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Zhang Y, Ma D, Zhang X, Chen W, Wang X, Sun R, Li K. miR-128-3p Reduces Proliferation and Immune Escape in Acute Myeloid Leukemia Through Targeted Regulation of ZEB1. Appl Biochem Biotechnol 2025:10.1007/s12010-025-05255-8. [PMID: 40381097 DOI: 10.1007/s12010-025-05255-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/02/2025] [Indexed: 05/19/2025]
Abstract
microRNAs have received wide attention as potential therapeutic targets. This study explored the action of miR-128-3p in acute myeloid leukemia (AML). miR-128-3p expression in AML was determined by quantitative PCR method. MTT proliferation assay and immunoblot assay were employed to detect proteins related to proliferation and apoptosis in THP-1 cells overexpressing miR-128-3p. RNA immunoprecipitation and dual luciferase reporting system were utilized to verify downstream targets of miR-128-3p. Flow cytometry was conducted to analyze the apoptosis rate and immune escape of THP-1 cells in the T-cell co-culture system. miR-128-3p was lowly expressed in AML patients (reduced by 41.6%). Overexpression of miR-128-3p inhibited THP-1 cell proliferation and immune escape, and stimulated apoptosis. ZEB1 was a downstream target of miR-128-3p, and up-regulation of miR-128-3p inhibited ZEB1 mRNA and protein expression (respectively reduced by 65.8% and 42.0%). Upregulating ZEB1 reversed the inhibitory effect of upregulating miR-128-3p on THP-1 cell proliferation and immune escape. Upregulating ZEB1 promoted PD-L1 protein expression (increased by 0.75-fold). Blocking PD-L1 reversed the promotion of THP-1 cell proliferation and immune escape by upregulating ZEB1. The miR-128-3p/ZEB1/PD-L1 axis is involved in regulating the proliferation and immune escape of AML cells, providing new insights into the molecular mechanism of miR-128-3p in AML and, more importantly, a new target for immunotherapy of AML.
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Affiliation(s)
- YanBin Zhang
- Department of Hematology, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing City, 100730, China
| | - DanDong Ma
- Department of Inspection Division, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang City, 441000, Hubei Province, China
| | - XiaoJuan Zhang
- Department of Hematology, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing City, 100730, China
| | - WenKun Chen
- Department of Hematology, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing City, 100730, China
| | - XueJiao Wang
- Department of Hematology, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing City, 100730, China
| | - Rui Sun
- Department of Hematology, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing City, 100730, China
| | - KuiXing Li
- Department of Hematology, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing City, 100730, China.
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2
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Israni DK, Patel ML, Dodiya RK. Exploring the versatility of miRNA-128: a comprehensive review on its role as a biomarker and therapeutic target in clinical pathways. Mol Biol Rep 2024; 51:860. [PMID: 39068606 DOI: 10.1007/s11033-024-09822-w] [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: 05/14/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
MicroRNAs (miRNAs/ miRs) are short, noncoding RNAs, usually consisting of 18 to 24 nucleotides, that control gene expression after the process of transcription and have crucial roles in several clinical processes. This article seeks to provide an in-depth review and evaluation of the many activities of miR-128, accentuating its potential as a versatile biomarker and target for therapy; The circulating miR-128 has garnered interest because of its substantial influence on gene regulation and its simplicity in extraction. Several miRNAs, such as miR-128, have been extracted from circulating blood cells, cerebrospinal fluid, and plasma/serum. The miR-128 molecule can specifically target a diverse range of genes, enabling it to have intricate physiological impacts by concurrently regulating many interrelated pathways. It has a vital function in several biological processes, such as modulating the immune system, regulating brain plasticity, organizing the cytoskeleton, and inducing neuronal death. In addition, miR-128 modulates genes associated with cell proliferation, the cell cycle, apoptosis, plasma LDL levels, and gene expression regulation in cardiac development. The dysregulation of miR-128 expression and activity is associated with the development of immunological responses, changes in neural plasticity, programmed cell death, cholesterol metabolism, and heightened vulnerability to autoimmune illnesses, neuroimmune disorders, cancer, and cardiac problems; The paper highlights the importance of studying the consequences of miR-128 dysregulation in these specific locations. By examining the implications of miRNA-128 dysregulation in these areas, the article underscores its significance in diagnosis and treatment, providing a foundation for research and clinical applications.
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Affiliation(s)
- Dipa K Israni
- Department of Pharmacology, L.J. Institute of Pharmacy, LJ University, SG Highway, Sanand Cross-Road, Ahmedabad, Gujarat, 382210, India.
| | - Manish L Patel
- LJ Institute of Pharmacy, LJ University, Ahmedabad, Gujarat, India
| | - Rohinee K Dodiya
- Department of Pharmacology, L.J. Institute of Pharmacy, LJ University, SG Highway, Sanand Cross-Road, Ahmedabad, Gujarat, 382210, India
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3
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Danishuddin, Haque MA, Malik MZ, Arya R, Singh P, Lee JS, Kim JJ, Lee KW, Jung TS. Unveiling the Mechanisms Underlying the Immunotherapeutic Potential of Gene-miRNA and Drugs in Head and Neck Cancer. Pharmaceuticals (Basel) 2024; 17:921. [PMID: 39065771 PMCID: PMC11280033 DOI: 10.3390/ph17070921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/02/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Head and neck cancer ranks as the sixth-most common malignancy worldwide, characterized by high mortality and recurrence rates. Research studies indicate that molecular diagnostics play a crucial role in the early detection and prognostic evaluation of these diseases. This study aimed to identify potential biomarkers for head and neck cancer and elucidate their interactions with miRNAs and possible therapeutic drugs. Four drivers, namely, FN1, IL1A, COL1A1, and MMP9, were identified using network biology and machine learning approaches. Gene set variation analysis (GSVA) showed that these genes were significantly involved in different biological processes and pathways, including coagulation, UV-response-down, apoptosis, NOTCH signaling, Wnt-beta catenin, and other signal pathways. The diagnostic value of these hub genes was validated using receiver operating characteristic (ROC) curves. The top interactive miRNAs, including miR-128-3p, miR-218-5p, miR-214-3p, miR-124-3p, miR-129-2-3p, and miR-1-3p, targeted the key genes. Furthermore, the interaction between the key genes and drugs was also identified. In summary, the key genes and miRNAs or drugs reported in this study might provide valuable information for potential biomarkers to increase the prognosis and diagnosis of head and neck cancer.
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Affiliation(s)
- Danishuddin
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea; (D.); (M.A.H.); (R.A.)
| | - Md Azizul Haque
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea; (D.); (M.A.H.); (R.A.)
| | - Md. Zubbair Malik
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute (DDI), Dasman 15462, Kuwait;
| | - Rakesh Arya
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea; (D.); (M.A.H.); (R.A.)
| | - Pooja Singh
- Division of Applied Life Science (BK21 Four), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU), Jinju 52828, Republic of Korea;
| | - Jeong-Sang Lee
- GSCRO, Research Spin-Off Company, Innopolis Jeonbuk, Jeonju 55069, Republic of Korea;
- Department of Food and Nutrition, College of Medical Science, Jeonju University, Jeonju 55069, Republic of Korea
| | - Jong-Joo Kim
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea; (D.); (M.A.H.); (R.A.)
| | - Keun-Woo Lee
- Korea Quantum Computing (KQC), Busan 48058, Republic of Korea
- Angel i-Drug Design (AiDD), Jinju 52650, Republic of Korea
| | - Tae-Sung Jung
- Laboratory of Aquatic Animal Diseases, Research Institute of Natural Science, College of Veterinary Medicine, Gyeongsang National University (GNU), Jinju 52828, Republic of Korea
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Kozłowska-Masłoń J, Guglas K, Kolenda T, Lamperska K, Makałowska I. miRNA in head and neck squamous cell carcinomas: promising but still distant future of personalized oncology. Rep Pract Oncol Radiother 2023; 28:681-697. [PMID: 38179293 PMCID: PMC10764040 DOI: 10.5603/rpor.96666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 07/24/2023] [Indexed: 01/06/2024] Open
Abstract
Head and neck squamous cell carcinoma is one of the most common and fatal cancers worldwide. Lack of appropriate preventive screening tests, late detection, and high heterogeneity of these tumors are the main reasons for the unsatisfactory effects of therapy and, consequently, unfavorable outcomes for patients. An opportunity to improve the quality of diagnostics and treatment of this group of cancers are microRNAs (miRNAs) - molecules with a great potential both as biomarkers and therapeutic targets. This review aims to present the characteristics of these short non-coding RNAs (ncRNAs) and summarize the current reports on their use in oncology focused on medical strategies tailored to patients' needs.
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Affiliation(s)
- Joanna Kozłowska-Masłoń
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
| | - Kacper Guglas
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Kolenda
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Research and Implementation Unit, Greater Poland Cancer Centre, Poznan, Poland
| | - Katarzyna Lamperska
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Research and Implementation Unit, Greater Poland Cancer Centre, Poznan, Poland
| | - Izabela Makałowska
- Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
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Bhattacharjee B, Syeda AF, Rynjah D, Hussain SM, Chandra Bora S, Pegu P, Sahu RK, Khan J. Pharmacological impact of microRNAs in head and neck squamous cell carcinoma: Prevailing insights on molecular pathways, diagnosis, and nanomedicine treatment. Front Pharmacol 2023; 14:1174330. [PMID: 37205904 PMCID: PMC10188950 DOI: 10.3389/fphar.2023.1174330] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 04/11/2023] [Indexed: 05/21/2023] Open
Abstract
Head and neck squamous cell carcinoma is a disease that most commonly produce tumours from the lining of the epithelial cells of the lips, larynx, nasopharynx, mouth, or oro-pharynx. It is one of the most deadly forms of cancer. About one to two percent of all neo-plasm-related deaths are attributed to head and neck squamous cell carcinoma, which is responsible for about six percent of all cancers. MicroRNAs play a critical role in cell proliferation, differentiation, tumorigenesis, stress response, triggering apoptosis, and other physiological process. MicroRNAs regulate gene expression and provide new diagnostic, prognostic, and therapeutic options for head and neck squamous cell carcinoma. In this work, the role of molecular signaling pathways related to head and neck squamous cell carcinoma is emphasized. We also provide an overview of MicroRNA downregulation and overexpression and its role as a diagnostic and prognostic marker in head and neck squamous cell carcinoma. In recent years, MicroRNA nano-based therapies for head and neck squamous cell carcinoma have been explored. In addition, nanotechnology-based alternatives have been discussed as a promising strategy in exploring therapeutic paradigms aimed at improving the efficacy of conventional cytotoxic chemotherapeutic agents against head and neck squamous cell carcinoma and attenuating their cytotoxicity. This article also provides information on ongoing and recently completed clinical trials for therapies based on nanotechnology.
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Affiliation(s)
| | - Ayesha Farhana Syeda
- Department of Pharmaceutics, Unaiza College of Pharmacy, Qassim University, Unaizah, Saudi Arabia
| | | | - Shalam M. Hussain
- Department of Clinical Pharmacy, College of Nursing and Health Sciences, Al-Rayyan Medical College, Madinah, Saudi Arabia
| | | | - Padmanath Pegu
- Girijananda Chowdhury Institute of Pharmaceutical Science, Tezpur, India
| | - Ram Kumar Sahu
- Department of Pharmaceutical Sciences, Hemvati Nandan Bahuguna Garhwal University (A Central University), Chauras Campus, Tehri Garhwal, Uttarakhand, India
| | - Jiyauddin Khan
- School of Pharmacy, Management and Science University, Shah Alam, Malaysia
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Budi HS, Younus LA, Lafta MH, Parveen S, Mohammad HJ, Al-qaim ZH, Jawad MA, Parra RMR, Mustafa YF, Alhachami FR, Karampoor S, Mirzaei R. The role of miR-128 in cancer development, prevention, drug resistance, and immunotherapy. Front Oncol 2023; 12:1067974. [PMID: 36793341 PMCID: PMC9923359 DOI: 10.3389/fonc.2022.1067974] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/30/2022] [Indexed: 02/03/2023] Open
Abstract
A growing body of evidence has revealed that microRNA (miRNA) expression is dysregulated in cancer, and they can act as either oncogenes or suppressors under certain conditions. Furthermore, some studies have discovered that miRNAs play a role in cancer cell drug resistance by targeting drug-resistance-related genes or influencing genes involved in cell proliferation, cell cycle, and apoptosis. In this regard, the abnormal expression of miRNA-128 (miR-128) has been found in various human malignancies, and its verified target genes are essential in cancer-related processes, including apoptosis, cell propagation, and differentiation. This review will discuss the functions and processes of miR-128 in multiple cancer types. Furthermore, the possible involvement of miR-128 in cancer drug resistance and tumor immunotherapeutic will be addressed.
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Affiliation(s)
- Hendrik Setia Budi
- Department of Oral Biology, Dental Pharmacology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Laith A. Younus
- Department of Clinical Laboratory Sciences, Faculty of Pharmacy, Jabir Ibn, Hayyan Medical University, Al Najaf Al Ashraf, Iraq
| | | | - Sameena Parveen
- Department of Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Jazan University, Jazan, Saudi Arabia
| | | | | | | | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Firas Rahi Alhachami
- Radiology Department, College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Nasiriyah, Iraq
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Mehterov N, Sacconi A, Pulito C, Vladimirov B, Haralanov G, Pazardjikliev D, Nonchev B, Berindan-Neagoe I, Blandino G, Sarafian V. A novel panel of clinically relevant miRNAs signature accurately differentiates oral cancer from normal mucosa. Front Oncol 2022; 12:1072579. [PMID: 36531016 PMCID: PMC9753689 DOI: 10.3389/fonc.2022.1072579] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/09/2022] [Indexed: 08/27/2023] Open
Abstract
INTRODUCTION Although a considerable body of knowledge has been accumulated regarding the early diagnosis and treatment of oral squamous cell carcinoma (OSCC), its survival rates have not improved over the last decades. Thus, deciphering the molecular mechanisms governing oral cancer will support the development of even better diagnostic and therapeutic strategies. Previous studies have linked aberrantly expressed microRNAs (miRNAs) with the development of OSCC. METHODS We combined bioinformatical and molecular methods to identify miRNAs with possible clinical significance as biomarkers in OSCC. A set of 10 miRNAs were selected via an in silico approach by analysing the 3'untranslated regions (3'UTRs) of cancer-related mRNAs such as FLRT2, NTRK3, and SLC8A1, TFCP2L1 and etc. RT-qPCR was used to compare the expression of in silico identified miRNAs in OSCC and normal tissues (n=32). RESULTS Among the screened miRNAs, miR-21-5p (p < 0.0001), miR-93-5p (p < 0.0197), miR-146b-5p (p <0.0012), miR-155-5p (p < 0.0001), miR-182-5p (p < 0.0001) were significantly overexpressed, whereas miR-133b (p < 0.05) was significantly downregulated in OSCC tissues, a scenario confirmed in two additional OSCC validation cohorts: Regina Elena National Cancer Institute (IRE cohort, N=74) and The Cancer Genome Atlas Data Portal (TCGA cohort, N=354). Initial stage tumors (T1, T2) expressed significantly higher levels of miR-133b (p < 0.0004) compared to more advanced ones (T3, T4). Also, we identified miR-93-5p (p < 0.0003), miR-133b (p < 0.0017) and miR-155-5p (p < 0.0004) as correlated with HPV-induced OSCC. The high expression of these 6 miRNAs as a signature predicted shorter disease-free survival (DFS) and could efficiently distinguish OSCC cases from healthy controls with areas under the curve (AUC) of 0.91 with sensitivity and specificity of 0.98 and 0.6, respectively. Further target identification analysis revealed enrichment of genes involved in FOXO, longevity, glycan biosynthesis and p53 cancer-related signaling pathways. Also, the selected targets were underexpressed in OSCC tissues and showed clinical significance related to overall survival (OS) and DFS. DISCUSSION Our results demonstrate that a novel panel consisting of miR-21-5p, miR-93-5p, miR-133b, miR-146b-5p, miR-155-5p and miR-182-5p could be used as OSCC-specific molecular signature with diagnostic and prognostic significance related to OS and DFS.
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Affiliation(s)
- Nikolay Mehterov
- Department of Medical Biology, Medical University-Plovdiv, Plovdiv, Bulgaria
- Research Institute, Medical University-Plovdiv, Plovdiv, Bulgaria
| | - Andrea Sacconi
- UOSD Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Claudio Pulito
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Boyan Vladimirov
- Department of Maxillofacial Surgery, Medical University-Plovdiv, Plovdiv, Bulgaria
| | - Georgi Haralanov
- Department of Maxillofacial Surgery, Medical University-Plovdiv, Plovdiv, Bulgaria
| | | | - Boyan Nonchev
- Department of Endocrinology, Medical University-Plovdiv, Plovdiv, Bulgaria
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Giovanni Blandino
- Translational Oncology Research Unit, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS, Regina Elena National Cancer Institute, Rome, Italy
| | - Victoria Sarafian
- Department of Medical Biology, Medical University-Plovdiv, Plovdiv, Bulgaria
- Research Institute, Medical University-Plovdiv, Plovdiv, Bulgaria
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Wang C, Jiang X, Qi J, Xu J, Yang G, Mi C. PAIP2 is a potential diagnostic and prognostic biomarker of breast cancer and is associated with immune infiltration. Front Genet 2022; 13:1009056. [PMID: 36437922 PMCID: PMC9685164 DOI: 10.3389/fgene.2022.1009056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 10/26/2022] [Indexed: 01/03/2024] Open
Abstract
Breast cancer is the second highest incidence of cancer in the world. It is of great significance to find biomarkers to diagnose breast cancer and predict the prognosis of breast cancer patients. PAIP2 is a poly (A) -binding protein interacting protein that regulates the expression of VEGF. However, the possible role of PAIP2 in the progression of breast cancer is still unknown. RT-qRCR and Western blotting were used to verify the expression of PAIP2 in breast cancer cells and normal breast cells. The data of breast cancer samples were obtained in the TCGA database and the HPA database to analyze the expression of PAIP2 in breast cancer samples. Transwell experiment and CCK8 experiment confirmed the changes in the invasion and proliferation ability of PAIP2 after siRNA was down-regulated. Using bioinformatics technology to explore the prognostic value of PAIP2 and its possible biological function, and its effect on tumor immunity and immunotherapy. Studies have shown that PAIP2 has higher expression in breast cancer tissues and breast cancer cells. PAIP2 can promote the proliferation and invasion of breast cancer cells and has significantly high expression in higher tumor stages. The high expression of PAIP2 is associated with better OS in breast cancer patients and is negatively correlated with most chemotherapeutic drug sensitivity and IPS in cancer immunotherapy. Our study explored the potential value of PAIP2 as a biomarker for diagnosis and prognosis and may predict the efficacy of immunotherapy, providing reference for the follow-up study on the role of PAIP2 in breast cancer.
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Affiliation(s)
- Chenyu Wang
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
- Department of Ultrasound, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Xianglai Jiang
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Jiaojiao Qi
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
- Department of Ultrasound, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Jiachao Xu
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
- Department of Ultrasound, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Guangfei Yang
- Department of Ultrasound, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Chengrong Mi
- Department of Ultrasound, General Hospital of Ningxia Medical University, Yinchuan, China
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9
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Chen X, Liu Y, Liu H, Wang ZW, Zhu X. Unraveling diverse roles of noncoding RNAs in various human papillomavirus negative cancers. Pharmacol Ther 2022; 238:108188. [PMID: 35421419 DOI: 10.1016/j.pharmthera.2022.108188] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/02/2022] [Accepted: 04/07/2022] [Indexed: 12/17/2022]
Abstract
Human papillomavirus (HPV)-negative tumors distinguish from cancers associated with HPV infection. Due to its high rate of lymph node metastasis and difficulty in inchoate discover and diagnosis, the treatment efficacy of HPV-negative cancers is unsatisfactory. Epidemiological evidence suggests that HPV-negative tumor patients have a poor prognosis, and the mortality is higher than that of cancer patients caused by HPV infection. Evidence has demonstrated that noncoding RNAs (ncRNAs) play a crucial role in regulation of physiological and developmental processes. Therefore, dysregulated ncRNAs are involved in the occurrence of diversified diseases, including cancer. In cumulative studies, ncRNAs are concerned with pathogenetic mechanisms of HPV-negative tumors via regulating gene expression and signal transduction. It is important to decipher the functions of ncRNAs in HPV-negative cancers and identify the potential biomarkers, which will bring new treatment strategies for improving outcome of cancer therapy. In this review, we demonstrated the effects of ncRNAs via regulating the development and progression of HPV- negative tumors by directly or indirectly acting on target molecules, which provide a basis for future tumor targeted therapy by targeting ncRNAs for HPV-negative cancers.
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Affiliation(s)
- Xin Chen
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Yi Liu
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Hejing Liu
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Zhi-Wei Wang
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; Department of Research and Development, Beijing Zhongwei Research Center of Biological and Translational Medicine, Beijing 100161, China.
| | - Xueqiong Zhu
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China.
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Druy AE, Tsaur GA, Shorikov EV, Tytgat GAM, Fechina LG. Suppressed miR-128-3p combined with TERT overexpression predicts dismal outcomes for neuroblastoma. Cancer Biomark 2022; 34:661-671. [PMID: 35634846 DOI: 10.3233/cbm-210414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Molecular and clinical diversity of neuroblastomas is notorious. The activating TERT rearrangements have been associated with dismal prognosis. Suppression of miR-128-3p may complement and enhance the adverse effects of TERT overexpression. OBJECTIVE The study aimed at evaluation of prognostic significance of the miR-128-3p/TERT expression in patients with primary neuroblastoma. METHODS RNA samples isolated from fresh-frozen tumor specimens (n= 103) were reverse transcribed for evaluation of miR-128-3p and TERT expression by qPCR. The normalized expression levels were tested for correlations with the event-free survival (EFS). ROC-analysis was used to establish threshold expression levels (TLs) for the possible best prediction of the outcomes. The median follow-up was 57 months. RESULTS Both TERT overexpression and miR-128-3p downregulation were independently associated with superior rates of adverse events (p= 0.027, TL =-2.32 log10 and p= 0.080, TL =-1.33 log10, respectively). The MYCN single-copy patients were stratified into groups based on the character of alterations in expression of the studied transcripts. Five-year EFS in the groups of patients with elevated TERT/normal miR-128-3p expression and normal TERT/reduced miR-128-3p expression were 0.74 ± 0.08 and 0.60 ± 0.16, respectively. The patients with elevated TERT/reduced miR-128-3p expression had the worst outcomes, with 5-year EFS of 0.40 ± 0.16 compared with 0.91 ± 0.06 for the patients with unaltered levels of both transcripts (p< 0.001). Cumulative incidence of relapse/progression for the groups constituted 0.23 ± 0.08, 0.40 ± 0.16, 0.60 ± 0.16 and 0.09 ± 0.06, respectively. Moreover, the loss of miR-128-3p was qualified as independent adverse predictor which outperformed the conventional clinical and genetic risk factors in the multivariate Cox regression model of EFS. CONCLUSIONS Combined expression levels of miR-128-3p and TERT represent a novel prognostic biomarker for neuroblastoma.
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Affiliation(s)
- A E Druy
- Laboratory of Molecular Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation.,Laboratory of the Cellular Therapy of Oncohematological Disorders, Research Institute of Medical Cell Technologies, Yekaterinburg, Russian Federation
| | - G A Tsaur
- Laboratory of the Cellular Therapy of Oncohematological Disorders, Research Institute of Medical Cell Technologies, Yekaterinburg, Russian Federation.,Pediatric Oncology and Hematology Center, Regional Children's Hospital, Yekaterinburg, Russian Federation.,Chair of Laboratory Medicine, Ural State Medical University, Yekaterinburg, Russian Federation
| | - E V Shorikov
- PET-Technology Center of Nuclear Medicine, Yekaterinburg, Russian Federation
| | - G A M Tytgat
- Princess Máxima Centre for Pediatric Oncology (PMC), Utrecht, The Netherlands
| | - L G Fechina
- Laboratory of the Cellular Therapy of Oncohematological Disorders, Research Institute of Medical Cell Technologies, Yekaterinburg, Russian Federation.,Pediatric Oncology and Hematology Center, Regional Children's Hospital, Yekaterinburg, Russian Federation
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11
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Zhou X, He J, Wang Q, Ma T. MiRNA-128-3p Restrains Malignant Melanoma Cell Malignancy by Targeting NTRK3. Front Oncol 2021; 10:538894. [PMID: 33575204 PMCID: PMC7871904 DOI: 10.3389/fonc.2020.538894] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 12/14/2020] [Indexed: 11/13/2022] Open
Abstract
The functions of non-coding RNA, including microRNA (miRNA), have attracted considerable attention in the field of oncology, In this report, we examined the roles and molecular mechanisms of miR-128-3p, as related to the biological behaviors of malignant melanoma (MM). We found that miR-128-3p was expressed in low levels in these MM cells and may serve as a tumor suppressor by inhibiting proliferation, migration, and invasion, as well as inducing apoptosis in these MM cells. Moreover, neurotrophin receptor 3 (NTRK3), which serves as an oncogene that can enhance malignant behaviors of MM cells, was up-regulated in MM cells. Our current survey disclosed a complementary binding between miR-128-3p and the NTRK3 3' untranslated regions (3'-UTR), while luciferase activities of NTRK3 3'-UTR were restrained by miR-128-3p in 293T cells. The effects of pre-miR-128-3p and sh-NTRK3 as well as anti-miR-128-3p and NTRK3(+) appeared to function synergistically in producing malignant progression. Moreover, there were possible to have counteracted effects for pre-miR-128-3p and NTRK3(+) in malignant progression. These findings established that miR-128-3p can function as a tumor suppressor by inhibiting carcinogenesis of the oncogene, NTRK3. Collectively, miR-128-3p and NTRK3 genes participate in modulating the malignant behavior of MM, and may represent new therapeutic targets for MM.
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Affiliation(s)
- Xinxin Zhou
- Academy of Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Jiayuan He
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China
| | - Qingyuan Wang
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China
| | - Teng Ma
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China
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12
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Ghafouri-Fard S, Gholipour M, Taheri M, Shirvani Farsani Z. MicroRNA profile in the squamous cell carcinoma: prognostic and diagnostic roles. Heliyon 2020; 6:e05436. [PMID: 33204886 PMCID: PMC7653070 DOI: 10.1016/j.heliyon.2020.e05436] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 07/27/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are human malignancies associated with both genetic and environmental factors. MicroRNAs (miRNAs) as a group of small non-coding RNAs have prominent roles in the development of this kind of cancer. Expressions of several miRNAs have been demonstrated to be increased in HNSCC samples vs. non-malignant tissues. In silico prediction tools and functional analyses have confirmed the function of some miRNAs in the modulation of cancer-associated targets, thus indicating these miRNAs as onco-miRs. Moreover, numerous miRNAs have been down-regulated in HNSCC samples. Their targets mostly enhance cell proliferation or inhibit apoptosis. miRNAs signature has practical implications in the diagnosis, staging, and management of HNSC. Most notably, numerous miRNAs have been shown to alter response of tumor cells to anti-cancer drugs such as cisplatin and doxorubicin. Circulating levels of these small transcripts have been suggested as promising biomarkers for diagnosis of HNSCC. In the present manuscript, we sum up the available literature regarding the miRNAs signature in HNSCC and their role as diagnostic/prognostic biomarkers.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Gholipour
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zeinab Shirvani Farsani
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Technology, Shahid Beheshti University G.C., Tehran, Iran
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13
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Yao Y, Xu Q, Yan L, Jiao Y, Su Q, Li X, Liu C, Zhao F. MiRNA-128 and MiRNA-142 Regulate Tumorigenesis and EMT in Oral Squamous Cell Carcinoma Through HOXA10. Cancer Manag Res 2020; 12:9987-9997. [PMID: 33116855 PMCID: PMC7567577 DOI: 10.2147/cmar.s250093] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 09/18/2020] [Indexed: 12/16/2022] Open
Abstract
Background Oral squamous cell carcinoma (OSCC) accounts for more than 90% of all oral cavity cancers, and the 5-year survival rate for OSCC patients remains unsatisfactory. MiRNA-128/miRNA-142 has been reported to work as a tumor suppressor in diverse tumors. However, the biological function of miR-128/miR-142 in OSCC is still unknown. Methods The expression of miR-128/miR-142 and homeobox A10 (HOXA10) in OSCC tissues and cells was measured by quantitative real-time polymerase chain reaction (RT-qPCR). The effects of miR-128/miR-142 or HOXA10 on proliferation, migration, invasion and apoptosis were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), transwell and flow cytometry assays, respectively. The expression levels of epithelial–mesenchymal transition (EMT)-associated proteins (E-cadherin, N-cadherin and Vimentin), proliferation-associated protein ki-67 and HOXA10 were detected by Western blot assay. The interaction between HOXA10 and miR-128/miR-142 was predicted by TargetScan, and then confirmed by dual-luciferase reporter assay. Results MiR-128/miR-142 was downregulated in OSCC tissues and cells. Overexpression of miR-128/miR-142 inhibited proliferation, migration, invasion and EMT and induced apoptosis in OSCC cells. HOXA10 as the target of miR-128/miR-142 was verified in OSCC cells. Knockdown of HOXA10 also repressed proliferation, migration, invasion and EMT and boosted apoptosis in OSCC cells. Upregulation of miR-128/miR-142 hindered the expression level of HOXA10, while introduction of HOXA10 weakened the effect. Conclusion MiR-128/miR-142 suppressed OSCC tumorigenesis and metastasis by targeting HOXA10, providing a new promising therapeutic approach for OSCC patient diagnosis and treatment.
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Affiliation(s)
- Yao Yao
- Department of Stomatology, Central Hospital of Taian, Taian, Shandong, People's Republic of China
| | - Qian Xu
- Department of Stomatology, Central Hospital of Taian, Taian, Shandong, People's Republic of China
| | - Liyong Yan
- Department of Stomatology, Central Hospital of Taian, Taian, Shandong, People's Republic of China
| | - Yan Jiao
- Department of Stomatology, Central Hospital of Taian, Taian, Shandong, People's Republic of China
| | - Qingqi Su
- Department of Stomatology, Central Hospital of Taian, Taian, Shandong, People's Republic of China
| | - Xiaoguang Li
- Department of Stomatology, Central Hospital of Taian, Taian, Shandong, People's Republic of China
| | - Cong Liu
- Department of Stomatology, Central Hospital of Taian, Taian, Shandong, People's Republic of China
| | - Feng Zhao
- Department of Stomatology, Central Hospital of Taian, Taian, Shandong, People's Republic of China
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14
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A comprehensive analysis of core polyadenylation sequences and regulation by microRNAs in a set of cancer predisposition genes. Gene 2019; 712:143943. [PMID: 31229581 DOI: 10.1016/j.gene.2019.143943] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 06/18/2019] [Accepted: 06/20/2019] [Indexed: 12/27/2022]
Abstract
Two core polyadenylation elements (CPE) located in the 3' untranslated region of eukaryotic pre-mRNAs play an essential role in their processing: the polyadenylation signal (PAS) AAUAAA and the cleavage site (CS), preferentially a CA dinucleotide. Herein, we characterized PAS and CS sequences in a set of cancer predisposition genes (CPGs) and performed an in silico investigation of microRNAs (miRNAs) regulation to identify potential tumor-suppressive and oncogenic miRNAs. NCBI and alternative polyadenylation databases were queried to characterize CPE sequences in 117 CPGs, including 81 and 17 known tumor suppressor genes and oncogenes, respectively. miRNA-mediated regulation analysis was performed using predicted and validated data sources. Based on NCBI analyses, we did not find an established PAS in 21 CPGs, and verified that the majority of PAS already described (74.4%) had the canonical sequence AAUAAA. Interestingly, "AA" dinucleotide was the most common CS (37.5%) associated with this set of genes. Approximately 90% of CPGs exhibited evidence of alternative polyadenylation (more than one functional PAS). Finally, the mir-192 family was significantly overrepresented as regulator of tumor suppressor genes (P < 0.01), which suggests a potential oncogenic function. Overall, this study provides a landscape of CPE in CPGs, which might be useful in development of future molecular analyses covering these frequently neglected regulatory sequences.
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15
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Hong YC, Wang Z, Peng B, Xia LG, Lin LW, Xu ZL. BAG2 Overexpression Correlates with Growth and Poor Prognosis of Esophageal Squamous Cell Carcinoma. Open Life Sci 2018; 13:582-588. [PMID: 33817129 PMCID: PMC7874702 DOI: 10.1515/biol-2018-0069] [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: 06/24/2018] [Accepted: 09/29/2018] [Indexed: 01/01/2023] Open
Abstract
Previous studies have suggested that Bcl2-associated athanogene 2 (BAG2) serves as a crucial regulator for tumorigenesis in multiple tumors. However, little is known about the effect of BAG2 on esophageal squamous cell carcinoma (ESCC). This study focused on investigating whether BAG2 functions as a cancer-promoting gene in ESCC. In this work, gene expression data and clinical information from the NCBI Gene Expression Omnibus (GEO), Oncomine and The Cancer Genome Atlas (TCGA) were collected and analyzed. Expression of BAG2 in ESCC was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). BAG2 was knocked down using small interference RNA (si-RNA) approach. Cell proliferation, migration and invasion were assessed by Cell Counting Kit-8 (CCK-8) and transwell assays. Molecular mechanism was detected by western blotting assay. The expression of BAG2 both in ESCC tissues and cells was upregulated and overexpression was associated with worsened prognosis. BAG2 silencing inhibited ESCC cell proliferation, migration and invasion, which was regulated by the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway. These results reveal contributions of BAG2 as a predictor and potential therapeutic target in ESCC.
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Affiliation(s)
- Ying-Cai Hong
- Department of Thoracic Surgery, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R.China
| | - Zheng Wang
- Department of Thoracic Surgery, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R.China
| | - Bin Peng
- Department of Thoracic Surgery, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R.China
| | - Li-Gang Xia
- Department of Gastrointestinal Surgery, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R.China
| | - Lie-Wen Lin
- Department of Gastrointestinal Surgery, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R.China
| | - Zheng-Lei Xu
- Department of Gastroenterology, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R.China
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16
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miR-128 targets the CC chemokine ligand 18 gene (CCL18) in cutaneous malignant melanoma progression. J Dermatol Sci 2018; 91:317-324. [DOI: 10.1016/j.jdermsci.2018.06.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 06/24/2018] [Accepted: 06/28/2018] [Indexed: 12/11/2022]
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17
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Atanasov G, Dietel C, Feldbrügge L, Benzing C, Krenzien F, Brandl A, Katou S, Schierle K, Robson SC, Splith K, Wiltberger G, Reutzel-Selke A, Jonas S, Pascher A, Bahra M, Pratschke J, Schmelzle M. Angiogenic miRNAs, the angiopoietin axis and related TIE2-expressing monocytes affect outcomes in cholangiocarcinoma. Oncotarget 2018; 9:29921-29933. [PMID: 30042823 PMCID: PMC6057457 DOI: 10.18632/oncotarget.25699] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 06/12/2018] [Indexed: 12/13/2022] Open
Abstract
Background Tumour angiogenesis is modulated on both an epigenetic and protein level and has potential implications for immune cell responses. However, the importance of related angiogenic biomarkers in cholangiocarcinoma (CCA) is unknown. This study assessed human CCA samples for the expression of angiogenesis-associated microRNAs, angiopoietins (Angs) and monocytes expressing the Ang-receptor, TIE2, with regards to prognostic significance after liver resection. Methods Angiogenic miRNAs were analysed in frozen samples of intrahepatic CCA (iCC; n = 43) and hilar CCA (HC; n = 45). Ang-1 and Ang-2, as well as TIE2-expressing monocytes (TEMs), were detected in paraffin-embedded iCC sections (n = 88). MiRNA expression and the abundance of TEMs and Angs were correlated with clinicopathological characteristics and survival. Results MiR-126 was downregulated in 76.7% of all CCA samples, with high relative expression associated with smaller tumours and reduced lymph node metastasis. High Ang-1 expression was associated with less lymphangiosis carcinomatosa and better histological grading (all p < 0.05). The absence of TEMs in iCC correlated with elevated CA19-9 levels. High relative miR-126 and low miR-128 levels were associated with improved survival in iCC and HC, respectively (all p < 0.05). High miR-126, low miR-128 and TEMs were independent prognostic factors for recurrence-free and overall survival (all p < 0.05). Conclusions These results suggest that angiogenic miRNAs, Angs and TEMs are of prognostic value in CCA. In addition to the possible functional links between angiogenic miRNA expression profiles, Angs and immune-cell responses by TEMs, these data have clinical implications as novel diagnostic tools.
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Affiliation(s)
- Georgi Atanasov
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
| | - Corinna Dietel
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Linda Feldbrügge
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
| | - Christian Benzing
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Felix Krenzien
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
| | - Andreas Brandl
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Shadi Katou
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Katrin Schierle
- Institute of Pathology, University Hospital Leipzig, Leipzig, Germany
| | - Simon C Robson
- The Transplant Institute and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA
| | - Katrin Splith
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Georg Wiltberger
- Department of General, Visceral and Transplantation Surgery, University Hospital of RWTH Aachen, Aachen, Germany
| | - Anja Reutzel-Selke
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Sven Jonas
- Department of General and Visceral Surgery, 310Klinik Nürnberg, Nürnberg, Germany
| | - Andreas Pascher
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Marcus Bahra
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Moritz Schmelzle
- Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
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18
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Allen B, Schneider A, Victoria B, Nunez Lopez YO, Muller M, Szewczyk M, Pazdrowski J, Majchrzak E, Barczak W, Golusinski W, Golusinski P, Masternak MM. Blood Serum From Head and Neck Squamous Cell Carcinoma Patients Induces Altered MicroRNA and Target Gene Expression Profile in Treated Cells. Front Oncol 2018; 8:217. [PMID: 29942793 PMCID: PMC6004400 DOI: 10.3389/fonc.2018.00217] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 05/25/2018] [Indexed: 12/16/2022] Open
Abstract
The head and neck squamous cell carcinoma (HNSCC) represents one of the most common cancers in humans. Close to 600,000 new diagnoses are made every year worldwide and over half of diagnosed patients will not survive. In view of this low survival rate, the development of novel cell-based assays for HNSCC will allow more mechanistic approaches for specific diagnostics for each individual patient. The cell-based assays will provide more informative data predicting cellular processes in treated patient, which in effect would improve patient follow up. More importantly, it will increase the specificity and effectiveness of therapeutic approaches. In this study, we investigated the role of serum from HNSCC patients on the regulation of microRNA (miRNA) expression in exposed cells in vitro. Next-generation sequencing of miRNA revealed that serum from HNSCC patients induced a different miRNA expression profile than the serum from healthy individuals. Out of 377 miRNA detected, we found that 16 miRNAs were differentially expressed when comparing cells exposed to serum from HNSCC or healthy individuals. The analysis of gene ontologies and pathway analysis revealed that these miRNA target genes were involved in biological cancer-related processes, including cell cycle and apoptosis. The real-time PCR analysis revealed that serum from HNSCC patients downregulate the expression level of five genes involved in carcinogenesis and two of these genes-P53 and SLC2A1-are direct targets of detected miRNAs. These novel findings provide new insight into how cancer-associated factors in circulation regulate the expression of genes and regulatory elements in distal cells in favor of tumorigenesis. This has the potential for new therapeutic approaches and more specific diagnostics with tumor-specific cell lines or single-cell in vitro assays for personalized treatment and early detection of primary tumors or metastasis.
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Affiliation(s)
- Brittany Allen
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Augusto Schneider
- Faculdade de Nutrição, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Berta Victoria
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Yury O Nunez Lopez
- Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, United States
| | - Mark Muller
- Epigenetics Division, TopoGEN Inc, Buena Vista, CO, United States
| | - Mateusz Szewczyk
- Department of Head and Neck Surgery, Poznań University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
| | - Jakub Pazdrowski
- Department of Head and Neck Surgery, Poznań University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
| | - Ewa Majchrzak
- Department of Head and Neck Surgery, Poznań University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
| | - Wojciech Barczak
- Department of Head and Neck Surgery, Poznań University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
| | - Wojciech Golusinski
- Department of Head and Neck Surgery, Poznań University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
| | - Pawel Golusinski
- Department of Head and Neck Surgery, Poznań University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland.,Biology and Environmental Studies, Head and Neck Cancer Biology Laboratory, Poznań University of Medical Sciences, Poznan, Poland
| | - Michal M Masternak
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States.,Department of Head and Neck Surgery, Poznań University of Medical Sciences, The Greater Poland Cancer Centre, Poznan, Poland
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19
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The SNAIL/miR-128 axis regulated growth, invasion, metastasis, and epithelial-to-mesenchymal transition of gastric cancer. Oncotarget 2018; 8:39280-39295. [PMID: 28424413 PMCID: PMC5503613 DOI: 10.18632/oncotarget.16849] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 03/11/2017] [Indexed: 02/07/2023] Open
Abstract
miR-128 is expressed in various tumors, but its expression and function in gastric cancer have not been defined. Thus, the goal of this study was to characterize miR-128 in gastric cancer. We found first that miR-128 is down-regulated in gastric cancer cell lines and tissues, and this dysregulation is correlated with DNA methylation and the transcription factor SNAIL. Using prediction tools, western blotting, and luciferase reporter assays, we found that Bmi-1 was the direct target of miR-128. Additionally, overexpression of miR-128 inhibited gastric cancer cell migration, invasion, and proliferation by targeting Bmi-1 in vitro and in vivo. We also documented, with receiver operating characteristic curves and Kaplan-Meier survival analysis, that miR-128 and Bmi-1 may be useful markers for diagnosing and estimating the prognosis of gastric cancer patients. As the epithelial-to-mesenchymal transition is an important mechanism associated with cancer invasion and metastasis, we inferred that miR-128 could regulate this mechanism in gastric cancer. In fact, we found that miR-128 could reverse epithelial-to-mesenchymal transition induced by Bmi-1 via the PI3K/AKT pathway. Because SNAIL also acts as a mesenchymal marker, our findings identified a novel positive feedback loop in which the transcription factor SNAIL curbs the expression of miR-128, and then down-regulated miR-128 promotes the expression of Bmi-1; finally, overexpression of Bmi-1 drives the epithelial-to-mesenchymal transition process via the PI3K/AKT pathway, and the expression of SNAIL is up-regulated.
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20
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Liang S, Song Z, Wu Y, Gao Y, Gao M, Liu F, Wang F, Zhang Y. MicroRNA-27b Modulates Inflammatory Response and Apoptosis during Mycobacterium tuberculosis Infection. THE JOURNAL OF IMMUNOLOGY 2018; 200:3506-3518. [PMID: 29661829 DOI: 10.4049/jimmunol.1701448] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 03/13/2018] [Indexed: 12/29/2022]
Abstract
Mycobacterium tuberculosis poses a significant global health threat. MicroRNAs play an important role in regulating host anti-mycobacterial defense; however, their role in apoptosis-mediated mycobacterial elimination and inflammatory response remains unclear. In this study, we explored the role of microRNA-27b (miR-27b) in murine macrophage responses to M. tuberculosis infection. We uncovered that the TLR-2/MyD88/NF-κB signaling pathway induced the expression of miR-27b and miR-27b suppressed the production of proinflammatory factors and the activity of NF-κB, thereby avoiding an excessive inflammation during M. tuberculosis infection. Luciferase reporter assay and Western blotting showed that miR-27b directly targeted Bcl-2-associated athanogene 2 (Bag2) in macrophages. Overexpression of Bag2 reversed miR-27b-mediated inhibition of the production of proinflammatory factors. In addition, miR-27b increased p53-dependent cell apoptosis and the production of reactive oxygen species and decreased the bacterial burden. We also showed that Bag2 interacts with p53 and negatively regulates its activity, thereby controlling cell apoptosis and facilitating bacterial survival. In summary, we revealed a novel role of the miR-27b/Bag2 axis in the regulation of inflammatory response and apoptosis and provide a potential molecular host defense mechanism against mycobacteria.
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Affiliation(s)
- Shuxin Liang
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.,Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China; and
| | - Zhigang Song
- Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Yongyan Wu
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.,Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China; and
| | - Yuanpeng Gao
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.,Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China; and
| | - Mingqing Gao
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.,Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China; and
| | - Fayang Liu
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.,Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China; and
| | - Fengyu Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.,Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China; and
| | - Yong Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; .,Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China; and
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21
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Zhao Y, Ling Z, Hao Y, Pang X, Han X, Califano JA, Shan L, Gu X. MiR-124 acts as a tumor suppressor by inhibiting the expression of sphingosine kinase 1 and its downstream signaling in head and neck squamous cell carcinoma. Oncotarget 2018; 8:25005-25020. [PMID: 28212569 PMCID: PMC5421905 DOI: 10.18632/oncotarget.15334] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 01/10/2017] [Indexed: 01/08/2023] Open
Abstract
By analyzing the expression profile of microRNAs in head and neck squamous cell carcinomas (HNSCC), we found that the expression level of miR-124 was 4.59-fold lower in tumors than in normal tissues. To understand its functions, we generated a miR-124-expressing subline (JHU-22miR124) and a mock vector-transfected subline (JHU-22vec) by transfecting the mimic of miR-124 into JHU-22 cancer cells. Restored expression of miR-124 in JHU-22miR124 cells led to reduced cell proliferation, delayed colony formation, and decreased tumor growth, indicating a tumor-suppressive effect of miR-124. Subsequent target search revealed that the 3′-UTR of SphK1 mRNA carries a complementary site for the seed region of miR-124. SphK1 was also detected to be overexpressed in HNSCC cell lines, but down-expressed in JHU-22miR124 cells and tumor xenografts. These results suggest that SphK1 is a target of miR-124. To confirm this finding, we constructed a 3′-UTR-Luc-SphK1 vector and a binding site-mutated luciferase reporter vector. Co-transfection of 3′-UTR-Luc-SphK1 with miR-124 expression vector exhibited a 9-fold decrease in luciferase activity compared with mutated vector, suggesting that miR-124 inhibits SphK1 activity directly. Further studies on downstream signaling demonstrated accumulation of ceramide, increased expression of the pro-apoptotic Bax, BAD and PARP, decreased expression of the anti-apoptotic Bcl-2 and Bcl-xL, and enhanced expression of cytochrome c and caspase proteins in JHU-22miR124 compared with JHU-22vec cells and tumor xenografts. We conclude that miR-124 acts as a tumor suppressor in HNSCC by directly inhibiting SphK1 activity and its downstream signals.
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Affiliation(s)
- Yuan Zhao
- Department of Oral Pathology, College of Dentistry, Howard University, Washington DC, USA
| | - Zhiqiang Ling
- Zhejiang Cancer Hospital, Zhejiang Cancer Research Institute, Hangzhou, Zhejiang, China
| | - Yubin Hao
- Department of Oral Pathology, College of Dentistry, Howard University, Washington DC, USA
| | - Xiaowu Pang
- Department of Oral Pathology, College of Dentistry, Howard University, Washington DC, USA
| | - Xianlin Han
- Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Joseph A Califano
- Department of Otolaryngology, Head and Neck Surgery, Johns Hopkins University, San Diego, California, USA
| | - Liang Shan
- Department of Oral Pathology, College of Dentistry, Howard University, Washington DC, USA.,Department of Radiology, College of Medicine, Howard University, Washington DC, USA
| | - Xinbin Gu
- Department of Oral Pathology, College of Dentistry, Howard University, Washington DC, USA.,Cancer Center, Howard University, Washington DC, USA
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22
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Shin SH, Cha HJ, Kim K, An IS, Kim KY, Ku JE, Jeong SH, An S. Epigallocatechin-3-gallate inhibits paclitaxel-induced apoptosis through the alteration of microRNA expression in human dermal papilla cells. BIOMEDICAL DERMATOLOGY 2018. [DOI: 10.1186/s41702-017-0016-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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23
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Osteoblast-targeted delivery of miR-33-5p attenuates osteopenia development induced by mechanical unloading in mice. Cell Death Dis 2018; 9:170. [PMID: 29415986 PMCID: PMC5833703 DOI: 10.1038/s41419-017-0210-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 11/11/2017] [Accepted: 12/06/2017] [Indexed: 01/06/2023]
Abstract
A growing body of evidence has revealed that microRNAs (miRNAs) play crucial roles in regulating osteoblasts and bone metabolism. However, the effects of miRNAs in osteoblast mechanotransduction remain to be defined. In this study, we investigated the regulatory effect of miR-33-5p in osteoblasts and tested its anti-osteopenia effect when delivered by an osteoblast-targeting delivery system in vivo. First, we demonstrated that miR-33-5p could promote the activity and mineralization of osteoblasts without influencing their proliferation in vitro. Then our data showed that supplementing miR-33-5p in osteoblasts by a targeted delivery system partially recovered the osteopenia induced by mechanical unloading at the biochemical, microstructural, and biomechanical levels. In summary, our findings demonstrate that miR-33-5p is a key factor in the occurrence and development of the osteopenia induced by mechanical unloading. In addition, targeted delivery of the mimics of miR-33-5p is a promising new strategy for the treatment of pathological osteopenia.
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24
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Fan L, Liu Z, Zhang Y, Zhu H, Yu H, Yang F, Yang R, Wu F. MiRNA373 induces cervical squamous cell carcinoma SiHa cell apoptosis. Cancer Biomark 2018; 21:455-460. [PMID: 29125482 DOI: 10.3233/cbm-170692] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Limei Fan
- Department of Gynaecology and Obstetrics, The Second Hospital of Jilin University, Changchun 130041, Jilin, China
| | - Zongyu Liu
- Bethune School of Medicine, Jilin University, Changchun 130021, Jilin, China
| | - Yong Zhang
- Deparment of Pathology and Pathophysiology, Bethune Medical College, Jilin University, Changchun 130021,Jilin, China
| | - He Zhu
- Department of Gynaecology and Obstetrics, The Second Hospital of Jilin University, Changchun 130041, Jilin, China
| | - Huimei Yu
- Deparment of Pathology and Pathophysiology, Bethune Medical College, Jilin University, Changchun 130021,Jilin, China
| | - Fan Yang
- Department of Pediatric Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Ruiqi Yang
- Department of Gynaecology and Obstetrics, The Second Hospital of Jilin University, Changchun 130041, Jilin, China
| | - Fei Wu
- Department of Gynaecology and Obstetrics, The Second Hospital of Jilin University, Changchun 130041, Jilin, China
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25
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Guzman H, Sanders K, Idica A, Bochnakian A, Jury D, Daugaard I, Zisoulis DG, Pedersen IM. miR-128 inhibits telomerase activity by targeting TERT mRNA. Oncotarget 2018; 9:13244-13253. [PMID: 29568354 PMCID: PMC5862575 DOI: 10.18632/oncotarget.24284] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 01/09/2018] [Indexed: 01/28/2023] Open
Abstract
Telomerase is a unique cellular reverse transcriptase (RT) essential for maintaining telomere stability and required for the unlimited proliferation of cancer cells. The limiting determinant of telomerase activity is the catalytic component TERT, and TERT expression is closely correlated with telomerase activity and cancer initiation and disease progression. For this reason the regulation of TERT levels in the cell is of great importance. microRNAs (miRs) function as an additional regulatory level in cells, crucial for defining expression boundaries, proper cell fate decisions, cell cycle control, genome integrity, cell death and metastasis. We performed an anti-miR library screen to identity novel miRs, which participate in the control of telomerase. We identified the tumor suppressor miR (miR-128) as a novel endogenous telomerase inhibitor and determined that miR-128 significantly reduces the mRNA and protein levels of Tert in a panel of cancer cell lines. We further evaluated the mechanism by which miR-128 regulates TERT and demonstrated that miR-128 interacts directly with the coding sequence of TERT mRNA in both HeLa cells and teratoma cells. Interestingly, the functional miR-128 binding site in TERT mRNA, is conserved between TERT and the other cellular reverse transcriptase encoded by Long Interspersed Elements-1 (LINE-1 or L1), which can also contribute to the oncogenic phenotype of cancer. This finding supports the novel idea that miRs may function in parallel pathways to inhibit tumorigenesis, by regulating a group of enzymes (such as RT) by targeting conserved binding sites in the coding region of both enzymes.
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Affiliation(s)
- Herlinda Guzman
- Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine 92697-3900, CA, USA
| | - Katie Sanders
- Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine 92697-3900, CA, USA
| | - Adam Idica
- Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine 92697-3900, CA, USA
| | - Aurore Bochnakian
- Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine 92697-3900, CA, USA
| | - Douglas Jury
- Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine 92697-3900, CA, USA
| | - Iben Daugaard
- Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine 92697-3900, CA, USA
| | - Dimitrios G Zisoulis
- Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine 92697-3900, CA, USA
| | - Irene Munk Pedersen
- Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine 92697-3900, CA, USA
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26
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Pacholewska A, Kraft MF, Gerber V, Jagannathan V. Differential Expression of Serum MicroRNAs Supports CD4⁺ T Cell Differentiation into Th2/Th17 Cells in Severe Equine Asthma. Genes (Basel) 2017; 8:E383. [PMID: 29231896 PMCID: PMC5748701 DOI: 10.3390/genes8120383] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 11/21/2017] [Accepted: 12/01/2017] [Indexed: 01/06/2023] Open
Abstract
MicroRNAs (miRNAs) regulate post-transcriptional gene expression and may be exported from cells via exosomes or in partnership with RNA-binding proteins. MiRNAs in body fluids can act in a hormone-like manner and play important roles in disease initiation and progression. Hence, miRNAs are promising candidates as biomarkers. To identify serum miRNA biomarkers in the equine model of asthma we investigated small RNA derived from the serum of 34 control and 37 asthmatic horses. These samples were used for next generation sequencing, novel miRNA identification and differential miRNA expression analysis. We identified 11 significantly differentially expressed miRNAs between case and control horses: eca-miR-128, eca-miR-744, eca-miR-197, eca-miR-103, eca-miR-107a, eca-miR-30d, eca-miR-140-3p, eca-miR-7, eca-miR-361-3p, eca-miR-148b-3p and eca-miR-215. Pathway enrichment using experimentally validated target genes of the human homologous miRNAs showed a significant enrichment in the regulation of epithelial-to-mesenchymal transition (key player in airway remodeling in asthma) and the phosphatidylinositol (3,4,5)-triphosphate (PIP3) signaling pathway (modulator of CD4⁺ T cell maturation and function). Downregulated miR-128 and miR-744 supports a Th2/Th17 type immune response in severe equine asthma.
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Affiliation(s)
- Alicja Pacholewska
- Department of Clinical Veterinary Medicine, Swiss Institute of Equine Medicine, Vetsuisse Faculty, University of Bern and Agroscope, Länggassstrasse 124, 3012 Bern, Switzerland.
- Department of Clinical Research and Veterinary Public Health, Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109A, 3012 Bern, Switzerland.
| | - Matthias F Kraft
- Department of Clinical Veterinary Medicine, Swiss Institute of Equine Medicine, Vetsuisse Faculty, University of Bern and Agroscope, Länggassstrasse 124, 3012 Bern, Switzerland.
- Department of Clinical Research and Veterinary Public Health, Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109A, 3012 Bern, Switzerland.
| | - Vincent Gerber
- Department of Clinical Veterinary Medicine, Swiss Institute of Equine Medicine, Vetsuisse Faculty, University of Bern and Agroscope, Länggassstrasse 124, 3012 Bern, Switzerland.
| | - Vidhya Jagannathan
- Department of Clinical Research and Veterinary Public Health, Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109A, 3012 Bern, Switzerland.
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27
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Sannigrahi MK, Sharma R, Panda NK, Khullar M. Role of non-coding RNAs in head and neck squamous cell carcinoma: A narrative review. Oral Dis 2017; 24:1417-1427. [PMID: 28941018 DOI: 10.1111/odi.12782] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 08/23/2017] [Accepted: 09/08/2017] [Indexed: 12/13/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with high recurrence, metastasis, and poor treatment outcome. Recent studies have reported that non-coding RNA (ncRNA) might play critical role in regulating different types of cancer. MicroRNAs (miRs) are short ncRNAs (20-25 nucleotides) responsible for post-transcriptional regulation of gene expression and may have a role in oncogenesis by acting as oncomiRs or tumor suppressor miRs. Long non-coding RNAs (lncRNAs) are heterogenous group of ncRNAs more than 200 nucleotides long, can act in cis and/or in trans, and have been also implicated in carcinogenesis. These molecules have been suggested to be promising candidates as diagnostic and prognostic biomarkers and for development of novel therapeutic approaches. In this review, we have summarized recent findings on role of these ncRNAs in HPV-negative (HPV-ve) and HPV-positive (HPV+ve) HNSCC. The available literature supports differential expression of both microRNAs and long non-coding RNAs, which include oncogenic ncRNAs (miR-21, miR-31, miR-155, miR-211, HOTAIR, and MALAT1) and tumor suppressor ncRNAs (let7d, miR-17, miR-375, miR-139, and MEG3) in HPV+ve HNSCC tumors as compared to HPV-ve tumors and they have distinct role in the pathophysiology of these two types of HNSCCs.
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Affiliation(s)
- M K Sannigrahi
- Department of Otolaryngology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - R Sharma
- Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, India
| | - N K Panda
- Department of Otolaryngology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - M Khullar
- Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, India
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28
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Zheng X, Wang S, Hong S, Liu S, Chen G, Tang W, Zhao Y, Gao H, Cha B. CXCR4/RhoA signaling pathway is involved in miR-128-regulated proliferation and apoptosis of human thyroid cancer cells. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:9213-9222. [PMID: 31966793 PMCID: PMC6965988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 03/09/2017] [Indexed: 06/10/2023]
Abstract
microRNA-128 (miR-128), a kind of short, noncoding RNAs, functioned as a tumor marker. However, the underlying function and mechanism of miR-128 in human thyroid cancer were uncertain. Therefore, in the present study, the effects of miR-128 on the proliferation and apoptosis of cultured human thyroid cancer cells were investigated. After slicing miR-128 in human thyroid cancer cells, the proliferation was measured by methyl thiazolyl tetrazolium (MTT) method, the expression of miR-128, CCAAT/enhancer binding protein-α (C/EBPα), peroxisome proliferator-activated receptor-γ (PPARγ), Caspase-3 and Caspase-9 was determined by RT-PCR, and protein expression of chemokine receptor 4 (CXCR4) and Ras homolog gene family, member A (RhoA) was analyzed by Western blot. It was found that knockdown of miR-128 promoted the optical density (OD) value of cells, enhanced mRNA expression of PPARγ and C/EBPα, while inhibited cell apoptotic rate, and Caspase-3, Caspase-9 expression. Furthermore, higher protein expression of CXCR4 and RhoA was found in the absence of miR-128. Notably, miRNA-128 over-expression-inhibited proliferation and induced-apoptosis of human thyroid cancer cells were partially changed following the block of CXCR4/RhoA signaling pathway by the CXCR4 inhibitor (AMD3100). It was indicated that miR-128 down-regulated proliferation while promoted apoptosis of human thyroid cancer cells through suppression of CXCR4/RhoA signaling pathway.
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Affiliation(s)
- Xucai Zheng
- Department of Head and Neck, Breast Surgery, Anhui Provincial Tumor Hospital (West Branch of Anhui Provincial Hospital)Hefei, China
| | - Shengying Wang
- Department of Head and Neck, Breast Surgery, Anhui Provincial Tumor Hospital (West Branch of Anhui Provincial Hospital)Hefei, China
| | - Shikai Hong
- Department of Head and Neck, Breast Surgery, Anhui Provincial Tumor Hospital (West Branch of Anhui Provincial Hospital)Hefei, China
| | - Song Liu
- Department of Head and Neck, Breast Surgery, Anhui Provincial Tumor Hospital (West Branch of Anhui Provincial Hospital)Hefei, China
| | - Gongpu Chen
- Department of Head and Neck, Breast Surgery, Anhui Provincial Tumor Hospital (West Branch of Anhui Provincial Hospital)Hefei, China
| | - Weifang Tang
- Department of Head and Neck, Breast Surgery, Anhui Provincial Tumor Hospital (West Branch of Anhui Provincial Hospital)Hefei, China
| | - Yuanyuan Zhao
- Department of Head and Neck, Breast Surgery, Anhui Provincial Tumor Hospital (West Branch of Anhui Provincial Hospital)Hefei, China
| | - Hong Gao
- Department of Head and Neck, Breast Surgery, Anhui Provincial Tumor Hospital (West Branch of Anhui Provincial Hospital)Hefei, China
| | - Baiwei Cha
- Department of Anesthesia, Anhui Provincial Tumor Hospital (West Branch of Anhui Provincial Hospital)Hefei, China
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29
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Cai J, Fang L, Huang Y, Li R, Xu X, Hu Z, Zhang L, Yang Y, Zhu X, Zhang H, Wu J, Huang Y, Li J, Zeng M, Song E, He Y, Zhang L, Li M. Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC. Nat Commun 2017. [PMID: 28627514 PMCID: PMC5481840 DOI: 10.1038/ncomms15870] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cancer chemoresistance and metastasis are tightly associated features. However, whether they share common molecular mechanisms and thus can be targeted with one common strategy remain unclear in non-small cell lung cancer (NSCLC). Here, we report that high levels of microRNA-128-3p (miR-128-3p) is key to concomitant development of chemoresistance and metastasis in residual NSCLC cells having survived repeated chemotherapy and correlates with chemoresistance, aggressiveness and poor prognosis in NSCLC patients. Mechanistically, miR-128-3p induces mesenchymal and stemness-like properties through downregulating multiple inhibitors of Wnt/β-catenin and TGF-β pathways, leading to their overactivation. Importantly, antagonism of miR-128-3p potently reverses metastasis and chemoresistance of highly malignant NSCLC cells, which could be completely reversed by restoring Wnt/β-catenin and TGF-β activities. Notably, correlations among miR-128-3p levels, activated β-catenin and TGF-β signalling, and pro-epithelial-to-mesenchymal transition/pro-metastatic protein levels are validated in NSCLC patient specimens. These findings suggest that miR-128-3p might be a potential target against both metastasis and chemoresistance in NSCLC.
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Affiliation(s)
- Junchao Cai
- Department of Microbiology, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.,Guangdong Engineering and Technology Research Center for Disease-Model Animals, Sun Yat-sen University, Guangzhou 510006, China
| | - Lishan Fang
- Department of Microbiology, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.,Central Laboratory of The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China
| | - Yongbo Huang
- State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
| | - Rong Li
- Department of Microbiology, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China
| | - Xiaonan Xu
- Department of Microbiology, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China
| | - Zhihuang Hu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Le Zhang
- Department of Microbiology, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China
| | - Yi Yang
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Xun Zhu
- Department of Microbiology, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China
| | - Heng Zhang
- Neurosurgery Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Jueheng Wu
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China
| | - Yan Huang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Jun Li
- Department of Biochemistry, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou 510080, China
| | - Musheng Zeng
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Erwei Song
- Department of Breast Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yukai He
- Department of Medicine and Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta University, Augusta, Georgia 30912, USA
| | - Li Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Mengfeng Li
- Department of Microbiology, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China
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30
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Li J, Li Q, Huang H, Li Y, Li L, Hou W, You Z. Overexpression of miRNA-221 promotes cell proliferation by targeting the apoptotic protease activating factor-1 and indicates a poor prognosis in ovarian cancer. Int J Oncol 2017; 50:1087-1096. [PMID: 28350128 PMCID: PMC5363885 DOI: 10.3892/ijo.2017.3898] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 02/16/2017] [Indexed: 11/18/2022] Open
Abstract
MicroRNAs are a class of small non-coding, endogenous RNAs involved in cancer development and progression. MicroRNA-221 (mir-221) has been reported to have both an oncogenic and tumor-suppressive role in human tumors, but the role of miR-221 in ovarian cancer is poorly understood. In the present study, the expression levels of miR-221 and the apoptosis protease activating factor 1 (APAF1) protein in 63 samples of ovarian cancer tissues and the cell lines, IOSE25, A2780, OVCAR3, SKOV3 and 3AO were detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot analysis, respectively. Cell proliferation was measured using Cell Counting kit-8 (CCK-8); cell migration and invasion were detected using a Transwell assay; cell apoptosis was evaluated by flow cytometry and Hoechst staining, and a luciferase assay was performed to verify a putative target site of miR-221 in the 3′-UTR of APAF1 mRNA. Expression of miR-221 was upregulated in ovarian cancer tissues. Patients with increased miR-221 expression levels had a reduced disease-free survival (P=0.0014) and overall survival (P=0.0058) compared with those with low miR-221 expression. Transfection of SKOV3 and A2780 cell lines with miR-221 inhibitor induced APAF1 protein expression, suppressed cell proliferation and migration and promoted tumor cell apoptosis. In conclusion, the APAF1 gene was confirmed as a direct target of miR-221 and overexpression of APAF1 suppressed ovarian cancer cell proliferation and induced cell apoptosis in vitro. These findings indicate that miR-221-APAF1 should be studied further as a potential new diagnostic or prognostic biomarker for ovarian cancer.
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Affiliation(s)
- Jie Li
- Department of Gynecology, The Eastern Hospital of the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China
| | - Qiang Li
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - He Huang
- Department of Gynecology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510000, P.R. China
| | - Yinguang Li
- Department of Gynecology, The Eastern Hospital of the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China
| | - Li Li
- Department of Gynecology, The Eastern Hospital of the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510700, P.R. China
| | - Wenhui Hou
- Department of Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Zeshan You
- Department of Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
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31
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Jiang J, Gao Q, Wang T, Lin H, Zhan Q, Chu Z, Huang R, Zhou X, Liang X, Guo W. MicroRNA expression profiles of granulocytic myeloid‑derived suppressor cells from mice bearing Lewis lung carcinoma. Mol Med Rep 2016; 14:4567-4574. [PMID: 27748875 PMCID: PMC5102002 DOI: 10.3892/mmr.2016.5845] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 09/22/2016] [Indexed: 01/01/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous myeloid cells that can suppress antitumor immunity. MDSCs are divided into granulocytic (G-MDSCs) and monocytic subsets. In the present study, the microRNA profiles of the G-MDSCs were determined and the differential expression of microRNAs between G-MDSCs from tumor-bearing mice and tumor-free mice was examined. The number of G-MDSCs in spleens of Lewis lung carcinoma (LLC)-bearing mice was ~6-fold higher than in spleens of normal mice (13.54±1.74% vs. 2.14±1.44%; P<0.01) and G-MDSCs account for about 72.9% of all MDSCs. The microRNA (miRNA) profiles of the G-MDSCs from spleen of LLC-bearing mice were obtained using a microRNA microarray and compared with their counterparts from spleens of tumor-free mice. A total of 43 miRNAs with >1.3-fold increased or decreased change were differentially expressed between the experimental and control group mice. The levels of nine of these differentially expressed miRNAs, miRNA-468 (miR-486), miR-192, miR-128, miR-125a, miR-149, miR-27a, miR-125b, miR-350 and miR-328, were also analyzed by RT-qPCR to validate the microarray data. The concordance rate between the results tested by the two methods was 88.9%. Bioinformatics analyses revealed that these miRNAs may act on various target genes, including Adar, Pik3r1, Rybp and Rabgap1, to regulate the survival, differentiation and the function of tumor-induced granulocytic MDSCs. The results revealed microRNAs and potential targets that may be vital for regulating survival, differentiation and function of G-MDSCs induced by LLC. Further investigation should be performed to clarify the roles of these microRNAs in regulating LLC-induced granulocytic MDSCs and the target genes that mediate their functions.
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Affiliation(s)
- Jingwei Jiang
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Qingmin Gao
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Tian Wang
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Hao Lin
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Qiong Zhan
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Zhaohui Chu
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Ruofan Huang
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Xinli Zhou
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Xiaohua Liang
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Weijian Guo
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
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32
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Zhang R, Liu C, Niu Y, Jing Y, Zhang H, Wang J, Yang J, Zen K, Zhang J, Zhang CY, Li D. MicroRNA-128-3p regulates mitomycin C-induced DNA damage response in lung cancer cells through repressing SPTAN1. Oncotarget 2016; 8:58098-58107. [PMID: 28938540 PMCID: PMC5601636 DOI: 10.18632/oncotarget.12300] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 09/20/2016] [Indexed: 01/08/2023] Open
Abstract
The DNA damage response is critical for maintaining genome integrity and preventing damage to DNA due to endogenous and exogenous insults. Mitomycin C (MMC), a potent DNA cross-linker, is used as a chemotherapeutic agent because it causes DNA inter-strand cross-links (DNA ICLs) in cancer cells. While many microRNAs, which may serve as oncogenes or tumor suppressors, are grossly dysregulated in human cancers, little is known about their roles in MMC-treated lung cancer. Here, we report that miR-128-3p can attenuate repair of DNA ICLs by targeting SPTAN1 (αII Sp), resulting in cell cycle arrest and promoting chromosomal aberrations in lung cancer cells treated with MMC. Using computational prediction and experimental validation, SPTAN1 was found to be a conserved target of miR-128-3p. We then found that miR-128-3p caused translational inhibition of SPTAN1, reducing its protein level. SPTAN1 repression via miR-128-3p also induced cell cycle arrest and chromosomal instability. Additionally, miR-128-3p significantly influenced interaction of the αII Sp/FANCA/XPF complex, thus limiting DNA repair. In summary, the results demonstrate that miR-128-3p accelerates cell cycle arrest and chromosomal instability in MMC-treated lung cancer cells by suppressing SPTAN1, and these findings could be applied for adjuvant chemotherapy of lung cancer.
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Affiliation(s)
- Rui Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences(NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.,Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Chang Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences(NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.,Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Yahan Niu
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences(NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.,Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Ying Jing
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences(NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.,Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Haiyang Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences(NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.,Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Jin Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences(NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.,Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Jie Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences(NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Ke Zen
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences(NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.,Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Junfeng Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences(NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.,Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Chen-Yu Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences(NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.,Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
| | - Donghai Li
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences(NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.,Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China
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33
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Huang T, She K, Peng G, Wang W, Huang J, Li J, Wang Z, He J. MicroRNA-186 suppresses cell proliferation and metastasis through targeting MAP3K2 in non-small cell lung cancer. Int J Oncol 2016; 49:1437-44. [PMID: 27498924 DOI: 10.3892/ijo.2016.3637] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 06/22/2016] [Indexed: 11/05/2022] Open
Abstract
MicroRNAs are a class of small endogenous non-coding RNAs that play crucial roles in the initiation and progression of human cancers. miR-186 was found decreased in various human malignancies and function as a tumor suppressor. However, the regulating mechanism of miR-186 in growth and metastasis of human non-small cell lung cancer (NSCLC) is still poorly understood. We investigated the role of miR-186 in the growth and metastasis of human NSCLC. In the present study, we found that miR-186 was significantly decreased in lung cancer tissues and cells. Furthermore, overexpression of miR-186 suppressed lung cancer cell proliferation, migration and invasion, and induced cell apoptosis. Moreover, we found that confirmed mitogen-activated protein kinase kinase kinase 2 (MAP3K2) protein was increased in lung cancer tissues and confirmed that MAP3K2 is a target gene of miR-186. In addition, knockdown of MAP3K2 by RNA interference inhibited lung cancer cell proliferation, migration and invasion, and promoted cell apoptosis in vitro. Furthermore, we observed tthat the overexpression of MAP3K2 partially reversed the inhibitory effect of miR-186 on the proliferation and metastasis of A549 and HCC827 cell lines. Taken together, our data indicated that miR-186 regulates lung cancer growth and metastasis through suppressing MAP3K2 expression, at least partly. Therefore, miR-186-MAP3K2 may represent a new and useful potential clinical treatment and diagnosis target for NSCLC.
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Affiliation(s)
- Tonghai Huang
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Kelin She
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Guilin Peng
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China
| | - Wei Wang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China
| | - Jun Huang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China
| | - Jingpei Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China
| | - Zheng Wang
- Department of Thoracic Surgery, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| | - Jianxing He
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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34
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Irani S. miRNAs Signature in Head and Neck Squamous Cell Carcinoma Metastasis: A Literature Review. JOURNAL OF DENTISTRY (SHIRAZ, IRAN) 2016; 17:71-83. [PMID: 27284551 PMCID: PMC4885676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
STATEMENT OF THE PROBLEM Head and neck cancers include epithelial tumors arising in the oral cavity, pharynx, larynx, paranasal sinuses, and nasal cavity. Metastasis is a hallmark of cancer. MicroRNAs (miRNAs) are endogenous small non-coding RNAs involved in cell proliferation, development, differentiation and metastasis. It is believed that miRNA alterations correlate with initiation and progression of cancer cell proliferation or inhibition of tumorigenesis. Moreover, miRNAs have different roles in development, progression, and metastasis of head and neck squamous cell carcinoma (HNSCC). Altered expression of miRNAs could be novel molecular biomarkers for the definite diagnosis of cancer, metastatic site, cancer stage, and its progression. PURPOSE The purpose of this review was to provide a comprehensive literature review of the role of miRNAs in head and neck cancer metastasis. SEARCH STRATEGY A relevant English literature search in PubMed, ScienceDirect, and Google Scholar was performed. The keywords 'miRNA', 'head and neck', and 'cancer' were searched in title and abstract of publications; limited from 1990 to 2015. The inclusion criterion was the role of miRNAs in cancer metastasis. The exclusion criterion was the other functions of miRNAs in cancers. Out of 15221 articles, the full texts of 442 articles were retrieved and only 133 articles met the inclusion criteria. CONCLUSION Despite the advances in cancer treatment, the mortality rate of HNSCC is still high. The potential application of miRNAs for cancer therapy has been demonstrated in many studies; miRNAs function as either tumor suppressor or oncogene. The recognition of metastamir and their targets may lead to better understanding of HNSCC oncogenesis, and consequently, development of new therapeutic strategies which is a necessity in cancer treatment. Development of therapeutic agents based on miRNAs is a promising target.
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Affiliation(s)
- Soussan Irani
- Dental Research Center, Dept. of Oral and Maxillofacial Pathology, School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran. and Lecturer at Griffith University, Gold Coast, Australia
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35
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Han B, Lian L, Li X, Zhao C, Qu L, Liu C, Song J, Yang N. Chicken gga-miR-130a targets HOXA3 and MDFIC and inhibits Marek's disease lymphoma cell proliferation and migration. Mol Biol Rep 2016; 43:667-76. [PMID: 27178573 DOI: 10.1007/s11033-016-4002-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 05/04/2016] [Indexed: 12/19/2022]
Abstract
Marek's disease (MD) is an infectious disease of chickens caused by MD virus (MDV), which is a herpesvirus that initiates tumor formation. Studies have indicated that microRNAs (miRNAs) are linked with the development of cancers or tumors. Previously, gga-miR-130a was discovered downregulated in MDV-infected tissues. Here, we aimed to explore the further function of gga-miR-130a in MD. The expression of gga-miR-130a in MDV-infected and uninfected spleens was detected by quantitative real-time PCR (qRT-PCR). Subsequently, proliferation and migration assays of MDV-transformed lymphoid cells (MSB1) were carried out by transfecting gga-miR-130a. The target genes of gga-miR-130a were predicted using TargetScan and miRDB and clustered through Gene Ontology analysis. The target genes were validated by western blot, qRT-PCR, and a dual luciferase reporter assay. Our results show that the expression of gga-miR-130a was reduced in MDV-infected spleens. Gga-miR-130a showed an inhibitory effect on MSB1 cell proliferation and migration. Two target genes, homeobox A3 (HOXA3) and MyoD family inhibitor domain containing (MDFIC), were predicted and clustered to cell proliferation. Results indicate that gga-miR-130a regulates HOXA3 and MDFIC at the protein level but not at the mRNA level. Moreover, the gga-miR-130a binding sites of two target genes have been confirmed. We conclude that gga-miR-130a can arrest MSB1 cell proliferation and migration, and target HOXA3 and MDFIC, which are both involved in the regulation of cell proliferation. Collectively, gga-miR-130a plays a critical role in the tumorigenesis associated with chicken MD.
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Affiliation(s)
- Bo Han
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Ling Lian
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Xin Li
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Chunfang Zhao
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Lujiang Qu
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Changjun Liu
- Division of Avian Infectious Diseases, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, 150001, China
| | - Jiuzhou Song
- Department of Animal & Avian Sciences, University of Maryland, College Park, MD, 20742, USA
| | - Ning Yang
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
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36
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de Nigris F. Epigenetic regulators: Polycomb-miRNA circuits in cancer. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2016; 1859:697-704. [PMID: 26975854 DOI: 10.1016/j.bbagrm.2016.03.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 02/09/2016] [Accepted: 03/10/2016] [Indexed: 01/23/2023]
Abstract
Polycomb group (PcG) proteins belong to a family of epigenetic modifiers and play a key role in dynamic control of their target genes. Several reports have found that aberrations in PcG-microRNA (miRNA) interplay in various cancer types often associated with poor clinical prognosis. This review discusses important PcG-miRNA molecular networks which act as critical interfaces between chromatin remodeling, and transcriptional and post-transcriptional regulation of their target genes in cancer. Moreover, here are discussed several compounds influencing the activity of PcG proteins entered in clinical arena for the treatment of solid tumors, multiple myeloma and B lymphomas, thus highlighting the therapeutic potential of targeting this protein family.
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Affiliation(s)
- Filomena de Nigris
- Department of Biochemistry Biophysics and General Pathology, Second University of Naples, Naples, Italy.
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37
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Yang Q, Zhang RW, Sui PC, He HT, Ding L. Dysregulation of non-coding RNAs in gastric cancer. World J Gastroenterol 2015; 21:10956-10981. [PMID: 26494954 PMCID: PMC4607897 DOI: 10.3748/wjg.v21.i39.10956] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/28/2015] [Accepted: 09/15/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the standard of care treatment, including surgery, chemotherapy and radiotherapy, remains poor. Developing novel treatment strategies, identifying new molecules for targeted therapy, and devising screening techniques to detect this cancer in its early stages are needed for GC patients. The discovery of non-coding RNAs (ncRNAs), primarily microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), helped to elucidate the mechanisms of tumorigenesis, diagnosis and treatment of GC. Recently, significant research has been conducted on non-coding RNAs and how the regulatory dysfunction of these RNAs impacts the tumorigenesis of GC. In this study, we review papers published in the last five years concerning the dysregulation of non-coding RNAs, especially miRNAs and lncRNAs, in GC. We summarize instances of aberrant expression of the ncRNAs in GC and their effect on survival-related events, including cell cycle regulation, AKT signaling, apoptosis and drug resistance. Additionally, we evaluate how ncRNA dysregulation affects the metastatic process, including the epithelial-mesenchymal transition, stem cells, transcription factor activity, and oncogene and tumor suppressor expression. Lastly, we determine how ncRNAs affect angiogenesis in the microenvironment of GC. We further discuss the use of ncRNAs as potential biomarkers for use in clinical screening, early diagnosis and prognosis of GC. At present, no ideal ncRNAs have been identified as targets for the treatment of GC.
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38
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Wu L, Shi B, Huang K, Fan G. MicroRNA-128 suppresses cell growth and metastasis in colorectal carcinoma by targeting IRS1. Oncol Rep 2015; 34:2797-805. [PMID: 26352220 DOI: 10.3892/or.2015.4251] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 08/03/2015] [Indexed: 01/24/2023] Open
Abstract
Evidence has shown that microRNAs play important roles in tumor development, progression, and metastasis. miR-128 has been reported to be deregulated in different tumor types, whereas the function of miR-128 in colorectal carcinoma (CRC) largely remains to be elucidated. The aim of the present study was to investigate the clinical significance, biological effects and underlying mechanisms of miR-128 in CRC using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. It was found that the expression of miR-128 was downregulated in CRC tissues and cell lines as determined by RT-qPCR. Furthermore, the expression of miR-128 in tumor tissues was significantly negatively correlated with TNM stage and lymph node metastasis in CRC patients. Functional assay revealed that the overexpression of miR-128 inhibited CRC cell proliferation, colony formation, migration and invasion and promoted apoptosis in vitro, and suppressed CRC xenograft tumor growth in vivo. In addition, insulin receptor substrate 1 (IRS1), a key mediator in oncogenic insulin-like growth factor (IGF) signaling, was confirmed as a direct target of miR-128 by a luciferase reporter assay. Western blot analysis indicated that the overexpression of miR-128 significantly downregulated IRS1 expression and its downstream Akt signaling in CRC cells. Moreover, miR-128 was negatively associated with IRS1 in CRC tissues compared to adjacent non-tumor tissues. Taken together, these data suggested that miR-128 serves as a tumor suppressor and blocks CRC growth and metastasis by targeting IRS1.
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Affiliation(s)
- Lan Wu
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Bo Shi
- The Experiment Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Kexin Huang
- The Experiment Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Guoyu Fan
- Department of Oncology, The Center Hospital of Jilin City, Fengman, Jilin 132011, P.R. China
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