is often achieved at an early stage of the disease with prostate biopsy, following a screening test showing elevated serum levels of prostate-specific antigen or a positive digital rectal examination. Early detection of PCa has led to a substantial decline in the number of metastatic patients. However, the prostate-specific antigen screening test has proved to be a double-edged sword so far, as it also accounts for PCa overdiagnosis. Due to the variability of PCa features, accurate prognosis of PCa patients is very important for determining treatment options. Therefore, this review focuses on the most promising prognostic and predictive biomarkers in PCa, which are likely to play a pivotal role, alone or in panels, in the personalized medicine era that has recently emerged.
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Affiliation(s)
- Christos K Kontos
- a Department of Biochemistry and Molecular Biology , University of Athens , Athens , Greece
| | | | - Andreas Scorilas
- a Department of Biochemistry and Molecular Biology , University of Athens , Athens , Greece
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