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Saadh MJ, Hussain QM, Alazzawi TS, Fahdil AA, Athab ZH, Yarmukhamedov B, Al-Nuaimi AMA, Alsaikhan F, Farhood B. MicroRNA as Key Players in Hepatocellular Carcinoma: Insights into Their Role in Metastasis. Biochem Genet 2025; 63:1014-1062. [PMID: 39103713 DOI: 10.1007/s10528-024-10897-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 07/29/2024] [Indexed: 08/07/2024]
Abstract
Liver cancer or hepatocellular carcinoma (HCC) remains the most common cancer in global epidemiology. Both the frequency and fatality of this malignancy have shown an upward trend over recent decades. Liver cancer is a significant concern due to its propensity for both intrahepatic and extrahepatic metastasis. Liver cancer metastasis is a multifaceted process characterized by cell detachment from the bulk tumor, modulation of cellular motility and invasiveness, enhanced proliferation, avoidance of the immune system, and spread either via lymphatic or blood vessels. MicroRNAs (miRNAs) are small non-coding ribonucleic acids (RNAs) playing a crucial function in the intricate mechanisms of tumor metastasis. A number of miRNAs can either increase or reduce metastasis via several mechanisms, such as control of motility, proliferation, attack by the immune system, cancer stem cell properties, altering the microenvironment, and the epithelial-mesenchymal transition (EMT). Besides, two other types of non-coding RNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) can competitively bind to endogenous miRNAs. This competition results in the impaired ability of the miRNAs to inhibit the expression of the specific messenger RNAs (mRNAs) that are targeted. Increasing evidence has shown that the regulatory axis comprising circRNA/lncRNA-miRNA-mRNA is correlated with the regulation of HCC metastasis. This review seeks to present a thorough summary of recent research on miRNAs in HCC, and their roles in the cellular processes of EMT, invasion and migration, as well as the metastasis of malignant cells. Finally, we discuss the function of the lncRNA/circRNA-miRNA-mRNA network as a crucial modulator of carcinogenesis and the regulation of signaling pathways or genes that are relevant to the metastasis of HCC. These findings have the potential to offer valuable insight into the discovery of novel therapeutic approaches for management of liver cancer metastasis.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | - Tuqa S Alazzawi
- College of Dentist, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Ali A Fahdil
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Bekhzod Yarmukhamedov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | | | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
- School of Pharmacy, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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2
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Cheng H, Li Y, Cheng J, Zhang Y, Zhang B. Study on the effect and mechanisms of piperine against cervical cancer based on network pharmacology and experimental validation. Biotechnol Genet Eng Rev 2024; 40:4875-4898. [PMID: 37235876 DOI: 10.1080/02648725.2023.2217611] [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: 03/21/2023] [Accepted: 05/19/2023] [Indexed: 05/28/2023]
Abstract
Piperine has immunomodulatory and anti-inflammatory properties, and its potential in treating cervical cancer needs further exploration. Using data from The Cancer Genome Atlas (TCGA), we identified immune-related differentially expressed genes (IRDEGs) in cervical cancer. Predicted targets of piperine were compared with cervical cancer-associated genes from various databases. Protein-protein interaction (PPI) network analysis, enrichment of GO and KEGG pathways, and molecular docking were performed. Kaplan-Meier survival analysis was done to assess prognostic significance. In vitro and in vivo experiments were conducted to confirm findings. We obtained 403 IRDEGs, 125 piperine targets, and 7037 cervical cancer genes. PPI network analysis revealed potential targets and pathways regulated by piperine. Molecular docking showed good binding activity of piperine with specific targets. In vitro, piperine inhibited cervical cancer cell proliferation, migration, and invasion, and promoted apoptosis. In vivo, piperine suppressed tumor growth and downregulated expression of IL-1β and NLRP3 in tumor cells. Piperine also downregulated expression of IL-17A, IL-21, IL-22, and RORγt, and decreased the number of Th17 cells in tumor tissues. Piperine may inhibit cervical cancer progression through modulation of Th17 cell activation mediated by the NLRP3/IL-1β axis. Further studies are warranted to explore the potential of piperine as an immunomodulatory agent in cervical cancer treatment.
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Affiliation(s)
- Hui Cheng
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Xuzhou, Jiangsu, China
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Yanyu Li
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Xuzhou, Jiangsu, China
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Jie Cheng
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Xuzhou, Jiangsu, China
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Yanling Zhang
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Xuzhou, Jiangsu, China
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Bei Zhang
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Xuzhou, Jiangsu, China
- Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
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Song G, Yu X, Shi H, Sun B, Amateau S. miRNAs in HCC, pathogenesis, and targets. Hepatology 2024:01515467-990000000-01097. [PMID: 39626210 DOI: 10.1097/hep.0000000000001177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Liver cancer is the third leading cause of cancer-related mortality worldwide. HCC, the most common type of primary liver cancer, is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally occurring small noncoding RNAs, play crucial roles in HCC by simultaneously modulating the expression of multiple genes in a fine-tuning manner. Significant progress has been made in understanding how miRNAs influence key oncogenic pathways, including cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), as well as their role in modulating the immune microenvironment in HCC. Due to the unexpected stability of miRNAs in the blood and fixed HCC tumors, recent advancements also highlight their potential as noninvasive diagnostic tools. Restoring or inhibiting specific miRNAs has offered promising strategies for targeted HCC treatment by suppressing malignant hepatocyte growth and enhancing antitumor immunity. In this comprehensive review, we consolidate previous research and provide the latest insights into how miRNAs regulate HCC and their therapeutic and diagnostic potential. We delve into the dysregulation of miRNA biogenesis in HCC, the roles of miRNAs in the proliferation and apoptosis of malignant hepatocytes, angiogenesis and metastasis of HCC, the immune microenvironment in HCC, and drug resistance. We also discuss the therapeutic and diagnostic potential of miRNAs and delivery approaches of miRNA drugs to overcome the limitations of current HCC treatment options. By thoroughly summarizing the roles of miRNAs in HCC, our goal is to advance the development of effective therapeutic drugs with minimal adverse effects and to establish precise tools for early diagnosis of HCC.
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Affiliation(s)
- Guisheng Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Xiaofan Yu
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Hongtao Shi
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan City, China
| | - Bo Sun
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Stuart Amateau
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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Elkot WF, Rayan AM, Malek G, Alsulami T, Elmahdy A, Al-Farga A, Abu-Taha HL, Tantawy AA. Assessment of using heart of date palm as a new source of protein and carbohydrate on the quality of low-fat bio fermented camel milk and its potential anticancer properties. Int J Biol Macromol 2024; 282:137174. [PMID: 39489267 DOI: 10.1016/j.ijbiomac.2024.137174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 10/16/2024] [Accepted: 10/30/2024] [Indexed: 11/05/2024]
Abstract
The heart of date palm (HDP) is a nutrient-dense vegetable, rich in protein and carbohydrate, obtained from the core of palm trees. Carbohydrates are the major component of the heart of date palm, providing a quick source of energy and fiber content can help digestion and contribute to feeling of fullness, making it good addition to a balanced diet. The study investigated the potential of incorporating HDP into low-fat bio fermented camel milk (BCM). The initial findings highlighted HDP's medicinal properties and its significant cytotoxic effects against HepG2 cells, indicating its potential as an anticancer agent. Over 21 days of cold storage, the addition of HDP improved the water-holding capacity, color, sensory qualities, bioactive compounds, and rheological properties of low-fat BCM. Moreover, no mold, yeasts, or coliforms were detected in any samples throughout the storage. The total number of viable probiotic cells remained functional (>106 log CFU/g) for 21 days. The sensory evaluation results suggested that high-quality low-fat BCM can be achieved by adding up to 20 % HDP. The molecular docking study supports the various biological activities of HDP particularly in relation to its cytotoxic effects against HepG2 cancer cells. This study opens the door for further exploration into utilizing HDP as a novel functional ingredient in dairy foods to create value-added products.
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Affiliation(s)
- Wael F Elkot
- Dairy Science and Technology Department, Faculty of Agriculture & Natural Resources, Aswan University, Aswan 81528, Egypt.
| | - Ahmed M Rayan
- Food Technology Department, Faculty of Agriculture, Suez canal University, Ismailia 41522, Egypt
| | - Gihan Malek
- Dairy Technology Research Department, Animal Production Research Institute, Agricultural Research Center, Dokky, Giza, Egypt
| | - Tawfiq Alsulami
- Department of Food Science & Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ahmed Elmahdy
- Department of Dairy Science, Faculty of Desert and Environmental Agriculture, Matrouh University, Matrouh, Egypt
| | - Ammar Al-Farga
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, PR China
| | - Hadeer Lotfy Abu-Taha
- Agricultural Engineering Department, Faculty of Agriculture, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Aml Abubakr Tantawy
- Food Science and Technology Department, Faculty of Agriculture& Natural Resources, Aswan University, Aswan 81528, Egypt
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Cabral LKD, Giraudi PJ, Giannelli G, Dituri F, Negro R, Tiribelli C, Sukowati CHC. Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models. Biomedicines 2023; 11:342. [PMID: 36830879 PMCID: PMC9953082 DOI: 10.3390/biomedicines11020342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/12/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy marked by heterogeneity. This study aimed to discover target molecules for potential therapeutic efficacy that may encompass HCC heterogeneity. In silico analysis using published datasets identified 16 proto-oncogenes as potential pharmacological targets. We used an immortalized hepatocyte (IHH) and five HCC cell lines under two subtypes: S1/TGFβ-Wnt-activated (HLE, HLF, and JHH6) and the S2/progenitor subtype (HepG2 and Huh7). Three treatment modalities, 5 µM 5-Azacytidine, 50 µM Sorafenib, and 20 nM PD-L1 gene silencing, were evaluated in vitro. The effect of treatments on the proto-oncogene targets was assessed by gene expression and Western blot analysis. Our results showed that 10/16 targets were upregulated in HCC cells, where cells belonging to the S2/progenitor subtype had more upregulated targets compared to the S1/TGFβ-Wnt-activated subtype (81% vs. 62%, respectively). Among the targets, FGR was consistently down-regulated in the cell lines following the three different treatments. Sorafenib was effective to down-regulate targets in S2/progenitor subtype while PD-L1 silencing was able to decrease targets in all HCC subtypes, suggesting that this treatment strategy may comprise cellular heterogeneity. This study strengthens the relevance of liver cancer cellular heterogeneity in response to cancer therapies.
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Affiliation(s)
- Loraine Kay D. Cabral
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (P.J.G.); (C.T.)
- Doctoral School in Molecular Biomedicine, University of Trieste, 34127 Trieste, Italy
| | - Pablo J. Giraudi
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (P.J.G.); (C.T.)
| | - Gianluigi Giannelli
- National Institute of Gastroenterology IRCCS “S. De Bellis” Research Hospital, 70013 Bari, Italy; (G.G.); (F.D.); (R.N.)
| | - Francesco Dituri
- National Institute of Gastroenterology IRCCS “S. De Bellis” Research Hospital, 70013 Bari, Italy; (G.G.); (F.D.); (R.N.)
| | - Roberto Negro
- National Institute of Gastroenterology IRCCS “S. De Bellis” Research Hospital, 70013 Bari, Italy; (G.G.); (F.D.); (R.N.)
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (P.J.G.); (C.T.)
| | - Caecilia H. C. Sukowati
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (P.J.G.); (C.T.)
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
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Novel Circulating Tumour Cell-Related Risk Model Indicates Prognosis and Immune Infiltration in Lung Adenocarcinoma. J Immunol Res 2022; 2022:6521290. [PMID: 35677538 PMCID: PMC9168189 DOI: 10.1155/2022/6521290] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 05/03/2022] [Indexed: 01/07/2023] Open
Abstract
Background Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer (LC) and one of the leading causes of cancer-related death worldwide. LUAD has a low survival rate owing to tumour invasion and metastasis. Circulating tumour cells (CTCs) are precursors of distant metastasis, which are considered to adopt the characteristics of cancer stem cells (CSCs). Therefore, analysing the risk factors of LUAD from the perspective of CTCs may provide novel insights into the metastatic mechanisms and may help to develop diagnostic and therapeutic strategies. Methods A total of 447 patients from TCGA dataset were included in the training cohort, and 460 patients from the GEO dataset were included in the validation cohort. A CTC-related-gene risk model was constructed using LASSO penalty–Cox analysis, and its predictive value was further verified. Functional enrichment analysis was performed on differentially expressed genes (DEGs), followed by immune correlation analysis based on the results. In addition, western blot, CCK-8 and colony formation assays were used to validate the biological function of RAB26 in LUAD. Results A novel in-silico CTC-related-gene risk model, named the CTCR model, was constructed, which successfully divided patients into the high- and low-risk groups. The prognosis of the high-risk group was worse than that of the low-risk group. ROC analysis revealed that the risk model outperformed traditional clinical markers in predicting the prognosis of patients with LUAD. Further study demonstrated that the identified DEGs were significantly enriched in immune-related pathways. The immune score of the low-risk group was higher than that of the high-risk group. In addition, RAB26 was found to promote the proliferation of LUAD. Conclusion A prognostic risk model based on CTC-related genes was successfully constructed, and the relationship between DEGs and tumour immunity was analysed. In addition, RAB26 was found to promote the proliferation of LUAD cells.
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Wang SM, Yang PW, Feng XJ, Zhu YW, Qiu FJ, Hu XD, Zhang SH. Apigenin Inhibits the Growth of Hepatocellular Carcinoma Cells by Affecting the Expression of microRNA Transcriptome. Front Oncol 2021; 11:657665. [PMID: 33959508 PMCID: PMC8095173 DOI: 10.3389/fonc.2021.657665] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 03/12/2021] [Indexed: 01/22/2023] Open
Abstract
Background Apigenin, as a natural flavonoid, has low intrinsic toxicity and has potential pharmacological effects against hepatocellular carcinoma (HCC). However, the molecular mechanisms involving microRNAs (miRNAs) and their target genes regulated by apigenin in the treatment of HCC have not been addressed. Objective In this study, the molecular mechanisms of apigenin involved in the prevention and treatment of HCC were explored in vivo and in vitro using miRNA transcriptomic sequencing to determine the basis for the clinical applications of apigenin in the treatment of HCC. Methods The effects of apigenin on the proliferation, cell cycle progression, apoptosis, and invasion of human hepatoma cell line Huh7 and Hep3B were studied in vitro, and the effects on the tumorigenicity of Huh7 cells were assessed in vivo. Then, a differential expression analysis of miRNAs regulated by apigenin in Huh7 cells was performed using next-generation RNA sequencing and further validated by qRT-PCR. The potential genes targeted by the differentially expressed miRNAs were identified using a curated miRTarBase miRNA database and their molecular functions were predicted using Gene Ontology and KEGG signaling pathway analysis. Results Compared with the control treatment group, apigenin significantly inhibited Huh7 cell proliferation, cell cycle, colony formation, and cell invasion in a concentration-dependent manner. Moreover, apigenin reduced tumor growth, promoted tumor cell necrosis, reduced the expression of Ki67, and increased the expression of Bax and Bcl-2 in the xenograft tumors of Huh7 cells. Bioinformatics analysis of the miRNA transcriptome showed that hsa-miR-24, hsa-miR-6769b-3p, hsa-miR-6836-3p, hsa-miR-199a-3p, hsa-miR-663a, hsa-miR-4739, hsa-miR-6892-3p, hsa-miR-7107-5p, hsa-miR-1273g-3p, hsa-miR-1343, and hsa-miR-6089 were the most significantly up-regulated miRNAs, and their key gene targets were MAPK1, PIK3CD, HRAS, CCND1, CDKN1A, E2F2, etc. The core regulatory pathways of the up-regulated miRNAs were associated with the hepatocellular carcinoma pathway. The down-regulated miRNAs were hsa-miR-181a-5p and hsa-miR-148a-3p, and the key target genes were MAPK1, HRAS, STAT3, FOS, BCL2, SMAD2, PPP3CA, IFNG, MET, and VAV2, with the core regulatory pathways identified as proteoglycans in cancer pathway. Conclusion Apigenin can inhibit the growth of HCC cells, which may be mediated by up-regulation or down-regulation of miRNA molecules and their related target genes.
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Affiliation(s)
- Shou-Mei Wang
- Department of Pathology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Chinese Medicine, Shanghai, China
| | - Pei-Wei Yang
- Department of Pathology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Chinese Medicine, Shanghai, China
| | - Xiao-Jun Feng
- Department of Pathology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Chinese Medicine, Shanghai, China
| | - Yi-Wei Zhu
- Department of Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Feng-Jun Qiu
- Department of Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xu-Dong Hu
- Department of Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shu-Hui Zhang
- Department of Pathology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Chinese Medicine, Shanghai, China
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SLC39A7, regulated by miR-139-5p, induces cell proliferation, migration and inhibits apoptosis in gastric cancer via Akt/mTOR signaling pathway. Biosci Rep 2021; 40:222123. [PMID: 32109290 PMCID: PMC7048674 DOI: 10.1042/bsr20200041] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/11/2020] [Accepted: 02/12/2020] [Indexed: 01/08/2023] Open
Abstract
As a zinc transporter, SLC39A7 (zip7) is vital in intestinal epithelial self-renewal, and recent studies suggested that SLC39A7 was related to cancer progression. Whereas, little is known about the role of SLC39A7 in gastric cancer (GC). In the present study, qRT-PCR analysis demonstrated that SLC39A7 mRNA level was increased in both GC tissues and cell lines. Overexpressing SLC39A7 boosted cell proliferation and migration, while inhibited apoptosis in GC. It was also found that si-SLC39A7 suppressed Akt/mTOR pathway and activation of Akt/mTOR pathway reversed the effects of si-SLC39A7 on GC development. Through prediction website, we found that SLC39A7 was directly regulated by miR-139-5p. miR-139-5p mimic had adverse effects on SLC39A7 expression and influence in the GC cell proliferation, migration and apoptosis by Akt/mTOR signaling pathway, while miR-139-5p inhibitor showed opposite effects. To conclude, our studies showed that SLC39A7 was negatively regulated by miR-139-5p. Besides, SLC39A7 positively regulated GC development through Akt/mTOR signaling pathway. These results indicate that SLC39A7 may be a candidate target gene for GC treatment.
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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Mungamuri SK, Nagasuryaprasad K. Epigenetic mechanisms of hepatocellular carcinoma progression: Potential therapeutic opportunities. EPIGENETICS AND METABOLOMICS 2021:279-296. [DOI: 10.1016/b978-0-323-85652-2.00008-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
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Al Haddad M, El-Rif R, Hanna S, Jaafar L, Dennaoui R, Abdellatef S, Miskolci V, Cox D, Hodgson L, El-Sibai M. Differential regulation of rho GTPases during lung adenocarcinoma migration and invasion reveals a novel role of the tumor suppressor StarD13 in invadopodia regulation. Cell Commun Signal 2020; 18:144. [PMID: 32900380 PMCID: PMC7487901 DOI: 10.1186/s12964-020-00635-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 08/03/2020] [Indexed: 11/11/2022] Open
Abstract
Background Lung cancer is the second most commonly occurring cancer. The ability to metastasize and spread to distant locations renders the tumor more aggressive. Members of the Rho subfamily of small GTP-binding proteins (GTPases) play a central role in the regulation of the actin cytoskeleton and in cancer cell migration and metastasis. In this study we investigated the role of the RhoA/Cdc42 GAP, StarD13, a previously described tumor suppressor, in malignancy, migration and invasion of the lung cancer cells A549. Methods We knocked down StarD13 expression in A549 lung cancer cells and tested the effect on cell migration and invadopodia formation using time lapse imaging and invasion assays. We also performed rescue experiments to determine the signaling pathways downstream of StarD13 and transfected the cells with FRET biosensors for RhoGTPases to identify the proteins involved in invadopodia formation. Results We observed a decrease in the level of expression of StarD13 in lung tumor tissues compared to normal lung tissues through immunohistochemistry. StarD13 also showed a lower expression in the lung adenocarcinoma cell line A549 compared to normal lung cells, WI38. In addition, the depletion of StarD13 increased cell proliferation and viability in WI38 and A549 cells, suggesting that StarD13 might potentially be a tumor suppressor in lung cancer. The depletion of StarD13, however, inhibited cell motility, conversely demonstrating a positive regulatory role in cell migration. This was potentially due to the constitutive activation of RhoA detected by pull down and FRET assays. Surprisingly, StarD13 suppressed cell invasion by inhibiting Cdc42-mediated invadopodia formation. Indeed, TKS4 staining and invadopodia assay revealed that StarD13 depletion increased Cdc42 activation as well as invadopodia formation and matrix degradation. Normal lung cells depleted of StarD13 also produced invadopodia, otherwise a unique hallmark of invasive cancer cells. Cdc42 knock down mimicked the effects of StarD13, while overexpression of a constitutively active Cdc42 mimicked the effects of its depletion. Finally, immunostaining and FRET analysis revealed the absence of StarD13 in invadopodia as compared to Cdc42, which was activated in invadopodia at the sites of matrix degradation. Conclusion In conclusion, StarD13 plays distinct roles in lung cancer cell migration and invasion through its differential regulation of Rho GTPases.
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Video abstract.
- Maria Al Haddad
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, P.O. Box: 13-5053. Chouran, Beirut, 1102 2801, Lebanon
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- Rayane El-Rif
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, P.O. Box: 13-5053. Chouran, Beirut, 1102 2801, Lebanon
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- Samer Hanna
- Department of Pediatrics HemeOnc division, Weill Cornell Medicine, Joan & Sanford I. Weill Medical College of Cornell University, New York, USA
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- Leila Jaafar
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, P.O. Box: 13-5053. Chouran, Beirut, 1102 2801, Lebanon
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- Rayanne Dennaoui
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, P.O. Box: 13-5053. Chouran, Beirut, 1102 2801, Lebanon
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- Sandra Abdellatef
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, P.O. Box: 13-5053. Chouran, Beirut, 1102 2801, Lebanon
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- Veronika Miskolci
- Department of Medical Microbiology and Immunology, University of Wisconsin - Madison, Madison, WI, 53706, USA
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- Dianne Cox
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, USA.,Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, USA
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- Louis Hodgson
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, USA.,Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, USA
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- Mirvat El-Sibai
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, P.O. Box: 13-5053. Chouran, Beirut, 1102 2801, Lebanon.
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12
Danbaran GR, Aslani S, Sharafkandi N, Hemmatzadeh M, Hosseinzadeh R, Azizi G, Jadidi-Niaragh F, Babaie F, Mohammadi H. How microRNAs affect the PD-L1 and its synthetic pathway in cancer.
Int Immunopharmacol 2020;
84:106594. [PMID:
32416456 DOI:
10.1016/j.intimp.2020.106594]
[Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/27/2020] [Accepted: 05/08/2020] [Indexed: 12/17/2022]
Abstract
Programmed cell death-ligand 1 (PD-L1) is a glycoprotein that is expressed on the cell surface of both hematopoietic and nonhematopoietic cells. PD-L1 play a role in the immune tolerance and protect self-tissues from immune system attack. Dysfunction of this molecule has been highlighted in the pathogenesis of tumors, autoimmunity, and infectious disorders. MicroRNAs (miRNAs) are endogenous molecules that are classified as small non-coding RNA with approximately 20-22 nucleotides (nt) length. The function of miRNAs is based on complementary interactions with target mRNA via matching completely or incompletely. The result of this function is decay of the target mRNA or preventing mRNA translation. In the past decades, several miRNAs have been discovered which play an important role in the regulation of PD-L1 in various malignancies. In this review, we discuss the effect of miRNAs on PD-L1 expression and consider the effect of miRNAs on the synthetic pathway of PD-L1, especially during cancers.
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Affiliation(s)
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- Saeed Aslani
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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- Nadia Sharafkandi
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
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- Maryam Hemmatzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
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- Ramin Hosseinzadeh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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- Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
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- Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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- Farhad Babaie
- Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
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- Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
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13
Qin H, Wen DY, Que Q, Zhou CY, Wang XD, Peng YT, He Y, Yang H, Liao BM. Reduced expression of microRNA-139-5p in hepatocellular carcinoma results in a poor outcome: An exploration the roles of microRNA-139-5p in tumorigenesis, advancement and prognosis at the molecular biological level using an integrated meta-analysis and bioinformatic investigation.
Oncol Lett 2019;
18:6704-6724. [PMID:
31807180 PMCID:
PMC6876336 DOI:
10.3892/ol.2019.11031]
[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: 05/10/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is generally considered one of the most common gastrointestinal malignant tumors, characterized by high invasiveness and metastatic rate, as well as insidious onset. A relationship between carcinogenicity and aberrant microRNA-139-5p (miR-139-5p) expression has been identified in multiple tumors while the specific molecular mechanisms of miR-139-5p in HCC have not yet been thoroughly elucidated. A meta-analysis of available data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus, ArrayExpress and Oncomine databases, as well as the published literature, was comprehensively conducted with the aim of examining the impact of miR-139-5p expression on HCC. Additionally, predicted downstream target genes were confirmed using a series of bioinformatics tools. Moreover, a correlative biological analysis was performed to ascertain the precise function of miR-139-5p in HCC. The results revealed that the expression of miR-139-5p was noticeably lower in HCC compared with non-tumor liver tissues according to the pooled standard mean difference, which was -0.84 [95% confidence interval (CI): -1.36 to -0.32; P<0.001]. Furthermore, associations were detected between miR-139-5p expression and certain clinicopathological characteristics of TCGA samples, including tumor grade, pathological stage and T stage. Moreover, the pooled hazard ratio (HR) for overall survival (HR=1.37; 95% CI: 1.07-1.76; P=0.001) indicated that decreased miR-139-5p expression was a risk factor for adverse outcomes. Additionally, 382 intersecting genes regulated by miR-139-5p were obtained and assembled in signaling pathways, including 'transcription factor activity, sequence-specific DNA binding', 'pathways in cancer' and 'Ras signaling pathway'. Notably, four targeted genes that were focused in 'pathways in cancer' were identified as hub genes and immunohistochemical staining of the proteins encoded by these four hub genes in liver tissues, explored using the Human Protein Atlas database, confirmed their expression patterns in HCC and normal liver tissues Findings of the present study suggest that reduced miR-139-5p expression is capable of accelerating tumor progression and is associated with a poor clinical outcome by modulating the expression of downstream target genes involved in tumor-associated signaling pathways.
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Affiliation(s)
- Hui Qin
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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- Dong-Yue Wen
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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- Qiao Que
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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- Chuan-Yang Zhou
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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- Xiao-Dong Wang
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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- Yu-Ting Peng
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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- Yun He
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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- Hong Yang
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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- Bo-Ming Liao
- Department of Internal Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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14
Wang X, Zhu W, Xu C, Wang F, Zhu X, Sun Y, Guo Y, Fu X, Zhang Y, Zang Y. MicroRNA-370 functions as a tumor suppressor in hepatocellular carcinoma via inhibition of the MAPK/JNK signaling pathway by targeting BEX2.
J Hum Genet 2019;
64:1203-1217. [PMID:
31530937 DOI:
10.1038/s10038-019-0653-x]
[Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 07/08/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. Accumulating studies have revealed that microRNAs (miRNAs) play a critical role in the development and progression of HCC. Through microarray-based gene expression profiling of HCC, miR-370, and BEX2 were identified in HCC. Hence, this study aimed to evaluate their abilities on the cellular processes in HCC. It was determined that BEX2 was highly expressed and miR-370 was poorly expressed in HCC cell lines and tissues. Then, the cell line presenting with the highest BEX2 expression and the lowest miR-370 expression was selected for subsequent gain- and loss-of-function experimentation. The antitumor effect of miR-370 on HCC cell proliferation, invasion, migration, and apoptosis, as well as the MAPK/JNK signaling pathway was examined. Meanwhile, the interaction among miR-370, BEX2, and MAPK/JNK signaling pathway was identified. BEX2 is verified to be a target of miR-370. Moreover, miR-370 exerted antitumor effect on HCC development through suppression of the MAPK/JNK signaling pathway by targeting BEX2. Later, it was further verified by in vivo experiment that overexpression of miR-370 inhibited tumor growth. Above results provide evidence that miR-370 could downregulate BEX2 gene and inhibit activation of MAPK/JNK signaling pathway, thus inhibiting the development of HCC. It provides a worth-trying novel therapeutic target for HCC treatment.
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Affiliation(s)
- Xin Wang
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
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- Wenyan Zhu
- Operating Room, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
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- Chuanshen Xu
- Transplantation Care Unit, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
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- Feng Wang
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
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- Xiaodan Zhu
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
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- Yandong Sun
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
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- Yuan Guo
- Department of Liver Surgery, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
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- Xiaoyue Fu
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
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- Yong Zhang
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
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- Yunjin Zang
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China.
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15
Wu X, Peng L, Zhang Y, Chen S, Lei Q, Li G, Zhang C. Identification of Key Genes and Pathways in Cervical Cancer by Bioinformatics Analysis.
Int J Med Sci 2019;
16:800-812. [PMID:
31337953 PMCID:
PMC6643108 DOI:
10.7150/ijms.34172]
[Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023] Open
Abstract
Cervical cancer is a common malignant tumour of the female reproductive system that seriously threatens the health of women. The aims of this study were to identify key genes and pathways and to illuminate new molecular mechanisms underlying cervical cancer. Altogether, 1829 DEGs were identified, including 794 significantly down-regulated DEGs and 1035 significantly up-regulated DEGs. GO analysis suggested that the up-regulated DEGs were mainly enriched in mitotic cell cycle processes, including DNA replication, organelle fission, chromosome segregation and cell cycle phase transition, and that the down-regulated DEGs were primarily enriched in development and differentiation processes, such as tissue development, epidermis development, skin development, keratinocyte differentiation, epidermal cell differentiation and epithelial cell differentiation. KEGG pathway analysis showed that the DEGs were significantly enriched in cell cycle, DNA replication, the p53 signalling pathway, pathways in cancer and oocyte meiosis. The top 9 hub genes with a high degree of connectivity (over 72 in the PPI network) were down-regulated TSPO, CCND1, and FOS and up-regulated CDK1, TOP2A, CCNB1, PCNA, BIRC5 and MAD2L1. Module analysis indicated that the top 3 modules were significantly enriched in mitotic cell cycle, DNA replication and regulation of cell cycle (P < 0.01). The heat map based on TCGA database preliminarily demonstrated the expression change of the key genes in cervical cancer. GSEA results were basically coincident with the front enrichment analysis results. By comprehensive analysis, we confirmed that cell cycle was a key biological process and a critical driver in cervical cancer. In conclusion, this study identified DEGs and screened the key genes and pathways closely related to cervical cancer by bioinformatics analysis, simultaneously deepening our understanding of the molecular mechanisms underlying the occurrence and progression of cervical cancer. These results might hold promise for finding potential therapeutic targets of cervical cancer.
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Affiliation(s)
- Xuan Wu
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China
- Cancer Research Institute, Central South University, Changsha, P.R. China
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- Li Peng
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
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- Yaqin Zhang
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China
- Cancer Research Institute, Central South University, Changsha, P.R. China
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- Shilian Chen
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China
- Cancer Research Institute, Central South University, Changsha, P.R. China
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- Qian Lei
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China
- Cancer Research Institute, Central South University, Changsha, P.R. China
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- Guancheng Li
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China
- Cancer Research Institute, Central South University, Changsha, P.R. China
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- Chaoyang Zhang
- Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China
- Division of Functional Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg, Germany
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16
Zan Y, Wang B, Liang L, Deng Y, Tian T, Dai Z, Dong L. MicroRNA-139 inhibits hepatocellular carcinoma cell growth through down-regulating karyopherin alpha 2.
J Exp Clin Cancer Res 2019;
38:182. [PMID:
31046781 PMCID:
PMC6498602 DOI:
10.1186/s13046-019-1175-2]
[Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 04/11/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND
MicroRNA-139-5p (miR-139) has been shown to play important roles in hepatocellular carcinoma (HCC) development. However, the exact mechanism of miR-139 in HCC remains largely unknown.
METHODS
We investigated the function in human cell lines and patient tissue samples by experimental techniques in molecular biology including Co-IP assay, cell viability assay, quantitative real-time-PCR, et al. In addition, datasets were used to verify the results by database analysis. Statistical analysis was performed by using the GraphPad Prism 6 (GraphPad Software Inc., USA). A P value < 0.05 was defined as statistically significant.
RESULTS
In this study, we found that miR-139 was significantly down-regulated in HCC. MiR-139 level was negatively associated with the stage of HCC, and HCC patients with higher miR-139 level had longer overall survival (OS) than these having lower miR-139 expression. Overexpression of miR-139 led to reduced cell viability, elevated apoptosis, and decreased colony forming, migratory and invasive capacities in HCC cells, while down-regulation of miR-139 led to opposite phenotypes. MiR-139 also inhibited HCC growth in a xenograft mouse model. We identified karyopherin alpha 2 (KPNA2) as a direct target of miR-139. KPNA2 is up-regulated in HCC and higher KPNA2 level is associated with poor patient prognosis. Silencing of KPNA2 expression led to similar phenotypic changes as miR-139 overexpression. Restoration of KPNA2 attenuated the suppressive effects of miR-139 overexpression on cell viability, apoptosis, colony formation, migration and invasion. In addition, miR-139 overexpression and KPNA2 depletion led to decreased nucleus level of POU class 5 homeobox 1 (POU5F1) and c-myc, two well-known pro-oncogenes.
CONCLUSION
In together, these data revealed the essential roles of the miR-139/KPNA2 axis in HCC.
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Affiliation(s)
- Ying Zan
- Department of Oncology, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004 China
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- Baofeng Wang
- Department of Oncology, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004 China
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- Liang Liang
- Department of Oncology, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004 China
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- Yujiao Deng
- Department of Oncology, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004 China
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- Tian Tian
- Department of Oncology, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004 China
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- Zhijun Dai
- Department of Oncology, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004 China
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- Lei Dong
- Department of Gastroenterology, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004 China
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17
Bioinformatics analysis to identify the key genes affecting the progression and prognosis of hepatocellular carcinoma.
Biosci Rep 2019;
39:BSR20181845. [PMID:
30705088 PMCID:
PMC6386764 DOI:
10.1042/bsr20181845]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 01/28/2019] [Accepted: 01/30/2019] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, which has poor outcome. The present study aimed to investigate the key genes implicated in the progression and prognosis of HCC. The RNA-sequencing data of HCC was extracted from The Cancer Genome Atlas (TCGA) database. Using the R package (DESeq), the differentially expressed genes (DEGs) were analyzed. Based on the Cluepedia plug-in in Cytoscape software, enrichment analysis for the protein-coding genes amongst the DEGs was conducted. Subsequently, protein–protein interaction (PPI) network was built by Cytoscape software. Using survival package, the genes that could distinguish the survival differences of the HCC samples were explored. Moreover, quantitative real-time reverse transcription-PCR (qRT-PCR) experiments were used to detect the expression of key genes. There were 2193 DEGs in HCC samples. For the protein-coding genes amongst the DEGs, multiple functional terms and pathways were enriched. In the PPI network, cyclin-dependent kinase 1 (CDK1), polo-like kinase 1 (PLK1), Fos proto-oncogene, AP-1 transcription factor subunit (FOS), serum amyloid A1 (SAA1), and lysophosphatidic acid receptor 3 (LPAR3) were hub nodes. CDK1 interacting with PLK1 and FOS, and LPAR3 interacting with FOS and SAA1 were found in the PPI network. Amongst the 40 network modules, 4 modules were with scores not less than 10. Survival analysis showed that anterior gradient 2 (AGR2) and RLN3 could differentiate the high- and low-risk groups, which were confirmed by qRT-PCR. CDK1, PLK1, FOS, SAA1, and LPAR3 might be key genes affecting the progression of HCC. Besides, AGR2 and RLN3 might be implicated in the prognosis of HCC.
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18
Xu F, Li CH, Wong CH, Chen GG, Lai PBS, Shao S, Chan SL, Chen Y. Genome-Wide Screening and Functional Analysis Identifies Tumor Suppressor Long Noncoding RNAs Epigenetically Silenced in Hepatocellular Carcinoma.
Cancer Res 2019;
79:1305-1317. [PMID:
30718359 DOI:
10.1158/0008-5472.can-18-1659]
[Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 09/27/2018] [Accepted: 01/31/2019] [Indexed: 11/16/2022]
Abstract
Long noncoding RNAs (lncRNA) play critical roles in the development of cancer, including hepatocellular carcinoma (HCC). However, the mechanisms underlying their deregulation remain largely unexplored. In this study, we report that two lncRNAs frequently downregulated in HCC function as tumor suppressors and are epigenetically silenced by histone methyltransferase EZH2. lncRNAs TCAM1P-004 and RP11-598D14.1 were inhibited by EZH-mediated trimethylation of H3K27me3 at their promoters. Downregulation of TCAM1P-004 and RP11-598D14.1 was frequently observed in HCC tumors compared with adjacent normal tissues. Both lncRNAs inhibited cell growth, cell survival, and transformation in HCC cells in vitro as well as tumor formation in vivo. Using RNA pull-down and mass spectrometry, we demonstrated that TCAM1P-004 bound IGF2BP1 and HIST1H1C, whereas RP11-598D14.1 bound IGF2BP1 and STAU1. These lncRNA-protein interactions were critical in regulating p53, MAPK, and HIF1α pathways that promoted cell proliferation in HCC. Overexpression of EZH2 was critical in repressing TCAM1P-004 and RP11-598D14.1, and EZH2-TCAM1P-004/RP11-598D14.1-regulated pathways were prevalent in human HCC. Aberrant suppression of TCAM1P-004 and RP11-598D14.1 led to loss of their tumor-suppressive effects by disrupting the interaction with IGF2BP1, HIST1H1C, and STAU1, which in turn promoted HCC development and progression. Collectively, these findings demonstrate the role of TCAMP1P-004 and RP11-598D14.1 in suppressing tumor growth and suggest that EZH2 may serve as a therapeutic target in HCC. SIGNIFICANCE: EZH2-mediated loss of lncRNAs TCAM1P-004 and RP11-598D14.1 hinders the formation of tumor suppressor lncRNA-protein complexes and subsequently promotes HCC growth.
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Affiliation(s)
- Feiyue Xu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
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- Chi Han Li
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
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- Chi Hin Wong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
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- George G Chen
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
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- Paul Bo San Lai
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
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- Shengwen Shao
- Institute of Microbiology and Immunology, Huzhou University, Huzhou, Zhejiang, China
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- Stephen L Chan
- Department of Clinical Oncology, State Key Laboratory in Oncology of South China and Institute of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
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- Yangchao Chen
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
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19
Li P, Xiao Z, Luo J, Zhang Y, Lin L. MiR-139-5p, miR-940 and miR-193a-5p inhibit the growth of hepatocellular carcinoma by targeting SPOCK1.
J Cell Mol Med 2019;
23:2475-2488. [PMID:
30710422 PMCID:
PMC6433657 DOI:
10.1111/jcmm.14121]
[Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 12/04/2018] [Accepted: 12/05/2018] [Indexed: 12/26/2022] Open
Abstract
The study was aimed to screen out miRNAs with differential expression in hepatocellular carcinoma (HCC), and to explore the influence of the expressions of these miRNAs and their target gene on HCC cell proliferation, invasion and apoptosis. MiRNAs with differential expression in HCC were screened out by microarray analysis. The common target gene of these miRNAs (miR‐139‐5p, miR‐940 and miR‐193a‐5p) was screened out by analysing the target genes profile (acquired from Targetscan) of the three miRNAs. Expression levels of miRNAs and SPOCK1 were determined by quantitative real time polymerase chain reaction (qRT‐PCR). The target relationships were verified by dual luciferase reporter gene assay and RNA pull‐down assay. Through 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide,thiazolyl blue tetrazolium bromide (MTT) and transwell assays and flow cytometry, HCC cell viability, invasion and apoptosis were determined. In vivo experiment was conducted in nude mice to investigate the influence of three miRNAs on tumour growth. Down‐regulation of miR‐139‐5p, miR‐940 and miR‐193a‐5p was found in HCC. Overexpression of these miRNAs suppressed HCC cell viability and invasion, promoted apoptosis and inhibited tumour growth. SPOCK1, the common target gene of miR‐139‐5p, miR‐940 and miR‐193a‐5p, was overexpressed in HCC. SPOCK1 overexpression promoted proliferation and invasion, and restrained apoptosis of HCC cells. MiR‐139‐5p, miR‐940 and miR‐193a‐5p inhibited HCC development through targeting SPOCK1.
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Affiliation(s)
- Peng Li
- Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
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- Zhiwei Xiao
- Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
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- Jiajun Luo
- Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
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- Yaojun Zhang
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
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- Lizhu Lin
- Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
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20
Zhang L, Liu M, Liu J, Li X, Yang M, Su B, Lin Y. 27-Hydroxycholesterol enhanced osteoclastogenesis in lung adenocarcinoma microenvironment.
J Cell Physiol 2018;
234:12692-12700. [PMID:
30511368 DOI:
10.1002/jcp.27883]
[Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 11/15/2018] [Indexed: 01/10/2023]
Abstract
27-Hydroxycholesterol (27-HC) has been implicated in the pathological process of estrogen receptor positive breast cancer. However, the role of 27-HC in lung adenocarcinoma is still unclear. Because bone metastasis is a main reason for the high mortality of lung adenocarcinoma, this study aimed to investigate the effect of 27-HC on osteoclastogenesis in lung adenocarcinoma microenvironment. The results showed that the conditioned media (CM) from lung adenocarcinoma cells cocultured with macrophages promoted osteoclast differentiation, which was enhanced by 27-HC. Further investigation showed that CM inhibited miR-139 expression and promoted c-Fos expression. Luciferase reporter assay identified c-Fos as a direct target of miR-139. CM also induced the expression and nuclear translocation of NFATc1 and STAT3 phosphorylation, which was enlarged by 27-HC but was attenuated by miR-139. Coimmunoprecipitation assay demonstrated that 27-HC increased the interaction between NFATc1 and phosphorylated STAT3, which was restricted by miR-139. Chromatin immunoprecipitation assay showed that pSTAT3 could bind to the promoter of c-Fos, c-Fos could bind to the promoter of NFATc1, and both pSTAT3 and NFATc1 could bind to the promoter of Oscar, which were enlarged by 27-HC but were blocked by miR-139. Knockdown of c-Fos mimicked the effect of miR-139. These results suggested that CM, especially containing 27-HC, promoted osteoclastogenesis by inhibiting miR-139 expression and activating the STAT3/c-Fos/NFATc1 pathway.
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Affiliation(s)
- Lishan Zhang
- Department of Hand and Foot Surgery, Shandong Provincial Hospital Affiliated to Shandong University, China
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- Ming Liu
- Department of Cardiothoracic Surgery, Gansu Provincial Hospital of TCM, Lanzhou, Jinan, China
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- Jinglei Liu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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- Xingkai Li
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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- Ming Yang
- Department of Ultrasound, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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- Benhua Su
- Department of Medical Engineering, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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- Yanliang Lin
- Department of Center Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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21
Li J, Li Q, Lin L, Wang R, Chen L, Du W, Jiang C, Li R. Targeting the Notch1 oncogene by miR-139-5p inhibits glioma metastasis and epithelial-mesenchymal transition (EMT).
BMC Neurol 2018;
18:133. [PMID:
30170559 PMCID:
PMC6117922 DOI:
10.1186/s12883-018-1139-8]
[Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/24/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND
Glioma metastasis, invasion, epithelial-mesenchymal transition (EMT) and chemoresistance indicate poor prognosis. Accumulating evidence reveals that Notch1 is an important factor in tumour progression. However, the role of Notch1 in glioma EMT and associated microRNAs (miRNAs) with the Notch pathway remain controversial.
METHODS
Utilizing cBioPortal database to examine the gene signature of NOTCH1 (encoding Notch1), CDH2 (encoding N-cadherin) and SNAI1 (encoding Snail-1) in disease-free survival (DFS) and overall survival (OS). We analyzed the Notch1 expression from Oncomine. We used Western blot (WB), immunohistochemistry (IHC) and immunofluorescence to determine protein levels. Transcription was evaluated by quantitative real-time (qRT)-PCR. siRNA and lentivirus were used to knock down Notch1 and overexpress miR-139-5p, respectively. The migration and invasion of glioma cells were assessed by wound healing and transwell assays. Luciferase reporter assays were utilized to verify the relationship between Notch1 and miR-139-5p. A U87-implanted intracranial model was used to study the effect of miR-139-5p on tumour growth and Notch1 suppression efficacy or EMT reversion.
RESULTS
It revealed the association of NOTCH1, CDH2, SNAI1 genomic alterations with decreases in DFS and OS. Notch1 was upregulated in classical and proneural subtypes of GBM, and associated with tumour grade. Notch1 inhibition suppressed the biological behaviours of metastasis, invasion and EMT. Notch1 was identified as a novel direct target of miR-139-5p. MiR-139-5p overexpression partially phenocopied Notch1 siRNA, whereas the forced expression of Notch1 reversed the effects of miR-139-5p on the invasion of glioma. Moreover, intracranial tumourigenicity and EMT behaviours were reduced by the introduction of miR-139-5p and partially mediated by the decreased Notch1 expression.
CONCLUSIONS
miR-139-5p was identified as a tumour suppressor by negatively targeting Notch1, and this work suggests a possible molecular mechanism of the miR-139/Notch1/EMT axis for glioma treatment.
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Affiliation(s)
- Jianlong Li
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang, 150086, Harbin, People's Republic of China.,Department of Orthopaedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
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- Qingbin Li
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang, 150086, Harbin, People's Republic of China.,Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China.,Chinese Glioma Cooperative Group (CGCG), Beijing, 100050, China
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- Lin Lin
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang, 150086, Harbin, People's Republic of China.,Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China.,Chinese Glioma Cooperative Group (CGCG), Beijing, 100050, China
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- Rui Wang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
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- Lingchao Chen
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
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- Wenzhong Du
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
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- Chuanlu Jiang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang, 150086, Harbin, People's Republic of China. .,Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. .,Chinese Glioma Cooperative Group (CGCG), Beijing, 100050, China.
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- Ruiyan Li
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang, 150086, Harbin, People's Republic of China. .,Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. .,Chinese Glioma Cooperative Group (CGCG), Beijing, 100050, China.
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22
Kadry MO, Abdel-Megeed RM, El-Meliegy E, Abdel-Hamid AHZ. Crosstalk between GSK-3, c-Fos, NFκB and TNF-α signaling pathways play an ambitious role in Chitosan Nanoparticles Cancer Therapy.
Toxicol Rep 2018;
5:723-727. [PMID:
30013938 PMCID:
PMC6024197 DOI:
10.1016/j.toxrep.2018.06.002]
[Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 05/15/2018] [Accepted: 06/01/2018] [Indexed: 12/13/2022] Open
Abstract
Nanotechnology is a promising era of medicine for developing targeted drug delivery system. Chitosan nanoparticles (CNPs) have attracted increasing attention for their wide applications as anticancer drugs. This article is concerned with the therapeutic index of chitosan nanoparticles against diethyl nitrosamine (DEN) induced hepatocellular carcinoma (HCC). HCC was induced in rats via repeated DEN administration in a dose of 200 mg/kg BW IP, 2 weeks later rats received (2 ml/kg BW) CCl4 orally for 2 months followed by daily treatment with chitosan nanoparticles in an oral dose of 12 mg/kg for 1 month. Then the gene expression of glycogen synthase kinase-3 (GSK-3), (c-FOS), nuclear factor kappa-B (NFκB) and tumor necrosis factor- α (TNF-α) were reported in rats sera and the correlation between GSK-3, C-Fos, NFƘB and TNF-α and liver tumorigenesis was investigated. The results elucidated that DEN significantly increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Marked increments in serum malondialdehyde (MDA) and nitric oxide (NOx) levels along with a slight reduction of glutathione (GSH) level were evidenced in HCC. Liver injury triggered an inflammatory response by enhancing the mRNA gene expression of NFκB and TNF-α. DEN effectively activated apoptotic markers GSK-3 and c-FOS. Oral administration of CNPs alleviated the oxidative, inflammatory and apoptotic hazards induced via DEN. The histopathological examination reinforced these results. The present study highlights the anti-inflammatory and anti-apoptotic potentials of CNPs against DEN-induced HCC.
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Affiliation(s)
- Mai O Kadry
- Biochemistry, Therapeutic Chemistry Department, National Research Centre, Dokki, Egypt
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- Rehab M Abdel-Megeed
- Molecular Biology, Therapeutic Chemistry Department, National Research Centre, Dokki, Egypt
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- Emad El-Meliegy
- Nanoceramics and technology, Department of biomaterials, National Research Centre, Dokki, Egypt
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23
Tu J, Zhao Z, Xu M, Lu X, Chang L, Ji J. NEAT1 upregulates TGF‐β1 to induce hepatocellular carcinoma progression by sponging hsa‐mir‐139‐5p.
J Cell Physiol 2018;
233:8578-8587. [DOI:
10.1002/jcp.26524]
[Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Accepted: 01/31/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Jianfei Tu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention ResearchThe Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang LishuiLishuiChina
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- Zhongwei Zhao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention ResearchThe Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang LishuiLishuiChina
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- Min Xu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention ResearchThe Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang LishuiLishuiChina
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- Liu Chang
- Institute of Foreign LanguagesJianghan UniversityWuhanChina
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- Jiansong Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention ResearchThe Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang LishuiLishuiChina
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24
Jiang C, Tong Z, Fang WL, Fu QB, Gu YJ, Lv TT, Liu DM, Xue W, Lv JW. Microrna-139-5p inhibits epithelial-mesenchymal transition and fibrosis in post-menopausal women with interstitial cystitis by targeting LPAR4 via the PI3K/Akt signaling pathway.
J Cell Biochem 2018;
119:6429-6441. [PMID:
29240250 DOI:
10.1002/jcb.26610]
[Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 12/07/2017] [Indexed: 01/06/2023]
Abstract
The study explores whether miR-139-5p targeting LPAR4 affects epithelial-mesenchymal transition (EMT) and fibrosis in post-menopausal women with interstitial cystitis (IC) via the PI3K/Akt signaling pathway. Bladder tissues of IC and normal bladder tissues were collected. The pathology of bladder tissues was observed by HE, Masson and Picrosirius red staining. LPAR4 positive expression rate were determined by IHC. ELISA was performed to detect the levels of IL-6, IL-8, IL-10, and TNF-α. Rat IC models were randomized into seven different groups. miR-139-5p, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, P13K, Akt, E-cadherin, N-cadherin, Vimentin, TGF-β1, and CTGF expression were determined by RT-qPCR and Western blotting. Dual luciferase reporter gene assay verified that LPAR4 is a target gene of miR-139-5p. Fibrosis was a pathological manifestation of IC. The IC group showed higher LPAR4, PI3K, Akt, p-PI3K, p-Akt, N-cadherin, Vimentin, TGF-β1, and CTGF expression but lower miR-139-5p and E-cadherin expression than the normal group. The levels of IL-6, IL-8, IL-10, and TNF-α expression decreased while HB-EGF increased in the IC group in comparison of the normal group. Compared with the blank and NC groups, E-cadherin expression was increased in the miR-139-5p mimic and siRNA-LPAR4 groups, while LPAR4, PI3K, Akt, p-P13K, p-Akt, N-cadherin, Vimentin, TGF-β1, and CTGF expression were decreased. An opposite trend was found in the miR-139-5p inhibitor group. The miR-139-5p decreased in the miR-139-5p inhibitor + siRNA-LPAR4 and miR-139-5p inhibitor + wortmannin groups. Conclusively, miR-139-5p targeting LPAR4 inhibits EMT and fibrosis in post-menopausal IC women through the PI3K/Akt signaling pathway.
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Affiliation(s)
- Chen Jiang
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
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- Zhen Tong
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
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- Wei-Lin Fang
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
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- Qi-Bo Fu
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
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- Yin-Jun Gu
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
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- Ting-Ting Lv
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
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- Dong-Ming Liu
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
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- Wei Xue
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
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- Jian-Wei Lv
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
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25
MTBP inhibits the Erk1/2-Elk-1 signaling in hepatocellular carcinoma.
Oncotarget 2018;
9:21429-21443. [PMID:
29765550 PMCID:
PMC5940416 DOI:
10.18632/oncotarget.25117]
[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: 11/08/2017] [Accepted: 03/21/2018] [Indexed: 01/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and the prognosis of HCC patients, especially those with metastasis, remains extremely poor. This is partly due to unclear molecular mechanisms underlying HCC metastasis. Our previous study indicates that MDM2 Binding Protein (MTBP) suppresses migration and metastasis of HCC cells. However, signaling pathways regulated by MTBP remain unknown. To identify metastasis-associated signaling pathways governed by MTBP, we have performed unbiased luciferase reporter-based signal array analyses and found that MTBP suppresses the activity of the ETS-domain transcription factor Elk-1, a downstream target of Erk1/2 MAP kinases. MTBP also inhibits phosphorylation of Elk-1 and decreases mRNA expression of Elk-1 target genes. Reduced Elk-1 activity is caused by inhibited nuclear translocation of phosphorylated Erk1/2 (p-Erk) by MTBP and subsequent inhibition of Elk-1 phosphorylation. We also reveal that MTBP inhibits the interaction of p-Erk with importin-7/RanBP7 (IPO7), an importin family member which shuttles p-Erk into the nucleus, by binding to IPO7. Moreover, high levels of MTBP in human HCC tissues are correlated with cytoplasmic localization of p-Erk1/2. Our study suggests that MTBP suppresses metastasis, at least partially, by down-modulating the Erk1/2-Elk-1 signaling pathway, thus identifying a novel regulatory mechanism of HCC metastasis by regulating the subcellular localization of p-Erk.
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26
Liao X, Zhu G, Huang R, Yang C, Wang X, Huang K, Yu T, Han C, Su H, Peng T. Identification of potential prognostic microRNA biomarkers for predicting survival in patients with hepatocellular carcinoma.
Cancer Manag Res 2018;
10:787-803. [PMID:
29713196 PMCID:
PMC5912208 DOI:
10.2147/cmar.s161334]
[Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background
The aim of the present study was to identify potential prognostic microRNA (miRNA) biomarkers for hepatocellular carcinoma (HCC) prognosis prediction based on a dataset from The Cancer Genome Atlas (TCGA).
Materials and methods
A miRNA sequencing dataset and corresponding clinical parameters of HCC were obtained from TCGA. Genome-wide univariate Cox regression analysis was used to screen prognostic differentially expressed miRNAs (DEMs), and multivariable Cox regression analysis was used for prognostic signature construction. Comprehensive survival analysis was performed to evaluate the prognostic value of the prognostic signature.
Results
Five miRNAs were regarded as prognostic DEMs and used for prognostic signature construction. The five-DEM prognostic signature performed well in prognosis prediction (adjusted P < 0.0001, adjusted hazard ratio = 2.249, 95% confidence interval =1.491-3.394), and time-dependent receiver-operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.765, 0.745, 0.725, and 0.687 for 1-, 2-, 3-, and 5-year HCC overall survival (OS) prediction, respectively. Comprehensive survival analysis of the prognostic signature suggests that the risk score model could serve as an independent factor of HCC and perform better in prognosis prediction than other traditional clinical indicators. Functional assessment of the target genes of hsa-mir-139 and hsa-mir-5003 indicates that they were significantly enriched in multiple biological processes and pathways, including cell proliferation and cell migration regulation, pathways in cancer, and the cyclic adenosine monophosphate (cAMP) signaling pathway.
Conclusion
Our study indicates that the novel miRNA expression signature may be a potential prognostic biomarker for HCC patients.
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Affiliation(s)
- Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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- Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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- Rui Huang
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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- Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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- Xiangkun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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- Ketuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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- Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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- Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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- Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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- Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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27
Fan W, Ye G. Microarray analysis for the identification of specific proteins and functional modules involved in the process of hepatocellular carcinoma originating from cirrhotic liver.
Mol Med Rep 2018;
17:5619-5626. [PMID:
29436633 PMCID:
PMC5866002 DOI:
10.3892/mmr.2018.8555]
[Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 06/30/2017] [Indexed: 02/06/2023] Open
Abstract
In order to identify the potential pathogenesis of hepatocellular carcinoma (HCC) developing from cirrhosis, a microarray‑based transcriptome profile was analyzed. The GSE63898 expression profile was downloaded from the Gene Expression Omnibus database, which included data from 228 HCC tissue samples and 168 cirrhotic tissue samples. The Robust Multi‑array Average in the Affy package of R was used for raw data processing and Student's t‑test was used to screen differentially expressed genes (DEGs). An enrichment analysis was then conducted using the Database for Annotation, Visualization and Integrated Discovery online tool, and the protein‑protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes and Cytoscape. Furthermore, the MCODE plug‑in of Cytoscape was used to conduct a sub‑module analysis. A total of 634 DEGs were identified between HCC and cirrhosis, of which 165 were upregulated and 469 were downregulated. According to the cut‑off criteria, the PPI network was constructed and Jun proto‑oncogene, AP‑1 transcription factor subunit (degree, 39), Fos proto‑oncogene, AP‑1 transcription factor subunit (degree, 34) and v‑myc avian myelocytomatosis viral oncogene homolog (degree, 32) were identified as the hub nodes of the PPI network. Based on the sub‑module analysis, four specific modules were identified. In particular, module 1 was significantly enriched in the chemokine signaling pathway, and C‑X‑C motif chemokine ligand 12, C‑C motif chemokine receptor 7 (CCR7) and C‑C motif chemokine ligand 5 (CCL5) were three important proteins in this module. Module 4 was significantly enriched in chemical carcinogenesis, and cytochrome P450 family 2 subfamily E member 1, cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and cytochrome P450 family 2 subfamily A member 6 (CYP2A6) were three important proteins in this module. In conclusion, the present study revealed that CCR7, CCL5, CYP2C9 and CYP2A6 are novel genes identified in the development of HCC; however, the actual functions of these genes require verification.
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Affiliation(s)
- Wufeng Fan
- Section of Medical Affairs, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei 441000, P.R. China
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- Guangming Ye
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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28
Catanzaro G, Besharat ZM, Miele E, Chiacchiarini M, Po A, Carai A, Marras CE, Antonelli M, Badiali M, Raso A, Mascelli S, Schrimpf D, Stichel D, Tartaglia M, Capper D, von Deimling A, Giangaspero F, Mastronuzzi A, Locatelli F, Ferretti E. The miR-139-5p regulates proliferation of supratentorial paediatric low-grade gliomas by targeting the PI3K/AKT/mTORC1 signalling.
Neuropathol Appl Neurobiol 2018;
44:687-706. [PMID:
29478280 DOI:
10.1111/nan.12479]
[Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 02/06/2018] [Indexed: 12/25/2022]
Abstract
AIMS
Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs.
METHODS
We performed microRNA profiling on 45 fresh-frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non-neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet.
RESULTS
One of the most markedly down-regulated microRNAs in our supratentorial pLGGs cohort was miR-139-5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3-kinase) catalytic unit, PIK3CA. We investigated the role of miR-139-5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR-139-5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated-p70 S6 kinase (p-p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR-139-5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002.
CONCLUSIONS
These findings provide the first evidence that down-regulation of miR-139-5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling.
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Affiliation(s)
- G Catanzaro
- Department of Experimental Medicine, Sapienza University, Rome, Italy
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- Z M Besharat
- Department of Molecular Medicine, Sapienza University, Rome, Italy
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- E Miele
- Center for Life NanoScience@Sapienza, IIT, Rome, Italy
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- M Chiacchiarini
- Department of Molecular Medicine, Sapienza University, Rome, Italy
- Center for Life NanoScience@Sapienza, IIT, Rome, Italy
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- A Po
- Department of Molecular Medicine, Sapienza University, Rome, Italy
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- A Carai
- Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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- C E Marras
- Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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- M Antonelli
- Department of Radiological, Oncological and Pathological Science, Sapienza University, Rome, Italy
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- M Badiali
- Bone Marrow Transplantation Unit, Microcitemico Children's Hospital, Cagliari, Italy
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- A Raso
- Giannina Gaslini Institute, Genoa, Italy
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- S Mascelli
- Giannina Gaslini Institute, Genoa, Italy
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- D Schrimpf
- Department of Neuropathology, Heidelberg University, Heidelberg, Germany
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Clinical Cooperation Unit (CCU) Neuropathology, Heidelberg, Germany
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- D Stichel
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Clinical Cooperation Unit (CCU) Neuropathology, Heidelberg, Germany
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- M Tartaglia
- Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Rome, Italy
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- D Capper
- Department of Neuropathology, Heidelberg University, Heidelberg, Germany
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Clinical Cooperation Unit (CCU) Neuropathology, Heidelberg, Germany
- Department of Neuropathology, Charité Universitätsmedizin Berlin, Berlin, Germany
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- A von Deimling
- Department of Neuropathology, Heidelberg University, Heidelberg, Germany
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Clinical Cooperation Unit (CCU) Neuropathology, Heidelberg, Germany
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- F Giangaspero
- Department of Radiological, Oncological and Pathological Science, Sapienza University, Rome, Italy
- IRCCS Neuromed, Pozzilli, Italy
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- A Mastronuzzi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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- F Locatelli
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- University of Pavia, Pavia, Italy
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- E Ferretti
- Department of Experimental Medicine, Sapienza University, Rome, Italy
- IRCCS Neuromed, Pozzilli, Italy
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29
Liu ZG, Jiang G, Tang J, Wang H, Feng G, Chen F, Tu Z, Liu G, Zhao Y, Peng MJ, He ZW, Chen XY, Lindsay H, Xia YF, Li XN. c-Fos over-expression promotes radioresistance and predicts poor prognosis in malignant glioma.
Oncotarget 2018;
7:65946-65956. [PMID:
27602752 PMCID:
PMC5323205 DOI:
10.18632/oncotarget.11779]
[Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 08/22/2016] [Indexed: 12/11/2022] Open
Abstract
c-Fos is a major component of activator protein (AP)-1 complex. It has been implicated in cell differentiation, proliferation, angiogenesis, invasion, and metastasis. To investigate the role of c-Fos in glioma radiosensitivity and to understand the underlying molecular mechanisms, we downregulated c-Fos gene expression by lentivirus-mediated shRNA in glioma cell lines and subsequently analyzed the radiosensitivity, DNA damage repair capacity, and cell cycle distribution. Finally, we explored its prognostic value in 41 malignant glioma patients by immunohistochemistry. Our results showed that silencing c-Fos sensitized glioma cells to radiation by increasing radiation-induced DNA double strand breaks (DSBs), disturbing the DNA damage repair process, promoting G2/M cell cycle arrest, and enhancing apoptosis. c-Fos protein overexpression correlated with poor prognosis in malignant glioma patients treated with standard therapy. Our findings provide new insights into the mechanism of radioresistance in malignant glioma and identify c-Fos as a potentially novel therapeutic target for malignant glioma patients.
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Affiliation(s)
- Zhi-Gang Liu
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
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- Guanmin Jiang
- Department of Clinical Laboratory, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
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- Jiao Tang
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
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- Hui Wang
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| |
- Guokai Feng
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| |
- Furong Chen
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| |
- Ziwei Tu
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| |
- Guiyun Liu
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| |
- Yu Zhao
- Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| |
- Ming-Jing Peng
- Translational Medicine Center, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| |
- Zheng-Wen He
- Department of Neurosurgery, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| |
- Xiao-Yan Chen
- Department of Pathology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 421001, P.R. China
| |
- Holly Lindsay
- Laboratory of Molecular Neuro-Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston TX, 77030, USA
| |
- Yun-Fei Xia
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China
| |
- Xiao-Nan Li
- Laboratory of Molecular Neuro-Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston TX, 77030, USA
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30
Jiang X, Hao Y. Analysis of expression profile data identifies key genes and pathways in hepatocellular carcinoma.
Oncol Lett 2018;
15:2625-2630. [PMID:
29434983 DOI:
10.3892/ol.2017.7534]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 07/20/2017] [Indexed: 12/12/2022] Open
Abstract
The aims of the present study were to identify key genes and pathways associated with hepatocellular carcinoma (HCC) progression and predict compounds potentially associated with this type of carcinogenesis. The gene expression profile data of the GSE49515 dataset was obtained from the Gene Expression Omnibus database. The limma software package was used to identify the differentially expressed genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using the Biological Networks Gene Ontology tool and the Database for Annotation, Visualization and Integrated Discovery, respectively. The Michigan Molecular Interactions database plugin within the Cytoscape software platform was used to perform protein-protein interaction (PPI) network analysis. Chemical-gene interaction data for HCC were obtained from the Comparative Toxicogenomics Database to evaluate the associations between drugs and specific genes. A total of 302 DEGs, including 231 downregulated and 71 upregulated, were identified. Cytokine-cytokine receptor interaction and chemokine signaling were the significantly enriched pathways. Additionally, PPI network analysis indicated a total of 13 highest degree hub nodes, including FBJ murine osteosarcoma viral oncogene homolog (FOS) and DNA damage-inducible transcript 3 protein (DDIT3). Chemical-gene interaction analysis revealed that FUN and FOS were targeted by >500 compounds, while >200 genes were targeted by 2,3,7,8-tetrachlorodibenzodioxin and benzo(α)pyrene. In conclusion, the present study demonstrated that FOS, DDIT3, the cytokine-cytokine receptor interaction pathway and the chemokine signaling pathway may be key genes and pathways associated with the development of HCC. Furthermore, exposure to 2,3,7,8-tetrachlorodibenzodioxin or benzo(α)pyrene may lead to hepatocarcinogenesis.
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Affiliation(s)
- Xuwei Jiang
- Department of General Surgery, Shanghai, Baoshan District Hospital of Integrated Traditional and Western Medicine, Shanghai 201900, P.R. China
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- Yuqing Hao
- Department of General Surgery, Shanghai, Baoshan District Hospital of Integrated Traditional and Western Medicine, Shanghai 201900, P.R. China
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31
RNA-binding protein AUF1 suppresses miR-122 biogenesis by down-regulating Dicer1 in hepatocellular carcinoma.
Oncotarget 2018;
9:14815-14827. [PMID:
29599909 PMCID:
PMC5871080 DOI:
10.18632/oncotarget.24079]
[Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 01/03/2018] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the common cancers worldwide, especially in developing countries. Although the chronic infections of hepatitis B and C viruses have been established as the etiological factors of HCC, the mechanism for the tumorigenesis and development of HCC is still unclear. The liver-specific microRNA-122 (miR-122), an established tumor-suppressor miRNA, is often down-regulated in HCC, while the underlying mechanism is not well understood. Here we report that the AU-rich element-binding factor AUF1 suppresses the expression of Dicer1, the type III RNase that is required for microRNA maturation, leading to the inhibited biogenesis of miR-122. Overexpression of AUF1 led to the decreased expression of Dicer1 and miR-122, while the level of the miR-122 precursor (pre-miR-122) was increased. On the other hand, siRNA of AUF1 (siAUF1) increased the levels of Dicer1 mRNA and miR-122, but it reduced the abundance of pre-miR-122. Consistent with the reported data, this study demonstrated that AUF1 and Dicer1 showed opposite expression pattern in both human HCC tissues and cell lines. In addition, AUF1 inhibited the expression of Dicer1 by interacting with the 3′ untranslated region (3′UTR) and coding region of DICER1 mRNA. Moreover, the knockdown of AUF1 by siRNA altered the expression of other miRNAs and promoted HCC cell death. In conclusion, AUF1 down-regulates the expression miR-122 by interacting with the 3′UTR and coding region of DICER1 mRNA and suppressing Dicer1 expression. The AUF1/Dicer1/miR-122 pathway might play a critical role in the development of HCC.
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32
Jiang L, Yan Q, Fang S, Liu M, Li Y, Yuan YF, Li Y, Zhu Y, Qi J, Yang X, Kwong DLW, Guan XY. Calcium-binding protein 39 promotes hepatocellular carcinoma growth and metastasis by activating extracellular signal-regulated kinase signaling pathway.
Hepatology 2017;
66:1529-1545. [PMID:
28605041 DOI:
10.1002/hep.29312]
[Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 05/01/2017] [Accepted: 06/08/2017] [Indexed: 01/18/2023]
Abstract
UNLABELLED
Calcium-binding protein (CAB39) is a key regulator of a group of sterile 20 kinases. Here, we report that CAB39 was frequently up-regulated in hepatocellular carcinoma (HCC), which was significantly associated with tumor metastasis (P = 0.000), poorer disease-free survival rate (P = 0.027), and poor prognosis (P = 0.000). Ectopic expression of CAB39 in immortalized human liver cell line LO2 and HCC cell lines QGY-7703 and BEL-7402 could increase foci formation, colony formation in soft agar, tumor formation in nude mice, and cell motility. Silencing CAB39 expression in two HCC cell lines, Huh7 and MHCC97H, with short hairpin RNA could effectively abolish its oncogenic function. Further study found that CAB39 contributed to extracellular signal-regulated kinase (ERK) pathway activation, and mutations of the key sites of CAB39 markedly decrease the level of phosphorylated ERK. In addition, CAB39 could promote epithelial-mesenchymal transition by up-regulating N-cadherin and Fibronectin and down-regulating E-cadherin and α-E-catenin. As a result, β-catenin nuclear translocation was increased and its downstream target gene, matrix metalloproteinase-9, was up-regulated.
CONCLUSION
Taken together, our findings suggested that CAB39 played very important oncogenic roles in HCC pathogenesis and progression by activating the ERK signaling pathway. Better understanding of CAB39 may lead to its clinical application as a biomarker for a prognosis predictor and a novel therapeutic target. (Hepatology 2017;66:1529-1545).
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Affiliation(s)
- Lingxi Jiang
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.,Center for Cancer Research, The University of Hong Kong, Hong Kong, China
| |
- Qian Yan
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.,Center for Cancer Research, The University of Hong Kong, Hong Kong, China
| |
- Shuo Fang
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.,Center for Cancer Research, The University of Hong Kong, Hong Kong, China
| |
- Ming Liu
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,Affiliated Cancer Hospital, Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| |
- Yan Li
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,Department of Biology, Southern University of Science and Technology, Shenzhen, China
| |
- Yun-Fei Yuan
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China
| |
- Yan Li
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China
| |
- Yinghui Zhu
- State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China
| |
- Jiali Qi
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.,Center for Cancer Research, The University of Hong Kong, Hong Kong, China
| |
- Xiaodong Yang
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.,Center for Cancer Research, The University of Hong Kong, Hong Kong, China
| |
- Dora Lai Wan Kwong
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,Center for Cancer Research, The University of Hong Kong, Hong Kong, China
| |
- Xin-Yuan Guan
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.,Center for Cancer Research, The University of Hong Kong, Hong Kong, China.,State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China
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33
Wang Q, Liu H, Wang Q, Zhou F, Liu Y, Zhang Y, Ding H, Yuan M, Li F, Chen Y. Involvement of c-Fos in cell proliferation, migration, and invasion in osteosarcoma cells accompanied by altered expression of Wnt2 and Fzd9.
PLoS One 2017;
12:e0180558. [PMID:
28665975 PMCID:
PMC5493424 DOI:
10.1371/journal.pone.0180558]
[Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 06/16/2017] [Indexed: 01/04/2023] Open
Abstract
Osteosarcoma (OS) is an aggressive bone tumor, and proto-oncogene c-Fos is involved in this lethal disease. However, the role and molecular mechanism of c-Fos in the development and progression of OS remain enigmatic. As one of the Wnt family members, Wnt2 is closely associated with the development of several malignant tumors. In the present study, the expression of c-Fos, Wnt2, and its receptor Fzd9 in human OS tissues, MG63 OS cell line, and human osteoblast hFOB 1.19 cell line was detected by Western blot analysis, immunohistochemical staining, or reverse transcription-polymerase chain reaction. The role of c-Fos in the OS was clarified by treating MG63 cells with small interfering RNA to knockdown c-Fos. Then, cell migration and invasion were assayed by transwell assays and wound healing assay; cell proliferation was assayed by MTS method and 5-ethynyl-2'-deoxyuridine DNA proliferation in vitro detection; cell apoptosis was assayed by flow cytometric method. Co-immunoprecipitation kit was used to confirm the relationship between c-Fos and Wnt2/Fzd9. We found that the expression of c-Fos, Wnt2, and Fzd9 protein was distinctly higher in human OS tissues than that in the adjacent non-cancerous tissues, and their expression in the MG63 OS cell line was markedly increased compared with that in the human osteoblast hFOB 1.19 cell line. Knockdown of c-Fos inhibited the proliferation, migration, and invasion of MG63 cells, and promoted the apoptosis of MG63 cells. Moreover, knockdown of c-Fos inhibited the expression of Wnt2 and Fzd9 mRNA and protein. Our data enforced the evidence that knockdown of c-Fos inhibited cell proliferation, migration, and invasion, and promoted the apoptosis of OS cells accompanied by altered expression of Wnt2 and Fzd9. These findings offer new clues for OS development and progression, and c-Fos may be a potential therapeutic target for OS.
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Affiliation(s)
- Qiaozhen Wang
- Department of Human Anatomy, Weifang Medical University, Weifang, Shandong, China
| |
- Huancai Liu
- Affiliated hospital, Weifang Medical University, Weifang, Shandong, China
| |
- Qing Wang
- Department of Human Anatomy, Weifang Medical University, Weifang, Shandong, China
| |
- Fenghua Zhou
- Department of Pathology, Weifang Medical University, Weifang, Shandong, China
| |
- Yongxin Liu
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, China
| |
- Yawen Zhang
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, China
| |
- Haoyu Ding
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, China
| |
- Meng Yuan
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, China
| |
- Fengjie Li
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, China
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- Yanchun Chen
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, China
- * E-mail:
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34
Huang LL, Huang LW, Wang L, Tong BD, Wei Q, Ding XS. Potential role of miR-139-5p in cancer diagnosis, prognosis and therapy.
Oncol Lett 2017;
14:1215-1222. [PMID:
28789336 PMCID:
PMC5529864 DOI:
10.3892/ol.2017.6351]
[Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 03/09/2017] [Indexed: 01/22/2023] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that regulate the expression of protein-coding genes by partially binding to specific target sites of mRNAs. miRNAs perform important functions in complicated cellular biological processes and their abnormal expression is involved in various disorders, including cancer. Among the miRNAs, differential expression of miR-139-5p serves a significant role in tumorigenesis, metastasis and recurrence, thus suggesting that it may potentially be used as a promising biomarker for cancer diagnosis, prognosis and therapy. miR-139-5p is expected to serve as a biomarker to eventually be implemented in a clinical setting. In the present review, we focus on the importance of miR-139-5p in cancer, summarize the association between miR-139-5p expression level and diagnosis and prognosis, and discuss the potential therapeutic implications for the future.
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Affiliation(s)
- Ling-Li Huang
- Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China
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- Ling-Wei Huang
- Key Laboratory for Space Biosciences and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shanxi 710072, P.R. China
| |
- Lei Wang
- Department of Pharmacy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, P.R. China
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- Ben-Ding Tong
- Department of Pharmacy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, P.R. China
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- Qing Wei
- Department of Pharmacy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, P.R. China
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- Xuan-Sheng Ding
- Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China
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35
Bakiri L, Hamacher R, Graña O, Guío-Carrión A, Campos-Olivas R, Martinez L, Dienes HP, Thomsen MK, Hasenfuss SC, Wagner EF. Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation.
J Exp Med 2017;
214:1387-1409. [PMID:
28356389 PMCID:
PMC5413325 DOI:
10.1084/jem.20160935]
[Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 12/12/2016] [Accepted: 02/07/2017] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular cancers arise in a background of liver damage and inflammation. Bakiri et al. describe the function of the transcription factor c-Fos/AP-1 using mouse models and human data. c-Fos affects cholesterol and bile acid metabolism and induces DNA damage and inflammation, thus promoting liver cancer.
Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos–expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.
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Affiliation(s)
- Latifa Bakiri
- Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain
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- Rainer Hamacher
- Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain
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- Osvaldo Graña
- Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain
| |
- Ana Guío-Carrión
- Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain
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- Ramón Campos-Olivas
- Spectroscopy and Nuclear Magnetic Resonance Spectroscopy Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain
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- Lola Martinez
- Flow Cytometry Core Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain
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- Hans P Dienes
- Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria
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- Martin K Thomsen
- Department of Clinical Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark
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- Sebastian C Hasenfuss
- Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain
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- Erwin F Wagner
- Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain
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36
MiR-139-5p as a novel serum biomarker for recurrence and metastasis in colorectal cancer.
Sci Rep 2017;
7:43393. [PMID:
28262692 PMCID:
PMC5338356 DOI:
10.1038/srep43393]
[Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 01/20/2017] [Indexed: 12/21/2022] Open
Abstract
Approximately 30-50% of colorectal cancer (CRC) patients who undergo curative resection subsequently experience tumor recurrence or metastasis. Although microRNAs (miRNAs) are a class of small noncoding RNAs frequently deregulated in various human malignancies, it remains unknown if these can help predict recurrence and metastasis in CRC patients. MiRNAs were initially screened using miRNA-microarray and miRNA-seq datasets with or without recurrence. Candidate miRNAs were then tested in two independent cohorts of 111 stage II/III and 139 stage I-III CRC patients, as well as serum samples and matched primary and metastatic liver tissues. An animal model of peritoneal dissemination was used to assess the oncogenic role of the target miRNA. Four candidate miRNAs were identified during the initial screening, and we subsequently validated upregulation of miR-139-5p in two independent clinical cohorts, wherein it associated with poor recurrence-free survival. Moreover, miR-139-5p were also upregulated in the serum of recurrence-positive CRC patients and yielded significantly shorter recurrence-free survival. Intriguingly, miR-139-5p was upregulated in metastatic liver tissues and negatively correlated with genes associated with epithelial-mesenchymal transition. Lastly, we showed that miR-139-5p overexpression enhanced peritoneal dissemination in a mouse model. In conclusion, we identified miR-139-5p as a novel biomarker for tumor recurrence and metastasis in CRC.
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37
Yoon EL, Yeon JE, Ko E, Lee HJ, Je JH, Yoo YJ, Kang SH, Suh SJ, Kim JH, Seo YS, Yim HJ, Byun KS. An Explorative Analysis for the Role of Serum miR-10b-3p Levels in Predicting Response to Sorafenib in Patients with Advanced Hepatocellular Carcinoma.
J Korean Med Sci 2017;
32:212-220. [PMID:
28049231 PMCID:
PMC5219986 DOI:
10.3346/jkms.2017.32.2.212]
[Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 11/11/2016] [Indexed: 12/17/2022] Open
Abstract
The prognostic role of aberrant serum miRNA expression for predicting response to sorafenib treatment in advanced hepatocellular carcinoma (HCC) patients has not been well characterized. We aimed to identify specific serum miRNAs that are associated with positive radiologic responses or improved survival in sorafenib-treated HCC patients. miR-18a, miR-21, miR-139-5p, miR-221, miR-224, and miR-10b-3p, were selected for analysis. Serum samples from 24 patients with advanced stage HCC and 25 patients with liver cirrhosis (LC) were analyzed. All of the miRNAs except miR-21 were found to be upregulated in serum samples from HCC patients. None of the miRNAs assayed differed significantly in terms of expression between the responder and non-responder groups among HCC patients. However, miR-10b-3p levels were significantly higher in the subgroup of HCC patients with worse overall survival (fold change = 5.8, P = 0.008). Serum miRNA-10b-3p was upregulated in the presence of macrovascular invasion (MVI), and those with higher serum miRNA-10b-3p had significantly shorter survival during treatment (P = 0.042). Although no single serum miRNA was predictive of response to sorafenib treatment, analysis of serum miR-10b-3p levels may be valuable for diagnosis of HCC and prediction of survival of sorafenib-treated patients.
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Affiliation(s)
- Eileen L Yoon
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea
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- Jong Eun Yeon
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
| |
- Eunjung Ko
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| |
- Hyun Jung Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| |
- Ji Hye Je
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| |
- Yang Jae Yoo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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- Seong Hee Kang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| |
- Sang Jun Suh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| |
- Ji Hoon Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| |
- Yeon Seok Seo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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- Hyung Joon Yim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| |
- Kwan Soo Byun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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38
Wu L, Bai X, Xie Y, Yang Z, Yang X, Lin J, Zhu C, Wang A, Zhang H, Miao R, Wu Y, Robson SC, Zhao Y, Sang X, Zhao H. MetastamiRs: A promising choice for antihepatocellular carcinoma nucleic acid drug development.
Hepatol Res 2017;
47:80-94. [PMID:
27138942 DOI:
10.1111/hepr.12737]
[Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 04/18/2016] [Accepted: 04/29/2016] [Indexed: 12/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, which can be explained at least in part by its propensity towards metastasis and the limited efficacy of adjuvant therapy. MetastamiRs are miRNAs that promote or suppress migration and metastasis of cancer cells, and their functional status is significantly correlated with HCC prognosis. Unlike targeted therapy, metastamiRs have the potential to target multiple genes and signaling pathways and dramatically suppress cancer metastasis. In this review, we discuss the regulatory role of metastamiRs in the HCC invasion-metastasis cascade. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis has shown that many extensively studied metastamiRs target several critical signaling pathways and these have remarkable therapeutic potential in HCC. The information reviewed here may assist in further anti-HCC miRNA drug screening and development.
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Affiliation(s)
- Liangcai Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| |
- Xue Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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- Yuan Xie
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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- Zhen Yang
- Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai, China
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- Xiaobo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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- Jianzhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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- Chengpei Zhu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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- Anqiang Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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- Haohai Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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- Ruoyu Miao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
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- Yan Wu
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
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- Simon C Robson
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| |
- Yi Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
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- Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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- Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Center of Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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39
Dai H, Gallagher D, Schmitt S, Pessetto ZY, Fan F, Godwin AK, Tawfik O. Role of miR-139 as a surrogate marker for tumor aggression in breast cancer.
Hum Pathol 2016;
61:68-77. [PMID:
27864119 DOI:
10.1016/j.humpath.2016.11.001]
[Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 11/01/2016] [Accepted: 11/03/2016] [Indexed: 02/07/2023]
Abstract
MicroRNAs are non-protein coding molecules that play a key role in oncogenesis, tumor progression, and metastasis in many types of malignancies including breast cancer. In the current study, we studied the expression of microRNA-139-5p (miR-139) in invasive ductal carcinoma (IDC) of the breast and correlated its expression with tumor grade, molecular subtype, hormonal status, human epidermal growth factor receptor 2 status, proliferation index, tumor size, lymph node status, patient's age, and overall survival in 74 IDC cases. In addition, we compared and correlated miR-139 expression in 18 paired serum and tissue samples from patients with IDC to assess its value as a serum marker. Our data showed that miR-139 was down-regulated in all tumor tissue samples compared with control. More pronounced down-regulation was seen in tumors that were higher grade, estrogen receptor negative, progesterone receptor negative, more proliferative, or larger in size (P < .05). Although not statistically significant, lower miR-139 level was frequently associated with human epidermal growth factor receptor 2 overexpression. In addition, significantly lower miR-139 tissue level was seen in patients who were deceased (P = .027), although older age (>50 years) and positive local nodal disease did not adversely affect miR-139 expression. In contrast, serum miR-139 profile of the patients appeared similar to that of normal control. In conclusion, our study demonstrated that down-regulation of miR-139 was associated with aggressive tumor behavior and disease progression in breast cancer. miR-139 may serve as a risk assessment biomarker in tailoring treatment options.
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MESH Headings
- Biomarkers, Tumor/classification
- Biomarkers, Tumor/genetics
- Biopsy
- Breast Neoplasms/blood
- Breast Neoplasms/genetics
- Breast Neoplasms/mortality
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/blood
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/mortality
- Carcinoma, Ductal, Breast/pathology
- Cell Proliferation
- Disease Progression
- Down-Regulation
- Female
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Humans
- MicroRNAs/blood
- MicroRNAs/genetics
- Middle Aged
- Neoplasm Grading
- Neoplasm Invasiveness
- Phenotype
- Retrospective Studies
- Reverse Transcriptase Polymerase Chain Reaction
- Risk Factors
- Survival Analysis
- Tumor Burden
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Affiliation(s)
- Hongyan Dai
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160
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- Dan Gallagher
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160
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- Sarah Schmitt
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160
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- Ziyan Y Pessetto
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160
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- Fang Fan
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160
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- Andrew K Godwin
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160
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- Ossama Tawfik
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160.
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40
Shikama Y, Cao M, Ono T, Feng X, Noji H, Kimura H, Ogawa K, Suzuki Y, Ikeda K, Takeishi Y, Kimura J. Reduction of c-Fos via Overexpression of miR-34a Results in Enhancement of TNF- Production by LPS in Neutrophils from Myelodysplastic Syndrome Patients.
PLoS One 2016;
11:e0158527. [PMID:
27513856 PMCID:
PMC4981319 DOI:
10.1371/journal.pone.0158527]
[Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 06/16/2016] [Indexed: 02/07/2023] Open
Abstract
Although increased TNF-α has been considered to cause ineffective hematopoiesis in myelodysplastic syndromes (MDS), the mechanisms of TNF-α elevation are not known. We recently found that c-Fos mRNA stabilization under translation-inhibiting stimuli was impaired in MDS-derived neutrophilic granulocytes. In the current study, we identified overexpression of c-Fos-targeting miR-34a and miR-155 as the cause of impairment. Expression levels of miR-34a but not miR-155 inversely correlated with ratios of c-Fos-positive cells in MDS-derived CD16+ neutrophils (r = -0.618, P<0.05), which were analyzed by flow cytometry. Among the seventeen patients, c-Fos was detectable in less than 60% of CD16+ cells in eight patients (Group A), while five (Group B) expressed c-Fos in more than 80% of CD16+ cells, which was consistent with the controls (88.6 ± 7.8%). Group A-derived granulocytes secreted more TNF-α in response to 1 μM LPS for 3 hours (735.4 ± 237.5 pg/mL) than Group B (143.5 ± 65.7 pg/mL, P<0.05) and healthy controls (150.8 ± 91.5 pg/mL, P<0.05). Knockdown of c-Fos in neutrophil-like differentiated HL60 increased the binding of NF-κB p65 to the promoter region of TNF-α DNA. Thus, c-Fos reduction via overexpression of miR-34a contributes to TNF-α overproduction under inflammatory stimuli in MDS.
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Affiliation(s)
- Yayoi Shikama
- Department of Pharmacology, Fukushima Medical University, Fukushima, Japan
- * E-mail:
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- Meiwan Cao
- Department of Pharmacology, Fukushima Medical University, Fukushima, Japan
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- Tomoyuki Ono
- Department of Pharmacology, Fukushima Medical University, Fukushima, Japan
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- Xiaomin Feng
- Department of Pharmacology, Fukushima Medical University, Fukushima, Japan
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- Hideyoshi Noji
- Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan
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- Hideo Kimura
- Department of Hematology, Kita Fukushima Medical Center, Date, Japan
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- Kazuei Ogawa
- Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan
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- Yuko Suzuki
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University, Fukushima, Japan
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- Kazuhiko Ikeda
- Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University, Fukushima, Japan
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- Yasuchika Takeishi
- Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan
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- Junko Kimura
- Department of Pharmacology, Fukushima Medical University, Fukushima, Japan
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41
Liu H, Yin Y, Hu Y, Feng Y, Bian Z, Yao S, Li M, You Q, Huang Z. miR-139-5p sensitizes colorectal cancer cells to 5-fluorouracil by targeting NOTCH-1.
Pathol Res Pract 2016;
212:643-649. [PMID:
27173050 DOI:
10.1016/j.prp.2016.04.011]
[Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 03/24/2016] [Accepted: 04/29/2016] [Indexed: 12/14/2022]
Abstract
Multidrug resistance (MDR), a phenomenon that often occurs with drug treatment and is characterized by relapse or attenuation of drug efficacy, is almost unavoidable in colorectal cancer (CRC) patients receiving 5-fluorouracil (5-FU)-based chemotherapy. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression. Our previous study has identified miR-139-5p as a potential tumor suppressor in CRC, but its role in chemoresistance of CRC has not been elucidated. In this study, we demonstrated that miR-139-5p was down-regulated either in CRC tumors receiving chemotherapy or in 5-FU-resistant CRC cell lines (HCT-8/5-FU and HCT-116/5-FU). Ectopic expression of miR-139-5p sensitized CRC cells to 5-FU by increasing 5-FU-induced apoptosis. In addition, miR-139-5p inhibited the expression of the miR-139-5p target gene NOTCH-1 and its downstream molecules MRP-1 and BCL-2, two key MDR-associated genes. Furthermore, silencing NOTCH-1 expression promoted the chemotherapeutic effects of 5-FU, and up-regulation of NOTCH-1 abrogated miR-139-5p-mediated sensitization to 5-FU in LoVo and HCT-116 cells. Taken together, our data indicate a new role of miR-139-5p/NOTCH-1 pathway in the drug resistance of CRC cells to 5-FU, which may be a promising therapeutic target for the anti-MDR treatment of CRC.
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Affiliation(s)
- Heyong Liu
- Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China; Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China
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- Yuan Yin
- Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China
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- Yaling Hu
- Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China
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- Yuyang Feng
- Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China
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- Zehua Bian
- Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China
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- Surui Yao
- Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China
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- Min Li
- Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China
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- Qingjun You
- Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China; Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China.
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- Zhaohui Huang
- Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China.
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42
Zou F, Mao R, Yang L, Lin S, Lei K, Zheng Y, Ding Y, Zhang P, Cai G, Liang X, Liu J. Targeted deletion of miR-139-5p activates MAPK, NF-κB and STAT3 signaling and promotes intestinal inflammation and colorectal cancer.
FEBS J 2016;
283:1438-52. [PMID:
26859226 DOI:
10.1111/febs.13678]
[Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 01/11/2016] [Accepted: 02/05/2016] [Indexed: 12/15/2022]
Abstract
miR-139-5p, which has been reported to be underexpressed in several types of cancer, is associated with tumorigenesis by participating in various biological processes via the modulation of different target genes. In the present study, we analyzed mice deficient in miR-139-5p, aiming to investigate its role in intestinal inflammation and colitis-associated colorectal cancer. We show that miR-139-5p knockout (KO) mice are highly susceptible to colitis and colon cancer, accompanied by elevated proliferation and decreased apoptosis, as well as an increased production of inflammatory cytokines, chemokines and tumorigenic factors. Furthermore, enhanced colon inflammation and colorectal tumor development in miR-139-5p KO mice are a result of the regulatory effects of miR-139-5p on its target genes for Rap1b and nuclear factor-kappa B, thus affecting the activity of the mitogen-activated protein kinase, nuclear factor-kappa B and signal transducer and activator of transcription 3 signaling pathways. These results reveal a critical part for miR-139-5p in maintaining intestinal homeostasis and protecting against colitis and colorectal cancer in vivo, providing new insights into the function of miR-139-5p with respect to linking inflammation to carcinogenesis.
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Affiliation(s)
- Fangyuan Zou
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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- Rurong Mao
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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- Liyan Yang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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- Shengchao Lin
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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- Kecheng Lei
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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- Yuanhong Zheng
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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- Yue Ding
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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- Peng Zhang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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- Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
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- Xin Liang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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- Jianwen Liu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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43
Mizuguchi Y, Takizawa T, Yoshida H, Uchida E. Dysregulated miRNA in progression of hepatocellular carcinoma: A systematic review.
Hepatol Res 2016;
46:391-406. [PMID:
26490438 DOI:
10.1111/hepr.12606]
[Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 10/13/2015] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most frequent cancer and the third cause of cancer-related mortality worldwide. The primary risk factor for HCC is liver cirrhosis secondary to persistent infection with hepatitis B virus or hepatitis C virus. Although a number of cellular phenomena and molecular events have been reported to facilitate tumor initiation, progression and metastasis, the exact etiology of HCC has not yet been fully uncovered. miRNA, a class of non-coding RNA, negatively regulate post-transcriptional processes that participate in crucial biological processes, including development, differentiation, apoptosis and proliferation. In the liver, specific miRNA can be negative regulators of gene expression. Recent studies have uncovered the contribution of miRNA to cancer pathogenesis as they can function as oncogenes or tumor suppressor genes. In addition, other studies have demonstrated their potential value in the clinical management of patients with HCC as some miRNA may be used as prognostic or diagnostic markers. In this review, we summarize the current knowledge about the roles of miRNA in the carcinogenesis and progression of HCC.
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Affiliation(s)
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- Hiroshi Yoshida
- Department of Surgery, Nippon Medical School Hospital, Tokyo, Japan
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- Eiji Uchida
- Department of Surgery, Nippon Medical School Hospital, Tokyo, Japan
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44
Park KU, Seo YS, Lee YH, Park J, Hwang I, Kang KJ, Nam J, Kim SW, Kim JY. Altered microRNA expression profile in hepatitis B virus-related hepatocellular carcinoma.
Gene 2015;
573:278-84. [DOI:
10.1016/j.gene.2015.07.053]
[Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 07/07/2015] [Accepted: 07/15/2015] [Indexed: 12/12/2022]
45
Wang L, Yue Y, Wang X, Jin H. Function and clinical potential of microRNAs in hepatocellular carcinoma.
Oncol Lett 2015;
10:3345-3353. [PMID:
26788134 DOI:
10.3892/ol.2015.3759]
[Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 08/25/2015] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs involved in the initiation and progression of several types of human cancer, including hepatocellular carcinoma (HCC), which is one of the most common types of cancer and the third leading cause of cancer-related mortality worldwide. Mounting evidence has demonstrated that miRNAs play a vital role in HCC, hepatitis, alcoholic liver disease, liver cell development and the metabolic functions of the liver. The aim of the present review was to summarize the most recent findings on the functions of miRNAs in the liver and discuss their potential roles in the diagnosis, prognosis and treatment of HCC.
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Affiliation(s)
- Lijuan Wang
- Department of Hematology, Hematology Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong 276003, P.R. China
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- Yongfang Yue
- Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
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- Xian Wang
- Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
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- Hongchuan Jin
- Department of Medical Oncology, Institute of Clinical Science, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
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46
Nam RK, Amemiya Y, Benatar T, Wallis CJD, Stojcic-Bendavid J, Bacopulos S, Sherman C, Sugar L, Naeim M, Yang W, Zhang A, Klotz LH, Narod SA, Seth A. Identification and Validation of a Five MicroRNA Signature Predictive of Prostate Cancer Recurrence and Metastasis: A Cohort Study.
J Cancer 2015;
6:1160-71. [PMID:
26516365 PMCID:
PMC4615353 DOI:
10.7150/jca.13397]
[Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 08/02/2015] [Indexed: 01/01/2023] Open
Abstract
Background: MicroRNA (miRNA) have been shown to be important in regulating gene expression in prostate cancer. We used next generation miRNA sequencing to conduct a whole miRNome analysis to identify miRNAs associated with prostate cancer metastasis.
Methods: We conducted discovery and validation analyses of miRNAs among a total of 546 men who underwent surgery for prostate cancer using the development of metastasis as an endpoint. Genome wide analysis was conducted among the discovery group (n=31) to identify new miRNAs associated with prostate cancer metastasis. Selected miRNAs were then analyzed using qPCR on prostatectomy specimens from an independent cohort (n=515) to determine whether their expression could predict the development of metastasis after surgery. To examine the biology underlying these associations, we created prostate cancer cell lines which overexpressed miR-301a for in vitro and in vivo functional assays.
Results: We identified 33 miRNAs associated with prostate cancer metastasis and selected a panel comprising miRs-301a, 652, 454, 223 and 139 which strongly predicted metastasis (AUC=95.3%, 95%C.I.:84%-99%). Among the validation cohort, the 15-year metastasis-free survival was 77.5% (95% C.I.:63.9%-86.4%) for patients with a high miRNA panel score and 98.8% (95% C.I.:94.9%-99.7%, p<0.0001 for difference) for those with a low score. After adjusting for grade, stage, and PSA, the hazard ratio for metastasis was 4.3 (95% C.I.: 1.7-11.1, p=0.002) for patients with a high miRNA panel score, compared to those with a low score. Prostate cancer cell lines overexpressing miR-301a had in significantly higher tumor growth and metastasis in a xenograft mouse model.
Conclusions: A panel of miRNAs is associated with prostate cancer metastasis. These could be used as potential new prognostic factors in the surgical management of prostate cancer.
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Affiliation(s)
- Robert K Nam
- 1. Division of Urology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Yutaka Amemiya
- 2. Department of Anatomic Pathology, Platform Biological Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Tania Benatar
- 2. Department of Anatomic Pathology, Platform Biological Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Christopher J D Wallis
- 1. Division of Urology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Jessica Stojcic-Bendavid
- 1. Division of Urology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Stephanie Bacopulos
- 2. Department of Anatomic Pathology, Platform Biological Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Christopher Sherman
- 3. Department of Laboratory Medicine and Pathobiology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Linda Sugar
- 3. Department of Laboratory Medicine and Pathobiology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Magda Naeim
- 3. Department of Laboratory Medicine and Pathobiology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Wenyi Yang
- 2. Department of Anatomic Pathology, Platform Biological Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Aiguo Zhang
- 2. Department of Anatomic Pathology, Platform Biological Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Laurence H Klotz
- 1. Division of Urology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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- Steven A Narod
- 4. Department of Public Health Sciences, University of Toronto, 790 Bay St., Toronto, ON, M5G 1N8, Canada
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- Arun Seth
- 2. Department of Anatomic Pathology, Platform Biological Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada
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47
Wang L, Liu M, Zhu H, Rong W, Wu F, An S, Liu F, Feng L, Wu J, Xu N. Identification of recurrence-related serum microRNAs in hepatocellular carcinoma following hepatectomy.
Cancer Biol Ther 2015;
16:1445-52. [PMID:
26176380 PMCID:
PMC4846138 DOI:
10.1080/15384047.2015.1071730]
[Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most deadly tumors. Prognosis of patients with HCC is generally poor due to the high recurrence rate. In the present study, TaqMan Real-time PCR microRNA Array was used to identify differentially expressed miRNAs from 10 tumor tissue samples (5 from recurrence group vs. 5 from non-recurrence group) and the matched serum samples. Four differentially expressed miRNAs (miR-486–5p, miR-422a, miR-125b and miR-139–5p) were further quantified in 20 tumor tissues and 116 HCC patients' serum before they received hepatectomy. Univariate analysis revealed that miR-486–5p, miR-422a and miR-125b were significantly associated with patients' relapse free survival (RFS). Multivariate analysis demonstrated that miR-486–5p, AFP and microvascular invasion (MVI) were the independent prognostic factors associated with RFS in this cohort (p = 0.000, 0.043, 0.000, respectively). Besides, the expression levels of miR-486–5p were positively correlated in tumor tissues and the paired serum samples, so was miR-422a. The probability of the prognostic accuracy of miR-486–5p in predicting postoperative recurrence of HCC within the first year was 76.79% (65.38% specificity and 81.58% sensitivity), which was almost equal to the classifier established by combination of AFP and MVI (75.98% probability, 63.13% specificity and 85.90% sensitivity). Furthermore, the combination of AFP, MVI and miR-486–5p yielded a ROC curve area of 88.02% (69.20% specificity and 92.10% sensitivity). Our study was the first to identify that serum miR-486–5p could be used to stratify the patients with higher recurrence risk before hepatic resection and potentially guide more effective surveillance strategies for them.
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Affiliation(s)
- Liming Wang
- a Department of Abdominal Surgery ; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , PR China
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- Mei Liu
- b Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology ; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , PR China
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- Hongxia Zhu
- b Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology ; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , PR China
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- Weiqi Rong
- a Department of Abdominal Surgery ; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , PR China
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- Fan Wu
- a Department of Abdominal Surgery ; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , PR China
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- Songlin An
- a Department of Abdominal Surgery ; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , PR China
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- Faqiang Liu
- a Department of Abdominal Surgery ; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , PR China
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- Li Feng
- a Department of Abdominal Surgery ; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , PR China
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- Jianxiong Wu
- a Department of Abdominal Surgery ; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , PR China
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- Ningzhi Xu
- b Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology ; Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College ; Beijing , PR China
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48
Saddic LA, Chang TW, Sigurdsson MI, Heydarpour M, Raby BA, Shernan SK, Aranki SF, Body SC, Muehlschlegel JD. Integrated microRNA and mRNA responses to acute human left ventricular ischemia.
Physiol Genomics 2015;
47:455-62. [PMID:
26175501 DOI:
10.1152/physiolgenomics.00049.2015]
[Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 07/08/2015] [Indexed: 12/22/2022] Open
Abstract
MicroRNAs (miRNAs) play a significant role in ischemic heart disease. Animal models of left ventricular (LV) ischemia demonstrate a unique miRNA profile; however, these models have limitations in describing human disease. In this study, we performed next-generation miRNA and mRNA sequencing on LV tissue from nine patients undergoing cardiac surgery with cardiopulmonary bypass and cardioplegic arrest. Samples were obtained immediately after aortic cross clamping (baseline) and before aortic cross clamp removal (postischemic). Of 1,237 identified miRNAs, 21 were differentially expressed between baseline and postischemic LV samples including the upregulated miRNAs miR-339-5p and miR-483-3p and the downregulated miRNA miR-139-5p. Target prediction analysis of these miRNAs was integrated with mRNA expression from the same LV samples to identify anticorrelated miRNA-mRNA pairs. Gene enrichment studies of candidate mRNA targets demonstrated an association with cardiovascular disease, cell death, and metabolism. Therapeutics that intervene on these miRNAs and their downstream targets may lead to novel mechanisms of mitigating the damage caused by ischemic insults on the human heart.
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Affiliation(s)
- Louis A Saddic
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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- Tzuu-Wang Chang
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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- Martin I Sigurdsson
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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- Mahyar Heydarpour
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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- Benjamin A Raby
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and
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- Stanton K Shernan
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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- Sary F Aranki
- Division of Cardiac Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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- Simon C Body
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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- Jochen D Muehlschlegel
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
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49
miR-139-5p controls translation in myeloid leukemia through EIF4G2.
Oncogene 2015;
35:1822-31. [PMID:
26165837 DOI:
10.1038/onc.2015.247]
[Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 05/21/2015] [Accepted: 05/22/2015] [Indexed: 12/15/2022]
Abstract
MicroRNAs (miRNAs) are crucial components of homeostatic and developmental gene regulation. In turn, dysregulation of miRNA expression is a common feature of different types of cancer, which can be harnessed therapeutically. Here we identify miR-139-5p suppression across several cytogenetically defined acute myeloid leukemia (AML) subgroups. The promoter of mir-139 was transcriptionally silenced and could be reactivated by histone deacetylase inhibitors in a dose-dependent manner. Restoration of mir-139 expression in cell lines representing the major AML subgroups (t[8;21], inv[16], mixed lineage leukemia-rearranged and complex karyotype AML) caused cell cycle arrest and apoptosis in vitro and in xenograft mouse models in vivo. During normal hematopoiesis, mir-139 is exclusively expressed in terminally differentiated neutrophils and macrophages. Ectopic expression of mir-139 repressed proliferation of normal CD34(+)-hematopoietic stem and progenitor cells and perturbed myelomonocytic in vitro differentiation. Mechanistically, mir-139 exerts its effects by repressing the translation initiation factor EIF4G2, thereby reducing overall protein synthesis while specifically inducing the translation of cell cycle inhibitor p27(Kip1). Knockdown of EIF4G2 recapitulated the effects of mir-139, whereas restoring EIF4G2 expression rescued the mir-139 phenotype. Moreover, elevated miR-139-5p expression is associated with a favorable outcome in a cohort of 165 pediatric patients with AML. Thus, mir-139 acts as a global tumor suppressor-miR in AML by controlling protein translation. As AML cells are dependent on high protein synthesis rates controlling the expression of mir-139 constitutes a novel path for the treatment of AML.
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50
Lyra-González I, Flores-Fong LE, González-García I, Medina-Preciado D, Armendáriz-Borunda J. MicroRNAs dysregulation in hepatocellular carcinoma: Insights in genomic medicine.
World J Hepatol 2015;
7:1530-1540. [PMID:
26085912 PMCID:
PMC4462691 DOI:
10.4254/wjh.v7.i11.1530]
[Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 12/22/2014] [Accepted: 05/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading primary liver cancer and its clinical outcome is still poor. MicroRNAs (miRNAs) have demonstrated an interesting potential to regulate gene expression at post-transcriptional level. Current findings suggest that miRNAs deregulation in cancer is caused by genetic and/or epigenetic, transcriptional and post-transcriptional modifications resulting in abnormal expression and hallmarks of malignant transformation: aberrant cell growth, cell death, differentiation, angiogenesis, invasion and metástasis. The important role of miRNAs in the development and progression of HCC has increased the efforts to understand and develop mechanisms of control overt this single-stranded RNAs. Several studies have analyzed tumoral response to the regulation and control of deregulated miRNAs with good results in vitro and in vivo, proving that targeting aberrant expression of miRNAs is a powerful anticancer therapeutic. Identification of up and/or down regulated miRNAs related to HCC has led to the discovery of new potential application for detection of their presence in the affected organism. MiRNAs represent a relevant new target for diagnosis, prognosis and treatment in a wide variety of pathologic entities, including HCC. This manuscript intends to summarize current knowledge regarding miRNAs and their role in HCC development.
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