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Yadollahi Farsani M, Amini Farsani Z, Teimuri S, Kolahdouzan M, Eshraghi Samani R, Teimori H. Deregulation of miR-1245b-5p and miR-92a-3p and their potential target gene, GATA3, in epithelial-mesenchymal transition pathway in breast cancer. Cancer Rep (Hoboken) 2024; 7:e1955. [PMID: 38173189 PMCID: PMC10849934 DOI: 10.1002/cnr2.1955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/30/2023] [Accepted: 12/04/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are small molecules that have prominent roles in tumor development and metastasis and can be used for diagnostic and therapeutic purposes. This study evaluated the expression of miR-92a-3p and miR-1245b-5p and their potential target gene, GATA3 in patients with breast cancer (BC). MATERIALS AND METHODS In the search for BC-related microRNAs, miR-124b-5p and miR-92a-3p were selected using Medline through PubMed, miR2disease, miRcancer and miRTarBase. Moreover, target gene GATA3 and their possible interaction in the regulating epithelial-mesenchymal transition (EMT) and invasion was evaluated using in silico tools including miRTarBase, TargetScan, STRING-db, and Cytoscape. The expression level of miR-92a-3p, miR1245b-5p, and GATA3 were assessed on extracted RNAs of tumor and nontumor tissues from 36 patients with BC using qPCR. Additionally, clinical-pathologic characteristics, such as tumor grade, tumor stage, lymph node were taken into consideration and the diagnostic power of these miRNAs and GATA3 was evaluated using the ROC curve analysis. RESULTS In silico evaluation of miR-92a-3p and miR-1245b-5p supports their potential association with EMT and invasion signaling pathways in BC pathogenesis. Comparing tumor tissues to nontumor tissues, we found a significant downregulation of miR-1245b-5p and miR-92a-3p and upregulation of GATA3. Patients with BC who had decreased miR-92a-3p expression also had higher rates of advanced stage/grade and ER expression, whereas decreased miR-1245b-5p expression was only linked to ER expression and was not associated with lymph node metastasis. The AUC of miR-1245b-5p, miR-92a-3p, and GATA3 using ROC curve was determined 0.6449 (p = .0239), 0.5980 (p = .1526), and 0.7415 (p < .0001), respectively, which showed a significant diagnostic accuracy of miR-1245b-5p and GATA3 between the BC patients and healthy individuals. CONCLUSION MiR-1245b-5p, miR-92a-3p, and GATA3 gene contribute to BC pathogenesis and they may be having potential regulatory roles in signaling pathways involved in invasion and EMT pathways in BC pathogenesis, as a result of these findings. More research is needed to determine the regulatory mechanisms that they control.
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Affiliation(s)
- Mahtab Yadollahi Farsani
- Department of Medical Biotechnology, School of Advanced TechnologiesShahrekord University of Medical SciencesShahrekordIran
| | - Zeinab Amini Farsani
- Cellular and Molecular Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesShahrekordIran
| | | | - Mohsen Kolahdouzan
- Department of Surgery, School of MedicineIsfahan University of Medical SciencesIsfahanIran
| | - Reza Eshraghi Samani
- Department of Surgery, School of MedicineIsfahan University of Medical SciencesIsfahanIran
| | - Hossein Teimori
- Cellular and Molecular Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesShahrekordIran
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Tafti A, Shojaei S, Zali H, Karima S, Mohammadi-Yeganeh S, Mondanizadeh M. A systems biology approach and in vitro experiment indicated Rapamycin targets key cancer and cell cycle-related genes and miRNAs in triple-negative breast cancer cells. Mol Carcinog 2023; 62:1960-1973. [PMID: 37787375 DOI: 10.1002/mc.23628] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 07/29/2023] [Accepted: 08/22/2023] [Indexed: 10/04/2023]
Abstract
An anticancer drug known as Rapamycin acts by inhibiting the mammalian target of the Rapamycin pathway. This agent has recently been investigated for its potential therapeutic benefits in sensitizing drug-resistant breast cancer (BC) treatment. The molecular mechanism underlying these effects, however, is still a mystery. Using a systems biology method and in vitro experiment, this study sought to discover essential genes and microRNAs (miRNAs) targeted by Rapamycin in triple-negative BC (TNBC) cells to aid prospective new medications with less adverse effects in BC treatment. We developed the transcription factor-miRNA-gene and protein-protein interaction networks using the freely accessible microarray data sets. FANMOD and MCODE were utilized to identify critical regulatory motifs, clusters, and seeds. Then, functional enrichment analyses were conducted. Using topological analysis and motif detection, the most important genes and miRNAs were discovered. We used quantitative real-time polymerase chain reaction (qRT-PCR) to examine the effect of Rapamycin on the expression of the selected genes and miRNAs to verify our findings. We performed flow cytometry to investigate Rapamycin's impact on cell cycle and apoptosis. Furthermore, wound healing and migration assays were done. Three downregulated (PTGS2, EGFR, VEGFA) and three upregulated (c-MYC, MAPK1, PIK3R1) genes were chosen as candidates for additional experimental verification. There were also three upregulated miRNAs (miR-92a, miR-16, miR-20a) and three downregulated miRNAs (miR-146a, miR-145, miR-27a) among the six selected miRNAs. The qRT-PCR findings in MDA-MB-231 cells indicated that c-MYC, MAPK1, PIK3R1, miR-92a, miR-16, and miR-20a expression levels were considerably elevated following Rapamycin treatment, whereas PTGS2, EGFR, VEGFA, miR-146a, and miR-145 expression levels were dramatically lowered (p < 0.05). These genes are engaged in cancer pathways, transcriptional dysregulation in cancer, and cell cycle, according to the top pathway enrichment findings. Migration and wound healing abilities of the cells declined after Rapamycin treatment, and the number of apoptotic cells increased. We demonstrated that Rapamycin suppresses cell migration and metastasis in the TNBC cell line. In addition, our data indicated that Rapamycin induces apoptosis in this cell line. The discovered vital genes and miRNAs affected by Rapamycin are anticipated to have crucial roles in the pathogenesis of TNBC and its therapeutic resistance.
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Affiliation(s)
- Ali Tafti
- Department of Biotechnology and Molecular Medicine, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Samaneh Shojaei
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hakimeh Zali
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Karima
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samira Mohammadi-Yeganeh
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdieh Mondanizadeh
- Department of Biotechnology and Molecular Medicine, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
- Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran
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Zhu J, Xu Z, Wu P, Zeng C, Peng C, Zhou Y, Xue Q. MicroRNA-92a-3p Inhibits Cell Proliferation and Invasion by Regulating the Transcription Factor 21/Steroidogenic Factor 1 Axis in Endometriosis. Reprod Sci 2023; 30:2188-2197. [PMID: 36650372 PMCID: PMC10310800 DOI: 10.1007/s43032-021-00734-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 09/02/2021] [Indexed: 01/18/2023]
Abstract
Endometriosis (EMS) is an estrogen-dependent disease. However, little is known about the regulation of estrogen, a potential therapeutic target, in EMS, which remains very poorly managed in the clinic. We hypothesized that microRNAs (miRNAs) can be exploited therapeutically to regulate transcription factor 21 (TCF21) and steroidogenic factor-1 (SF-1) gene expression. In our study, paired eutopic and ectopic endometrial samples were obtained from women with EMS and processed by a standard protocol to obtain human endometrial stromal cells (EMs) for in vitro studies. We found that miR-92a-3p levels were decreased in ectopic endometrium and ectopic stromal cells (ESCs) compared with paired eutopic lesions. miR-92a-3p overexpression significantly suppressed the proliferation and migration of ESCs, whereas a decreased level of miR-92a-3p generated the opposite results. Next, we identified TCF21 as a candidate target gene of miR-92a-3p. In vitro cell experiments showed that miR-92a-3p negatively regulated the expression of TCF21 and its downstream target gene SF-1. Moreover, cell proliferation and invasion ability decreased after the silencing of SF-1 and increased after SF-1 overexpression. We also observed that silencing SF-1 while inhibiting miR-92a-3p partially blocked the increase in cell proliferation and invasion ability caused by miR-92a-3p knockdown while overexpressing both SF-1 and miR-92a-3p mitigated the impairment in cell proliferation and invasion ability caused by miR-92a-3p overexpression. Our results may provide a novel potential therapeutic target for the treatment of EMS.
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Affiliation(s)
- Jingwen Zhu
- Department of Obstetrics and Gynecology, Peking University First Hospital, No.1 Xi'anmen Street, Beijing, 100034, China
| | - Zijin Xu
- Department of Reproductive Medicine, Key Laboratory for Major Obstetric Diseases of Guangdong Province, and Key Laboratory for Reproduction and Genetics of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Peili Wu
- Department of Obstetrics and Gynecology, Peking University First Hospital, No.1 Xi'anmen Street, Beijing, 100034, China
| | - Cheng Zeng
- Department of Obstetrics and Gynecology, Peking University First Hospital, No.1 Xi'anmen Street, Beijing, 100034, China
| | - Chao Peng
- Department of Obstetrics and Gynecology, Peking University First Hospital, No.1 Xi'anmen Street, Beijing, 100034, China
| | - Yingfang Zhou
- Department of Obstetrics and Gynecology, Peking University First Hospital, No.1 Xi'anmen Street, Beijing, 100034, China
| | - Qing Xue
- Department of Obstetrics and Gynecology, Peking University First Hospital, No.1 Xi'anmen Street, Beijing, 100034, China.
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Rajput S, Sharma PK, Malviya R. Biomarkers and Treatment Strategies for Breast Cancer Recurrence. Curr Drug Targets 2023; 24:1209-1220. [PMID: 38164731 DOI: 10.2174/0113894501258059231103072025] [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: 04/15/2023] [Revised: 07/14/2023] [Accepted: 10/03/2023] [Indexed: 01/03/2024]
Abstract
Despite recent treatment advancements, breast cancer remains a life-threatening disease. Although treatment is successful in the early stages, a significant proportion of individuals with breast cancer eventually experience a recurrence of the disease. Breast tumour recurrence poses a significant medical issue. Despite tumours being a primary cause of mortality, there remains a limited understanding of the fundamental mechanisms underlying tumour recurrence. The majority of the time, after surgery or medical treatment, this metastatic disease manifests itself after the disease is undiagnosed for a considerable amount of time. This phenomenon is commonly referred to as a relapse or recurrence. Metastatic breast cancer has the potential to recur at varying intervals, ranging from a few months to several decades following the initial diagnosis and treatment. This article aimed to summarise the primary causes of breast cancer recurrence and highlight the key issues that need to be addressed in order to effectively decrease the mortality rate among breast cancer patients. This article discusses various therapeutic approaches currently employed and emerging treatment strategies that hold the potential for the complete cure of cancer.
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Affiliation(s)
- Shivam Rajput
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Pramod Kumar Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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Zhou X, Chen B, Zhang Z, Huang Y, Li J, Wei Q, Cao D, Ai J. Crosstalk between Tumor-Associated Macrophages and MicroRNAs: A Key Role in Tumor Microenvironment. Int J Mol Sci 2022; 23:13258. [PMID: 36362044 PMCID: PMC9653885 DOI: 10.3390/ijms232113258] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/25/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022] Open
Abstract
As an in-depth understanding of immunotherapy continues to grow, current anticancer therapy research is increasingly focused on the tumor microenvironment (TME). MicroRNAs (miRNAs) play crucial roles in the regulation of genetic information and expression and mediate interactions between tumor cells and components in the TME, such as tumor-associated macrophages (macrophages). Macrophages are abundant in the TME, and their different polarization directions can promote or inhibit tumor growth and progression. By regulating biological behaviors, such as macrophage recruitment, infiltration, and polarization, miRNAs can affect various molecular pathways to regulate tumor progression and treatment response. In this review, we discuss in detail the effects of macrophages on tumors and the multifaceted effects of miRNAs on macrophages. We also discuss the potential clinical applications and prospects of targeted therapy based on miRNAs, novel clinical biomarkers, and drug delivery systems.
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Affiliation(s)
| | | | | | | | | | | | - Dehong Cao
- Department of Urology, Institute of Urology, Sichuan University, Chengdu 610041, China
| | - Jianzhong Ai
- Department of Urology, Institute of Urology, Sichuan University, Chengdu 610041, China
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Ogunleye AZ, Piyawajanusorn C, Gonçalves A, Ghislat G, Ballester PJ. Interpretable Machine Learning Models to Predict the Resistance of Breast Cancer Patients to Doxorubicin from Their microRNA Profiles. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201501. [PMID: 35785523 PMCID: PMC9403644 DOI: 10.1002/advs.202201501] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/02/2022] [Indexed: 05/05/2023]
Abstract
Doxorubicin is a common treatment for breast cancer. However, not all patients respond to this drug, which sometimes causes life-threatening side effects. Accurately anticipating doxorubicin-resistant patients would therefore permit to spare them this risk while considering alternative treatments without delay. Stratifying patients based on molecular markers in their pretreatment tumors is a promising approach to advance toward this ambitious goal, but single-gene gene markers such as HER2 expression have not shown to be sufficiently predictive. The recent availability of matched doxorubicin-response and diverse molecular profiles across breast cancer patients permits now analysis at a much larger scale. 16 machine learning algorithms and 8 molecular profiles are systematically evaluated on the same cohort of patients. Only 2 of the 128 resulting models are substantially predictive, showing that they can be easily missed by a standard-scale analysis. The best model is classification and regression tree (CART) nonlinearly combining 4 selected miRNA isoforms to predict doxorubicin response (median Matthew correlation coefficient (MCC) and area under the curve (AUC) of 0.56 and 0.80, respectively). By contrast, HER2 expression is significantly less predictive (median MCC and AUC of 0.14 and 0.57, respectively). As the predictive accuracy of this CART model increases with larger training sets, its update with future data should result in even better accuracy.
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Affiliation(s)
- Adeolu Z. Ogunleye
- Cancer Research Center of Marseille (CRCM)INSERM U1068MarseilleF‐13009France
- Cancer Research Center of Marseille (CRCM)Institut Paoli‐CalmettesMarseilleF‐13009France
- Cancer Research Center of Marseille (CRCM)Aix‐Marseille UniversitéMarseilleF‐13284France
- Cancer Research Center of Marseille (CRCM)CNRS UMR7258MarseilleF‐13009France
| | - Chayanit Piyawajanusorn
- Cancer Research Center of Marseille (CRCM)INSERM U1068MarseilleF‐13009France
- Cancer Research Center of Marseille (CRCM)Institut Paoli‐CalmettesMarseilleF‐13009France
- Cancer Research Center of Marseille (CRCM)Aix‐Marseille UniversitéMarseilleF‐13284France
- Cancer Research Center of Marseille (CRCM)CNRS UMR7258MarseilleF‐13009France
| | - Anthony Gonçalves
- Cancer Research Center of Marseille (CRCM)INSERM U1068MarseilleF‐13009France
- Cancer Research Center of Marseille (CRCM)Institut Paoli‐CalmettesMarseilleF‐13009France
- Cancer Research Center of Marseille (CRCM)Aix‐Marseille UniversitéMarseilleF‐13284France
- Cancer Research Center of Marseille (CRCM)CNRS UMR7258MarseilleF‐13009France
| | - Ghita Ghislat
- Cancer Research Center of Marseille (CRCM)INSERM U1068MarseilleF‐13009France
- Cancer Research Center of Marseille (CRCM)Institut Paoli‐CalmettesMarseilleF‐13009France
- Cancer Research Center of Marseille (CRCM)Aix‐Marseille UniversitéMarseilleF‐13284France
- Cancer Research Center of Marseille (CRCM)CNRS UMR7258MarseilleF‐13009France
| | - Pedro J. Ballester
- Cancer Research Center of Marseille (CRCM)INSERM U1068MarseilleF‐13009France
- Cancer Research Center of Marseille (CRCM)Institut Paoli‐CalmettesMarseilleF‐13009France
- Cancer Research Center of Marseille (CRCM)Aix‐Marseille UniversitéMarseilleF‐13284France
- Cancer Research Center of Marseille (CRCM)CNRS UMR7258MarseilleF‐13009France
- Department of BioengineeringImperial College LondonLondonSW7 2AZUK
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7
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An Eleven-microRNA Signature Related to Tumor-Associated Macrophages Predicts Prognosis of Breast Cancer. Int J Mol Sci 2022; 23:ijms23136994. [PMID: 35805995 PMCID: PMC9266835 DOI: 10.3390/ijms23136994] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/11/2022] [Accepted: 06/13/2022] [Indexed: 11/16/2022] Open
Abstract
The dysregulation of microRNAs (miRNAs) has been known to play important roles in tumor development and progression. However, the understanding of the involvement of miRNAs in regulating tumor-associated macrophages (TAMs) and how these TAM-related miRNAs (TRMs) modulate cancer progression is still in its infancy. This study aims to explore the prognostic value of TRMs in breast cancer via the construction of a novel TRM signature. Potential TRMs were identified from the literature, and their prognostic value was evaluated using 1063 cases in The Cancer Genome Atlas Breast Cancer database. The TRM signature was further validated in the external Gene Expression Omnibus GSE22220 dataset. Gene sets enrichment analyses were performed to gain insight into the biological functions of this TRM signature. An eleven-TRM signature consisting of mir-21, mir-24-2, mir-125a, mir-221, mir-22, mir-501, mir-365b, mir-660, mir-146a, let-7b and mir-31 was constructed. This signature significantly differentiated the high-risk group from the low-risk in terms of overall survival (OS)/ distant-relapse free survival (DRFS) (p value < 0.001). The prognostic value of the signature was further enhanced by incorporating other independent prognostic factors in a nomogram-based prediction model, yielding the highest AUC of 0.79 (95% CI: 0.72−0.86) at 5-year OS. Enrichment analyses confirmed that the differentially expressed genes were mainly involved in immune-related pathways such as adaptive immune response, humoral immune response and Th1 and Th2 cell differentiation. This eleven-TRM signature has great potential as a prognostic factor for breast cancer patients besides unravelling the dysregulated immune pathways in high-risk breast cancer.
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Entezari M, Sadrkhanloo M, Rashidi M, Asnaf SE, Taheriazam A, Hashemi M, Ashrafizadeh M, Zarrabi A, Rabiee N, Hushmandi K, Mirzaei S, Sethi G. Non-coding RNAs and macrophage interaction in tumor progression. Crit Rev Oncol Hematol 2022; 173:103680. [PMID: 35405273 DOI: 10.1016/j.critrevonc.2022.103680] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 03/25/2022] [Accepted: 04/06/2022] [Indexed: 12/12/2022] Open
Abstract
The macrophages are abundantly found in TME and their M2 polarization is in favor of tumor malignancy. On the other hand, non-coding RNAs (ncRNAs) can modulate macrophage polarization in TME to affect cancer progression. The miRNAs can dually induce/suppress M2 polarization of macrophages and by affecting various molecular pathways, they modulate tumor progression and therapy response. The lncRNAs can affect miRNAs via sponging and other molecular pathways to modulate macrophage polarization. A few experiments have also examined role of circRNAs in targeting signaling networks and affecting macrophages. The therapeutic targeting of these ncRNAs can mediate TME remodeling and affect macrophage polarization. Furthermore, exosomal ncRNAs derived from tumor cells or macrophages can modulate polarization and TME remodeling. Suppressing biogenesis and secretion of exosomes can inhibit ncRNA-mediated M2 polarization of macrophages and prevent tumor progression. The ncRNAs, especially exosomal ncRNAs can be considered as non-invasive biomarkers for tumor diagnosis.
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Affiliation(s)
- Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sholeh Etehad Asnaf
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey
| | - Navid Rabiee
- School of Engineering, Macquarie University, Sydney, New South Wales 2109, Australia
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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9
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Miglioli C, Bakalli G, Orso S, Karemera M, Molinari R, Guerrier S, Mili N. Evidence of antagonistic predictive effects of miRNAs in breast cancer cohorts through data-driven networks. Sci Rep 2022; 12:5166. [PMID: 35338170 PMCID: PMC8956684 DOI: 10.1038/s41598-022-08737-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 03/07/2022] [Indexed: 12/03/2022] Open
Abstract
Non-coding micro RNAs (miRNAs) dysregulation seems to play an important role in the pathways involved in breast cancer occurrence and progression. In different studies, opposite functions may be assigned to the same miRNA, either promoting the disease or protecting from it. Our research tackles the following issues: (i) why aren’t there any concordant findings in many research studies regarding the role of miRNAs in the progression of breast cancer? (ii) could a miRNA have either an activating effect or an inhibiting one in cancer progression according to the other miRNAs with which it interacts? For this purpose, we analyse the AHUS dataset made available on the ArrayExpress platform by Haakensen et al. The breast tissue specimens were collected over 7 years between 2003 and 2009. miRNA-expression profiling was obtained for 55 invasive carcinomas and 70 normal breast tissue samples. Our statistical analysis is based on a recently developed model and feature selection technique which, instead of selecting a single model (i.e. a unique combination of miRNAs), delivers a set of models with equivalent predictive capabilities that allows to interpret and visualize the interaction of these features. As a result, we discover a set of 112 indistinguishable models (in a predictive sense) each with 4 or 5 miRNAs. Within this set, by comparing the model coefficients, we are able to identify three classes of miRNA: (i) oncogenic miRNAs; (ii) protective miRNAs; (iii) undefined miRNAs which can play both an oncogenic and a protective role according to the network with which they interact. These results shed new light on the biological action of miRNAs in breast cancer and may contribute to explain why, in some cases, different studies attribute opposite functions to the same miRNA.
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Affiliation(s)
- Cesare Miglioli
- University of Geneva, Geneva School of Economics and Management, Geneva, 1205, Switzerland.
| | - Gaetan Bakalli
- Auburn University, Department of Mathematics and Statistics, Auburn, AL, 36849, USA
| | - Samuel Orso
- University of Geneva, Geneva School of Economics and Management, Geneva, 1205, Switzerland
| | - Mucyo Karemera
- Auburn University, Department of Mathematics and Statistics, Auburn, AL, 36849, USA
| | - Roberto Molinari
- Auburn University, Department of Mathematics and Statistics, Auburn, AL, 36849, USA
| | - Stéphane Guerrier
- University of Geneva, Geneva School of Economics and Management, Geneva, 1205, Switzerland.,University of Geneva, Faculty of Science, Geneva, 1211, Switzerland
| | - Nabil Mili
- University of Lausanne, Lausanne, 1015, Switzerland.
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Wang Y, Li L, Zhang X, Zhao X. Long non-coding RNA OIP5-AS1 suppresses microRNA-92a to augment proliferation and metastasis of ovarian cancer cells through upregulating ITGA6. J Ovarian Res 2022; 15:25. [PMID: 35168644 PMCID: PMC8848981 DOI: 10.1186/s13048-021-00937-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/15/2021] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Recently, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as essential biomarkers during development of malignancies. This study was performed to study the roles of lncRNA opa-interacting protein 5 antisense transcript 1 (OIP5-AS1) and miR-92a in ovarian cancer (OC). METHODS OIP5-AS1, miR-92a and integrin alpha 6 (ITGA6) expression in OC tissues and cells was assessed. The screened OC cells were respectively with OIP5-AS1-, miR-92a- and ITGA6-related vectors or oligonucleotides . The viability, migration, invasion and apoptosis of the cells were determined and the levels of epithelial-mesenchymal transition (EMT)-related proteins were also measured. The interactions between OIP5-AS1 and miR-92a, and between miR-92a and ITGA6 were confirmed. RESULTS OIP5-AS1 and ITGA6 were upregulated while miR-92a was downregulated in OC. Inhibited OIP5-AS1 or downregulated ITGA6 or elevated miR-92a repressed EMT, viability, migration and invasion, and promoted apoptosis of OC cells. OIP5-AS1 as a competing endogenous RNA interacted with miR-92a to regulate ITGA6. These effects that induced by silenced OIP5-AS1 could be reversed by miR-92a inhibition while those that induced by up-regulated miR-92a were reduced by restored ITGA6. CONCLUSION OIP5-AS1 silencing promoted miR-92a to repress proliferation and metastasis of OC cells through inhibiting ITGA6.
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Affiliation(s)
- Yujue Wang
- Gynaecology and Obstetrics Department, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, No. 32, West Second Section First Ring Rd, Chengdu, 610072, Sichuan, China
| | - Lingling Li
- Gynaecology and Obstetrics Department, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, No. 32, West Second Section First Ring Rd, Chengdu, 610072, Sichuan, China
| | - Xun Zhang
- Gynaecology and Obstetrics Department, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, No. 32, West Second Section First Ring Rd, Chengdu, 610072, Sichuan, China.
| | - Xiaolan Zhao
- Gynaecology and Obstetrics Department, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, No. 32, West Second Section First Ring Rd, Chengdu, 610072, Sichuan, China.
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11
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The Role of miRNAs 340-5p, 92a-3p, and 381-3p in Patients with Endometriosis: A Plasma and Mesenchymal Stem-Like Cell Study. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5298006. [PMID: 34631883 PMCID: PMC8494557 DOI: 10.1155/2021/5298006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 09/05/2021] [Accepted: 09/09/2021] [Indexed: 01/07/2023]
Abstract
Background Endometriosis is the most prevalent gynecological disease with elusive etiology. The mysterious entity and the lack of noninvasive diagnostic methods affect women's lives negatively. This study is aimed at finding the relationship between miR-340-5p, 92a-3p, and miR-381-3p and the pathogenesis of endometriosis in endometrial mesenchymal stem-like cells (eMSCs) of endometriosis and assessing their potential as a noninvasive biomarker in plasma. Methods Peripheral blood and eMSC specimens were collected from suspected women of endometriosis before laparoscopy. Total RNA was isolated from plasma and cultured eMSCs to synthesize complementary DNA. The expression of miR-340-5p, miR-92a-3p, and miR-381-3p was analyzed by RT-qPCR. To understand these miRNAs' role, we also did a bioinformatic analysis. Results There was a downregulation of miR-340-5p, miR-92a-3p, and miR-381-3p in plasma, and the upregulation of miR-340-5p and the downregulation of miR-92a-3p and miR-381-3p in eMSCs of women with endometriosis. There was a positive concordance between the expression of miR-92a-3p and miR-381-3p in plasma and eMSCs. Our study also showed three genes, Solute Carrier Family 6 Member 8 (SLC6A8), Zinc Finger Protein 264 (ZNF264), and mouse double minute 2 (MDM2), as common targets of these miRNAs. Conclusions This study has been one of the first attempts to examine the expression of miR-340-5p, miR-92a-3p, and miR-381-3p in both plasma and eMSCs and revealed their possible role in endometriosis based on in silico analysis. Biomarkers pave the way to develop a new therapeutic approach to the management or treatment of endometriosis patients. Our result as a first report shows that combined levels of miRNAs 340-5p and 381-3p may have the potential to be utilized as diagnostic biomarkers for endometriosis.
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12
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miR-125a-5p impairs the metastatic potential in breast cancer via IP 6K1 targeting. Cancer Lett 2021; 520:48-56. [PMID: 34229060 DOI: 10.1016/j.canlet.2021.07.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/25/2021] [Accepted: 07/01/2021] [Indexed: 02/07/2023]
Abstract
The deregulation of PI3K/Akt signaling is among the most causes in inducing the acquisition of a metastatic phenotype in breast cancer cells, leading to Epithelial-Mesenchymal Transition (EMT). Inhibition of the PI3K/Akt pathway is known to be beneficial in the clinical setting. However, the activation of secondary pathways and toxicity profiles of available inhibitors, hindering optimal therapeutic results. Preliminary studies showed that myo-Inositol inhibits the PI3K/Akt pathway by exerting a pleiotropic anti-tumor action. Herein, we demonstrate that myo-Inositol triggers a prompt and profound remodeling of delineated expression pattern in triple-negative breast cancer cells (MDA-MB-231). Consequently, it inhibits metastasis and tumor progression through miR-125a-5p transcription and the subsequent inhibition of IP6K1. In contrast, hormone-responsive breast cancer cells (MCF-7) are insensitive to myo-Inositol. This is due to the persistence of MDM2 synthesis promoted by estrogen-dependent pathways. Conversely, the counteraction of estrogen effects recovered the sensitivity to myo-Inositol in the hormone-responsive model. Overall, these results identify a novel axis primed by miR-125a-5p to downregulate IP6K1 gene that inhibits metastasis. Thus, administration of myo-Inositol can activate this axis as a molecular target therapy in breast cancer.
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13
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Nair MG, Somashekaraiah VM, Ramamurthy V, Prabhu JS, Sridhar TS. miRNAs: Critical mediators of breast cancer metastatic programming. Exp Cell Res 2021; 401:112518. [PMID: 33607102 DOI: 10.1016/j.yexcr.2021.112518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/06/2021] [Accepted: 02/08/2021] [Indexed: 12/14/2022]
Abstract
MicroRNA mediated aberrant gene regulation has been implicated in several diseases including cancer. Recent research has highlighted the role of epigenetic modulation of the complex process of breast cancer metastasis by miRNAs. miRNAs play a crucial role in the process of metastatic evolution by facilitating alterations in the phenotype of tumor cells and the tumor microenvironment that promote this process. They act as critical determinants of the multi-step progression starting from carcinogenesis all the way to organotropism. In this review, we focus on the current understanding of the compelling role of miRNAs in breast cancer metastasis.
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Affiliation(s)
- Madhumathy G Nair
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
| | | | - Vishakha Ramamurthy
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
| | - Jyothi S Prabhu
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
| | - T S Sridhar
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
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14
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The Role of miRNAs, miRNA Clusters, and isomiRs in Development of Cancer Stem Cell Populations in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22031424. [PMID: 33572600 PMCID: PMC7867000 DOI: 10.3390/ijms22031424] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/17/2021] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs or miRs) have a critical role in regulating stem cells (SCs) during development and altered expression can cause developmental defects and/or disease. Indeed, aberrant miRNA expression leads to wide-spread transcriptional dysregulation which has been linked to many cancers. Mounting evidence also indicates a role for miRNAs in the development of the cancer SC (CSC) phenotype. Our goal herein is to provide a review of: (i) current research on miRNAs and their targets in colorectal cancer (CRC), and (ii) miRNAs that are differentially expressed in colon CSCs. MicroRNAs can work in clusters or alone when targeting different SC genes to influence CSC phenotype. Accordingly, we discuss the specific miRNA cluster classifications and isomiRs that are predicted to target the ALDH1, CD166, BMI1, LRIG1, and LGR5 SC genes. miR-23b and miR-92A are of particular interest because our previously reported studies on miRNA expression in isolated normal versus malignant human colonic SCs showed that miR-23b and miR-92a are regulators of the LGR5 and LRIG1 SC genes, respectively. We also identify additional miRNAs whose expression inversely correlated with mRNA levels of their target genes and associated with CRC patient survival. Altogether, our deliberation on miRNAs, their clusters, and isomiRs in regulation of SC genes could provide insight into how dysregulation of miRNAs leads to the emergence of different CSC populations and SC overpopulation in CRC.
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15
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Chen C, Liu JM, Luo YP. MicroRNAs in tumor immunity: functional regulation in tumor-associated macrophages. J Zhejiang Univ Sci B 2020; 21:12-28. [PMID: 31898439 DOI: 10.1631/jzus.b1900452] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and are critical for cancer initiation and progression. MicroRNAs (miRNAs) could notably influence the phenotype of TAMs through various targets and signal pathways during cancer progression due to their post-transcriptional regulation. In this review, we discuss mainly the regulatory function of miRNAs on macrophage differentiation, functional polarization, and cellular crosstalk. Firstly, during the generation process, miRNAs take part in the differentiation from myeloid cells to mature macrophages, and this maturation process directly influences their recruitment into the TME, attracted by tumor cells. Secondly, macrophages in the TME can be either tumor-promoting or tumor-suppressing, depending on their functional polarization. Large numbers of miRNAs can influence the polarization of macrophages, which is crucial for tumor progression, including tumor cell invasion, intravasation, extravasation, and premetastatic site formation. Thirdly, crosstalk between tumor cells and macrophages is essential for TME formation and tumor progression, and miRNAs can be the mediator of communication in different forms, especially when encapsulated in microvesicles or exosomes. We also assess the potential value of certain macrophage-related miRNAs (MRMs) as diagnostic and prognostic markers, and discuss the possible development of MRM-based therapies.
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Affiliation(s)
- Chong Chen
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.,Collaborative Innovation Center for Biotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Jia-Ming Liu
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.,Collaborative Innovation Center for Biotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Yun-Ping Luo
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.,Collaborative Innovation Center for Biotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
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16
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Zeng R, Huang J, Sun Y, Luo J. Cell proliferation is induced in renal cell carcinoma through miR-92a-3p upregulation by targeting FBXW7. Oncol Lett 2020; 19:3258-3268. [PMID: 32256821 PMCID: PMC7074420 DOI: 10.3892/ol.2020.11443] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 08/06/2019] [Indexed: 01/06/2023] Open
Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer whose incidence has gradually increased worldwide. MicroRNAs (miRNAs) represent a type of short endogenous non-coding RNA containing approximately 22 nucleotides, which are capable of regulating mRNAs at the post-transcriptional level in human cells. miRNAs have been demonstrated to mediate gene expression by influencing important regulatory genes. Accumulating evidence indicates that certain miRNAs are involved in RCC development. The present study investigated the underlying mechanism and functional role of miR-92a-3p in RCC cells using reverse transcription-quantitative polymerase chain reaction, western blotting, 3′ UTR luciferase assay, cell proliferation assay and soft agar assay. The results demonstrated that miR-92a-3p expression level is significantly upregulated in RCC tissues and cell lines; however, F-box and WD repeat domain containing 7 (FBXW7) expression level was significantly downregulated in RCC tissues and cell lines. Subsequently, whether FBXW7 could be considered as a direct target of miR-92a-3p in RCC cells was investigated. The results demonstrated that miR-92a-3p overexpression significantly promoted RCC cell proliferation and colony formation. Conversely, miR-92a-3p downregulation significantly inhibited RCC cell proliferation and colony formation. In addition, FBXW7 knockdown significantly enhanced RCC cell proliferation and colony formation. Conversely, FBXW7 overexpression significantly inhibited RCC cell proliferation and colony formation. Collectively, these results demonstrated that miR-92a-3p/FBXW7 pathway may represent a novel strategy and therapeutic target for RCC.
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Affiliation(s)
- Rong Zeng
- Teaching Experimental Center, School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Jing Huang
- Teaching Experimental Center, School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Yujie Sun
- Teaching Experimental Center, School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Juan Luo
- Department of Internal Medicine, The Second Hospital of Wuhan Iron and Steel (Group) Corporation, Wuhan, Hubei 430085, P.R. China
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17
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Wang Y, Wang H, Zhang C, Zhang C, Yang H, Gao R, Tong Z. Plasma Hsa-miR-92a-3p in correlation with lipocalin-2 is associated with sepsis-induced coagulopathy. BMC Infect Dis 2020; 20:155. [PMID: 32075600 PMCID: PMC7031893 DOI: 10.1186/s12879-020-4853-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 02/06/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Sepsis is a life-threatening situation, and it can be rendered more severe by coagulopathy. We here examine a novel plasma biomarker for sepsis-induced coagulopathy. METHODS A total of 116 patients diagnosed with sepsis were recruited and divided into two groups by whether they also had coagulopathy. Plasma samples were collected on arrival at the intensive care unit. Fifteen sepsis-alone and 15 sepsis-induced coagulopathy plasma samples were mixed and sent for microRNA sequencing. Differently expressed microRNAs were then validated by quantitative reverse transcriptase polymerase chain reaction in 52 sepsis-alone and 34 sepsis-induced coagulopathy patients; plasma lipocalin-2 was measured as well. RESULTS Four microRNAs were selected from microRNA sequencing. Only hsa-mir-92a-3p was differently expressed in the validation set. Its level of expression was significantly lower in sepsis-induced coagulopathy group. Hsa-mir-92a-3p had an area under a receiver operating characteristic curve of 0.660 (95% confidence interval, 0.537, 0.782). The plasma Hsa-mir-92a-3p level was related to activated partial thromboplastin time, prothrombin activity, and plasma lipocalin-2 level. A binary logistic model showed an association between hsa-mir-92a-3p and fibrinogen with SIC. CONCLUSIONS The utility of hsa-mir-92a-3p as a biomarker for sepsis-induced coagulopathy needs more verification, and the regulatory mechanism of hsa-mir-92a-3p in coagulation disorder and its potency as a therapeutic target must be confirmed.
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Affiliation(s)
- Yishan Wang
- Department of Respiratory and Critical Care Medicine, Beijing Engineering Research Center of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, NO. 8, Gong Ti South Road, Chao-Yang District, Beijing, 100020, China
| | - Huijuan Wang
- Department of Respiratory and Critical Care Medicine, Beijing Engineering Research Center of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, NO. 8, Gong Ti South Road, Chao-Yang District, Beijing, 100020, China
| | - Chunfang Zhang
- Department of Anesthesiology, Pain Medicine and Critical Care Medicine, Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine, Chinese Academy of Sciences, Beijing, 100012, China
| | - Chao Zhang
- Department of Respiratory and Critical Care Medicine, Beijing Engineering Research Center of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, NO. 8, Gong Ti South Road, Chao-Yang District, Beijing, 100020, China
| | - Huqin Yang
- Department of Respiratory and Critical Care Medicine, Beijing Engineering Research Center of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, NO. 8, Gong Ti South Road, Chao-Yang District, Beijing, 100020, China
| | - Ruiyue Gao
- Department of Respiratory and Critical Care Medicine, Beijing Engineering Research Center of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, NO. 8, Gong Ti South Road, Chao-Yang District, Beijing, 100020, China
| | - Zhaohui Tong
- Department of Respiratory and Critical Care Medicine, Beijing Engineering Research Center of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, NO. 8, Gong Ti South Road, Chao-Yang District, Beijing, 100020, China.
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18
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Bile-derived circulating extracellular miR-30d-5p and miR-92a-3p as potential biomarkers for cholangiocarcinoma. Hepatobiliary Pancreat Dis Int 2020; 19:41-50. [PMID: 31784323 DOI: 10.1016/j.hbpd.2019.10.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 10/31/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is from cholangiocytes, and therefore bile is a potentially rich source of biomarkers for CCA. The aim of the study was to identify and validate microRNAs (miRNAs) in bile samples that are differentially expressed between benign biliary disease (BBD) and CCA. METHODS Bile samples from 106 patients with obstructive biliary disease were allocated consecutively to a discovery set (10 patients with BBD and 11 with CCA) and then a validation set (48 patients with BBD and 37 with CCA). An miRNA microarray platform was used to screen 1209 miRNAs in the discovery set. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to validate the profiling results in the discovery and validation sets. In addition, the levels of carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) were determined from patient serum samples. RESULTS Microarray profiling showed that miR-30d-5p and miR-92a-3p were significantly upregulated in bile from the CCA group compared with those from the BBD group. qRT-PCR results indicated that the expression levels of miR-30d-5p and of miR-92a-3p were significantly upregulated in the CCA group compared to the BBD group, validating the miRNA microarray results. Pathway analysis suggested that putative target genes of miR-30d-5p and of miR-92a-3p were involved in CCA-associated signalling pathways, such as Hippo, Wnt, p53, MAPK, and EGFR. Receiver operating curve analysis revealed that the areas under the curve for bile miR-30d-5p, miR-92a-3p, serum CA19-9, and CEA were 0.730, 0.652, 0.675, and 0.603, respectively, and bile miR-30d-5p showed the best diagnostic performance with a sensitivity of 81.1% and a specificity of 60.5%. CONCLUSIONS The levels of extracellular miR-30d-5p and miR-92a-3p in bile were significantly higher in patients with CCA than those in patients with BBD. Bile-derived circulating extracellular miR-30d-5p and miR-92a-3p are potential biomarkers for discriminating CCA from BBD.
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19
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Liu LQ, Hu L, Hu XB, Xu J, Wu AM, Chen H, Gu PY, Hu SL. MiR-92a antagonized the facilitation effect of extracellular matrix protein 1 in GC metastasis through targeting its 3′UTR region. Food Chem Toxicol 2019; 133:110779. [DOI: 10.1016/j.fct.2019.110779] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 08/18/2019] [Accepted: 08/20/2019] [Indexed: 12/12/2022]
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20
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Peng Y, Huang D, Qing X, Tang L, Shao Z. Investigation of MiR-92a as a Prognostic Indicator in Cancer Patients: a Meta-Analysis. J Cancer 2019; 10:4430-4441. [PMID: 31413763 PMCID: PMC6691717 DOI: 10.7150/jca.30313] [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: 09/30/2018] [Accepted: 06/23/2019] [Indexed: 12/30/2022] Open
Abstract
Background: MiR-92a has been discovered to be involved in the malignant behavior of various types of cancers. However, the particular clinical and prognostic roles of miR-92a in tumors still need to be identified more precisely. The current meta-analysis assessed the prognostic value of miR-92a in various carcinomas. Methods: Systematic literature searches of PubMed, PMC, Web of Science (WOS), Embase in English and Wanfang, SinoMed and the China National Knowledge Infrastructure (CNKI) in Chinese up to Jan 15th 2019 were conducted for eligible studies. Twenty studies involving a total of 2573 patients were included in the analysis. Pooled hazard ratios (HR) for overall survival (OS) and disease-free survival (DFS), progression-free survival (PFS) and recurrence-free survival (RFS) were assessed using fixed-effects and random-effects models. Meta-regression and subgroup analyses were carried out to explore the source of heterogeneity. Odds ratio (OR) and 95%CIs were applied to evaluate the relationship between miR-92a expression levels and clinicopathological characteristics. Results: A significant association between miR-92a levels and OS (HR=2.18) was identified. The random pooling model also revealed significance of consistency (HR=2.14), indicating that the stability of the results. Subgroup analyses were performed and the corresponding significance was recognized in Chinese cancer patients (HR=2.35), studies of specimen derived from tissues (HR=2.43), non-hematological cancer (HR=2.35), osteosarcoma (HR=2.54), non-small cell lung cancer (HR=2.33), hepatocellular carcinoma (HR=2.40) and so on. There were significant relations observed of the expression level of miR-92a to tumor size (≥5 vs <5 cm) (OR=2.13), lymph node metastasis (present vs. absent) (OR=1.87), distant metastasis (present vs. absent) (OR=2.99) and so on. Conclusions: the over expression of miR-92a is associated with unfavorable prognosis of Chinese cancer patients. In addition, patients of elevated miR-92a expression level are likely to develop the cancers of more malignant behaviors.
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Affiliation(s)
- Yizhong Peng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Donghua Huang
- Musculoskeletal Tumor Center, Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Xiangcheng Qing
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lu Tang
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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21
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Shidal C, Singh NP, Nagarkatti P, Nagarkatti M. MicroRNA-92 Expression in CD133 + Melanoma Stem Cells Regulates Immunosuppression in the Tumor Microenvironment via Integrin-Dependent Activation of TGFβ. Cancer Res 2019; 79:3622-3635. [PMID: 31015227 DOI: 10.1158/0008-5472.can-18-2659] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 03/19/2019] [Accepted: 04/18/2019] [Indexed: 12/27/2022]
Abstract
In addition to being refractory to treatment, melanoma cancer stem cells (CSC) are known to suppress host antitumor immunity, the underlying mechanisms of which need further elucidation. In this study, we established a novel role for miR-92 and its associated gene networks in immunosuppression. CSCs were isolated from the B16-F10 murine melanoma cell line based on expression of the putative CSC marker CD133 (Prominin-1). CD133+ cells were functionally distinct from CD133- cells and showed increased proliferation in vitro and enhanced tumorigenesis in vivo. CD133+ CSCs also exhibited a greater capacity to recruit immunosuppressive cell types during tumor formation, including FoxP3+ Tregs, myeloid-derived suppressor cells (MDSC), and M2 macrophages. Using microarray technology, we identified several miRs that were significantly downregulated in CD133+ cells compared with CD133- cells, including miR-92. Decreased expression of miR-92 in CSCs led to higher expression of target molecules integrin αV and α5 subunits, which, in turn, enhanced TGFβ activation, as evidenced by increased phosphorylation of SMAD2. CD133+ cells transfected with miR-92a mimic and injected in vivo showed significantly decreased tumor burden, which was associated with reduced immunosuppressive phenotype intratumorally. Using The Cancer Genome Atlas database of patients with melanoma, we also noted a positive correlation between integrin α5 and TGFβ1 expression levels and an inverse association between miR-92 expression and integrin alpha subunit expression. Collectively, this study suggests that a miR-92-driven signaling axis involving integrin activation of TGFβ in CSCs promotes enhanced tumorigenesis through induction of intratumoral immunosuppression. SIGNIFICANCE: CD133+ cells play an active role in suppressing melanoma antitumor immunity by modulating miR-92, which increases influx of immunosuppressive cells and TGFβ1 expression.
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Affiliation(s)
- Chris Shidal
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina
| | - Narendra P Singh
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina.
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22
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Huang S, Xu W, Hu P, Lakowski TM. Integrative Analysis Reveals Subtype-Specific Regulatory Determinants in Triple Negative Breast Cancer. Cancers (Basel) 2019; 11:cancers11040507. [PMID: 30974831 PMCID: PMC6521146 DOI: 10.3390/cancers11040507] [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: 02/07/2019] [Revised: 04/02/2019] [Accepted: 04/02/2019] [Indexed: 12/20/2022] Open
Abstract
Different breast cancer (BC) subtypes have unique gene expression patterns, but their regulatory mechanisms have yet to be fully elucidated. We hypothesized that the top upregulated (Yin) and downregulated (Yang) genes determine the fate of cancer cells. To reveal the regulatory determinants of these Yin and Yang genes in different BC subtypes, we developed a lasso regression model integrating DNA methylation (DM), copy number variation (CNV) and microRNA (miRNA) expression of 391 BC patients, coupled with miRNA–target interactions and transcription factor (TF) binding sites. A total of 25, 20, 15 and 24 key regulators were identified for luminal A, luminal B, Her2-enriched, and triple negative (TN) subtypes, respectively. Many of the 24 TN regulators were found to regulate the PPARA and FOXM1 pathways. The Yin Yang gene expression mean ratio (YMR) and combined risk score (CRS) signatures built with either the targets of or the TN regulators were associated with the BC patients’ survival. Previously, we identified FOXM1 and PPARA as the top Yin and Yang pathways in TN, respectively. These two pathways and their regulators could be further explored experimentally, which might help to identify potential therapeutic targets for TN.
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Affiliation(s)
- Shujun Huang
- College of Pharmacy, University of Manitoba, Winnipeg, MB R3E 0T5, Canada; huangs12@myumanitoba (S.H.); (W.X.)
| | - Wayne Xu
- College of Pharmacy, University of Manitoba, Winnipeg, MB R3E 0T5, Canada; huangs12@myumanitoba (S.H.); (W.X.)
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Research Institute in Oncology and Hematology, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Pingzhao Hu
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Research Institute in Oncology and Hematology, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Correspondence: (P.H.); (T.M.L.); Tel.: +1-204-789-3229 (P.H.); +1-204-272-3173 (T.M.L.)
| | - Ted M. Lakowski
- College of Pharmacy, University of Manitoba, Winnipeg, MB R3E 0T5, Canada; huangs12@myumanitoba (S.H.); (W.X.)
- Correspondence: (P.H.); (T.M.L.); Tel.: +1-204-789-3229 (P.H.); +1-204-272-3173 (T.M.L.)
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Rezaei N, Talebi F, Ghorbani S, Rezaei A, Esmaeili A, Noorbakhsh F, Hakemi MG. MicroRNA-92a Drives Th1 Responses in the Experimental Autoimmune Encephalomyelitis. Inflammation 2019; 42:235-245. [PMID: 30411211 DOI: 10.1007/s10753-018-0887-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Dysregulation of microRNAs (miRNAs) has been linked to the progress of a number of autoimmune diseases including multiple sclerosis (MS), and its animal model, experimental autoimmune encephalomyelitis (EAE). IFN-γ-producing Th1 cells are major players in MS/EAE pathogenesis. It is known that differentiation of T cells towards the Th1 phenotype is influenced by various factors including miRNAs. The miR-92a shows substantial upregulation in MS; however, little is known about its role in the development of autoimmune and inflammatory responses. Herein, we investigated the role of miR-92a in the pathogenesis of MS, focusing on its potential effects on differentiation of Th1 cells. The expression levels of miR-92a were assessed in the spinal cord tissues and splenocytes from mice with EAE using real-time RT-PCR. Next, using transfection with miR-92a mimic sequences, the potential involvement of miR-92a in Th1 polarization was investigated by flow cytometric analysis. Moreover, the expression levels of miR-92a targets were explored in spinal cord tissues of EAE mice. miR-92a expression was enhanced in mouse spinal cord samples at the peak of EAE disease. Overexpression of miR-92a in splenocytes led to increased differentiation of Th1 cells compared with cells transfected with negative control sequences. Enhanced miR-92a expression was accompanied by reduced expression TSC1 or DUSP10, predicted miR-92a targets, in EAE spinal cords. Our data point to a potential role for miR-92a in neuroinflammatory responses in EAE. Our results indicate that miR-92a might affect Th1 differentiation, likely due to downregulation of TSC1 and DUSP10.
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Affiliation(s)
- Nahid Rezaei
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Farideh Talebi
- Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Ghorbani
- Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Rezaei
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Abolghasem Esmaeili
- Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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24
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Tandon I, Sharma NK. Macrophage Flipping from Foe to Friend: A Matter of Interest in Breast Carcinoma Heterogeneity Driving Drug Resistance. Curr Cancer Drug Targets 2019; 19:189-198. [PMID: 29952260 DOI: 10.2174/1568009618666180628102247] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 05/09/2018] [Accepted: 06/13/2018] [Indexed: 02/06/2023]
Abstract
Tumor heterogeneity within various cancer types including breast carcinoma is pivotal in the manifestations of tumor hallmarks. Tumor heterogeneity is seen as a common landscape where intra-tumoral components including cellular and non-cellular factors create an interface with outside environment that leads to the unique identity of a specific cancer type. Among various contributors to tumor heterogeneity, cellular heterogeneity immensely plays a role in drug resistance and relapse of cancer. Within cellular heterogeneity of tumor, tumor-associated macrophages (TAMs) are the pro-tumor type of immune cells that promote growth, metastasis and drug resistance in breast carcinoma and other cancer types. Revealing the molecular aspects of TAMs can provide a breakthrough to remove therapeutics blockade to existing drugs and this understanding in future will pave the way for a new class of cancer immunotherapeutic. This review addresses current understanding of the role of TAMs in breast carcinoma hallmarks and clarifies the current scenario of pre-clinical drugs directed to tame pro-cancer TAMs.
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Affiliation(s)
- Ishita Tandon
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra 411033, India
| | - Nilesh Kumar Sharma
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra 411033, India
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25
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Zhao X, Sun B, Liu T, Shao B, Sun R, Zhu D, Zhang Y, Gu Q, Dong X, Liu F, Zhao N, Zhang D, Li Y, Meng J, Gong W, Zheng Y, Zheng X. Long noncoding RNA n339260 promotes vasculogenic mimicry and cancer stem cell development in hepatocellular carcinoma. Cancer Sci 2018; 109:3197-3208. [PMID: 30022558 PMCID: PMC6172069 DOI: 10.1111/cas.13740] [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] [Received: 05/22/2018] [Revised: 07/04/2018] [Accepted: 07/10/2018] [Indexed: 12/25/2022] Open
Abstract
Vasculogenic mimicry (VM) refers to the unique capability of aggressive tumor cells to mimic the pattern of embryonic vasculogenic networks. Cancer stem cells (CSC) represent a subpopulation of tumor cells endowed with the capacity for self‐renewal and multilineage differentiation. Previous studies have indicated that CSC may participate in the formation of VM. With the advance of high‐resolution microarrays and massively parallel sequencing technology, long noncoding RNAs (lncRNAs) are suggested to play a critical role in tumorigenesis and, in particular, the development of human hepatocellular carcinoma (HCC). Currently, no definitive relationship between lncRNA and VM formation has been described. In the current study, we demonstrated that expression of the lncRNA, n339260, is associated with CSC phenotype in HCC, and n339260 level correlated with VM, metastasis, and shorter survival time in an animal model. Overexpression of n339260 in HepG2 cells was associated with a significant increase in CSC. Additionally, the appearance of VM and vascular endothelial (VE)‐cadherin, a molecular marker of VM, was also induced by n339260 overexpression. Using a short hairpin RNA approach, n339260 was silenced in tumor cells, and knockdown of n339260 was associated with reduced VM and CSC. The results of this study indicate that n339260 promotes VM, possibly by the development of CSC. The related molecular pathways may be used as novel therapeutic targets for the inhibition of HCC angiogenesis and metastasis.
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Affiliation(s)
- Xiulan Zhao
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.,Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Baocun Sun
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.,Department of Pathology, Tianjin Medical University, Tianjin, China.,Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin, China
| | - Tieju Liu
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.,Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Bing Shao
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Ran Sun
- Tianjin Nankai Hospital, Tianjin, China
| | - Dongwang Zhu
- Stomatology Hospital of Tianjin Medical University, Tianjin, China
| | - Yanhui Zhang
- Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin, China
| | - Qiang Gu
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.,Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Xueyi Dong
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.,Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Fang Liu
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.,Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Nan Zhao
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.,Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Danfang Zhang
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.,Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Yanlei Li
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.,Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Jie Meng
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.,Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Wenchen Gong
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Yanjun Zheng
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Xu Zheng
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
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26
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Decker JT, Hall MS, Blaisdell RB, Schwark K, Jeruss JS, Shea LD. Dynamic microRNA activity identifies therapeutic targets in trastuzumab-resistant HER2 + breast cancer. Biotechnol Bioeng 2018; 115:2613-2623. [PMID: 29981261 DOI: 10.1002/bit.26791] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 06/28/2018] [Accepted: 07/02/2018] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are implicated in numerous physiologic and pathologic processes, such as the development of resistance to chemotherapy. Determining the role of miRNAs in these processes is often accomplished through measuring miRNA abundance by polymerase chain reaction, sequencing, or microarrays. We have developed a system for the large-scale monitoring of dynamic miRNA activity and have applied this system to identify the contribution miRNA activity to the development of trastuzumab resistance in a cell model of HER2+ breast cancer. MiRNA activity measurements identified significantly different activity levels between BT474 cells (HER2 + breast cancer) and BT474R cells (HER2 + breast cancer cells selected for resistance to trastuzumab). We created a library of 32 miRNA reporter constructs, which were delivered by lentiviral transduction into cells, and miRNA activity was quantified by bioluminescence imaging. Upon treatment with the bioimmune therapy, trastuzumab, the activity of 11 miRNAs were significantly altered in parental BT474 cells, and 20 miRNAs had significantly altered activity in the therapy-resistant BT474R cell line. A combination of statistical, network and classification analysis was applied to the dynamic data, which identified miR-21 as a controlling factor in trastuzumab response. Our data suggested downregulation of miR-21 activity was associated with resistance, which was confirmed in an additional HER2 + breast cancer cell line, SKBR3. Collectively, the dynamic miRNA activity measurements and analysis provided a system to identify new potential therapeutic targets in treatment-resistant cancers.
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Affiliation(s)
- Joseph T Decker
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Matthew S Hall
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Rachel B Blaisdell
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Kallen Schwark
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Jacqueline S Jeruss
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.,Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
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27
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Guo J, Wen N, Yang S, Guan X, Cang S. MiR-92a regulates oral squamous cell carcinoma (OSCC) cell growth by targeting FOXP1 expression. Biomed Pharmacother 2018; 104:77-86. [DOI: 10.1016/j.biopha.2018.05.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 04/27/2018] [Accepted: 05/07/2018] [Indexed: 01/06/2023] Open
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28
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Lamb CA, Fabris VT, Jacobsen B, Molinolo AA, Lanari C. Biological and clinical impact of imbalanced progesterone receptor isoform ratios in breast cancer. Endocr Relat Cancer 2018; 25:ERC-18-0179. [PMID: 29991638 DOI: 10.1530/erc-18-0179] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 07/04/2018] [Accepted: 07/09/2018] [Indexed: 12/17/2022]
Abstract
There is a consensus that progestins and thus their cognate receptor molecules, the progesterone receptors (PR), are essential in the development of the adult mammary gland and regulators of proliferation and lactation. However, a role for natural progestins in breast carcinogenesis remains poorly understood. A hint to that possible role came from studies in which the synthetic progestin medroxyprogesterone acetate was associated with an increased breast cancer risk in women under hormone replacement therapy. However, progestins have been also used for breast cancer treatment and to inhibit the growth of several experimental breast cancer models. More recently, PR have been shown to be regulators of estrogen receptor signaling. With all this information, the question is how can we target PR, and if so, which patients may benefit from such an approach? PR are not single unique molecules. Two main PR isoforms have been characterized, PRA and PRB, that exert different functions and the relative abundance of one isoform respect to the other determines the response of PR agonists and antagonists. Immunohistochemistry with standard antibodies against PR do not discriminate between isoforms. In this review, we summarize the current knowledge on the expression of both PR isoforms in mammary glands, in experimental models of breast cancer and in breast cancer patients, to better understand how the PRA/PRB ratio can be exploited therapeutically to design personalized therapeutic strategies.
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Affiliation(s)
- Caroline A Lamb
- C Lamb, Laboratorio de Carcinogénesis Hormonal, Instituto de Biología y Medicina Experimental, Buenos Aires, Argentina
| | - Victoria T Fabris
- V Fabris, Laboratorio de Carcinogénesis Hormonal, Instituto de Biología y Medicina Experimental, Buenos Aires, Argentina
| | - Britta Jacobsen
- B Jacobsen, Department of Pathology, University of Colorado at Denver - Anschutz Medical Campus, Aurora, United States
| | - Alfredo A Molinolo
- A Molinolo, Biorepository and Tissue Technology Shared Resource, University of California San Diego Moores Cancer Center, La Jolla, United States
| | - Claudia Lanari
- C Lanari, Laboratorio de Carcinogénesis Hormonal, Instituto de Biología y Medicina Experimental, Buenos Aires, Argentina
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29
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Shin VY, Siu MT, Liu X, Ng EKO, Kwong A, Chu KM. MiR-92 suppresses proliferation and induces apoptosis by targeting EP4/Notch1 axis in gastric cancer. Oncotarget 2018; 9:24209-24220. [PMID: 29849934 PMCID: PMC5966267 DOI: 10.18632/oncotarget.24819] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 02/27/2018] [Indexed: 12/19/2022] Open
Abstract
MiR-92a has been shown to be dysregulated in various cancers and exhibited differential role in carcinogenesis. In this study, we sought to delineate the functional role of miR-92a and its regulatory pathway in gastric cancer. MiR-92a expression were underexpressed in tissues of gastric cancer patients with the area under curve (AUC) of 0.78. Low expression in plasma was due to the increased promoter DNA methylation of miR-92a. Overexpression of miR-92a inhibited cell proliferation and invasion, and induced apoptosis. Furthermore, miR-92a reduced tumor growth in xenograft model. EP4 and Notch 1 were identified to be negatively regulated by miR-92a, and involved in cell growth. Moreover, NF-κB expression was inversely correlated with miR-92a in gastric cancer tissues and suppressed the expression of miR-92. This study unravels the tumor suppressive role of miR-92a involving EP4/Notch 1 signaling regulated by NF-κB in gastric cancer. Further studies on miR-92a and EP4/Notch1 may provide a new treatment strategy for gastric cancer.
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Affiliation(s)
| | - Man-Ting Siu
- Department of Surgery, The University of Hong Kong, Hong Kong SAR
| | - Xin Liu
- Department of Surgery, The University of Hong Kong, Hong Kong SAR
| | - Enders K O Ng
- Department of Surgery, The University of Hong Kong, Hong Kong SAR
| | - Ava Kwong
- Department of Surgery, The University of Hong Kong, Hong Kong SAR.,Department of Surgery, Hong Kong Sanatorium and Hospital, Hong Kong SAR.,Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong SAR
| | - Kent-Man Chu
- Department of Surgery, The University of Hong Kong, Hong Kong SAR
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30
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Grigorian-Shamagian L, Fereydooni S, Liu W, Echavez A, Marbán E. Harnessing the heart's resistance to malignant tumors: cardiac-derived extracellular vesicles decrease fibrosarcoma growth and leukemia-related mortality in rodents. Oncotarget 2017; 8:99624-99636. [PMID: 29245929 PMCID: PMC5725120 DOI: 10.18632/oncotarget.20454] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 07/14/2017] [Indexed: 11/25/2022] Open
Abstract
The heart is known for its resistance to cancer. Although different conjectures have been proposed to explain this phenomenon, none has been tested. We propose that the heart microenvironment may exert anti-cancer properties. So, our objective was to test the anti-oncogenic potential of cardiac-derived extracellular vesicles (EVs). For that EVs secreted by cardiosphere-derived cells (CDCs, heart progenitor cells) were tested in vitro on fibrosarcoma HT1080. In vivo models comprised the xenograft HT1080 fibrosarcoma in athymic mice (n=35), and spontaneous acute lymphocyte leukemia in old rats (n=44). CDC-EVs were compared with two control groups: EVs secreted by bone-marrow derived mesenchymal stem cells (MSC-EVs) and phosphate-buffered saline (PBS). Injection of CDC-EVs led to a 2.5-fold decrease of fibrosarcoma growth in mice (p<0.01 and p<0.05 for human and rat EVs, respectively) vs PBS group. The effect was associated with 2-fold decrease of tumor cells proliferation (p<0.001) and 1.5-fold increase of apoptosis (p<0.05) in CDC-EV vs PBS mice. Salutary changes in tumor gene and protein expression were observed in CDC-EV animals. CDC-EVs reduced tumor vascularization compared with PBS (p<0.05) and MSC-EVs (p<0.01). Moreover, CDC-EVs increased leukemia-free survival (p<0.05) in old rats vs PBS. MiR-146, highly enriched in CDC-EVs, may be implicated in part of the observed effects. In conclusion, this study presents the first evidence that ties together the long-recognized enigma of the "heart immunity to cancer" with an antioncogenic effect of heart-derived EVs. These findings open up cancer as a new therapeutic target for CDC-EVs.
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Affiliation(s)
| | - Soraya Fereydooni
- Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America
- Department of Biology, Stanford University, Stanford, CA, United States of America
| | - Weixin Liu
- Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America
| | - Antonio Echavez
- Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America
| | - Eduardo Marbán
- Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America
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31
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McFall T, McKnight B, Rosati R, Kim S, Huang Y, Viola-Villegas N, Ratnam M. Progesterone receptor A promotes invasiveness and metastasis of luminal breast cancer by suppressing regulation of critical microRNAs by estrogen. J Biol Chem 2017; 293:1163-1177. [PMID: 29162724 DOI: 10.1074/jbc.m117.812438] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 10/24/2017] [Indexed: 11/06/2022] Open
Abstract
Distal metastasis of luminal breast cancer is frequent and incurable, yet the metastasis mechanisms are poorly understood. Estrogen, even at postmenopausal concentrations, suppresses invasiveness of luminal breast cancer cells through the estrogen receptor (ER). Invasive tumors overexpress the short progesterone receptor A (PR-A) isoform. Even at postmenopausal concentrations, progesterone activates PR-A, inducing invasiveness by counteracting estrogen's effects, particularly when cells are hypersensitized to progesterone by PR-A overexpression. To interrogate the role of this cross-talk in metastasis, we investigated selective cross-talk mechanisms of PR-A with ER. We developed a quantitative PCR-based lymph node infiltration assay to address the slowness of metastasis of tumor xenografts. We found that 15 microRNAs (miRNAs) are regulated by progesterone via PR-A, but not the longer PR-B isoform, with increased progesterone sensitivity when PR-A was overexpressed. Two of these miRNAs whose induction (miR-92a-3p) or repression (miR-26b-5p) by estrogen was suppressed by progesterone plus PR-A were critical for the PR-A-ER cross-talk causing a gene-regulatory pattern of invasiveness and metastasis and complete rescue of invasiveness in vitro Constitutive expression of miR-92a-3p or inhibition of miR-26b-5p profoundly suppressed metastasis. Finally, in primary breast tumors, PR-A expression was correlated negatively with miR-92a-3p expression and positively with miR-26b-5p expression. Therefore, hormonal cross-talk of PR-A with ER is probably a fundamental mechanism that enables metastasis of luminal breast cancer. Moreover, miRNA biomarkers of hyperactive PR-A may help predict metastatic potential of luminal breast tumors. Further, miR-92a-3p and miR-26b-5p may reveal target pathways for selective intervention to suppress hormone-regulated metastasis, both pre- and postmenopause.
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Affiliation(s)
- Thomas McFall
- From the Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, Michigan 48201-2013
| | - Brooke McKnight
- From the Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, Michigan 48201-2013
| | - Rayna Rosati
- From the Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, Michigan 48201-2013
| | - Seongho Kim
- From the Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, Michigan 48201-2013
| | - Yanfang Huang
- From the Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, Michigan 48201-2013
| | - Nerissa Viola-Villegas
- From the Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, Michigan 48201-2013
| | - Manohar Ratnam
- From the Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, Michigan 48201-2013
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32
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Seclaman E, Narita D, Anghel A, Cireap N, Ilina R, Sirbu IO, Marian C. MicroRNA Expression in Laser Micro-dissected Breast Cancer Tissue Samples - a Pilot Study. Pathol Oncol Res 2017; 25:233-239. [PMID: 29081035 DOI: 10.1007/s12253-017-0343-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 10/20/2017] [Indexed: 12/12/2022]
Abstract
Breast cancer continues to represent a significant public health burden despite outstanding research advances regarding the molecular mechanisms of cancer biology, biomarkers for diagnostics and prognostic and therapeutic management of this disease. The studies of micro RNAs in breast cancer have underlined their potential as biomarkers and therapeutic targets; however most of these studies are still done on largely heterogeneous whole breast tissue samples. In this pilot study we have investigated the expression of four micro RNAs (miR-21, 145, 155, 92) known to be involved in breast cancer, in homogenous cell populations collected by laser capture microdissection from breast tissue section slides. Micro RNA expression was assessed by real time PCR, and associations with clinical and pathological characteristics were also explored. Our results have confirmed previous associations of miR-21 expression with poor prognosis characteristics of breast cancers such as high stage, large and highly proliferative tumors. No statistically significant associations were found with the other micro RNAs investigated, possibly due to the small sample size of our study. Our results also suggest that miR-484 could be a suitable endogenous control for data normalization in breast tissues, these results needing further confirmation by future studies. In summary, our pilot study showed the feasibility of detecting micro RNAs expression in homogenous laser captured microdissected invasive breast cancer samples, and confirmed some of the previously reported associations with poor prognostic characteristics of breast tumors.
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Affiliation(s)
- Edward Seclaman
- Department of Biochemistry and Pharmacology, "Victor Babeş" University of Medicine and Pharmacy, Pta Eftimie Murgu Nr. 2, 300041, Timişoara, Romania
| | - Diana Narita
- Department of Biochemistry and Pharmacology, "Victor Babeş" University of Medicine and Pharmacy, Pta Eftimie Murgu Nr. 2, 300041, Timişoara, Romania.,Donauisar Klinikum, Institute for Laboratory Diagnostic and Transfusion Medicine, Deggendorf, Germany
| | - Andrei Anghel
- Department of Biochemistry and Pharmacology, "Victor Babeş" University of Medicine and Pharmacy, Pta Eftimie Murgu Nr. 2, 300041, Timişoara, Romania
| | - Natalia Cireap
- Department of Surgical Oncology, University of Medicine and Pharmacy "Victor Babes", and Municipal Hospital, Timisoara, Romania
| | - Razvan Ilina
- Department of Surgical Oncology, University of Medicine and Pharmacy "Victor Babes", and Municipal Hospital, Timisoara, Romania
| | - Ioan Ovidiu Sirbu
- Department of Biochemistry and Pharmacology, "Victor Babeş" University of Medicine and Pharmacy, Pta Eftimie Murgu Nr. 2, 300041, Timişoara, Romania
| | - Catalin Marian
- Department of Biochemistry and Pharmacology, "Victor Babeş" University of Medicine and Pharmacy, Pta Eftimie Murgu Nr. 2, 300041, Timişoara, Romania.
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33
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Graham ÉA, Mallet JF, Jambi M, Nishioka H, Homma K, Matar C. MicroRNA signature in the chemoprevention of functionally-enriched stem and progenitor pools (FESPP) by Active Hexose Correlated Compound (AHCC). Cancer Biol Ther 2017; 18:765-774. [PMID: 28886271 PMCID: PMC5678688 DOI: 10.1080/15384047.2017.1373211] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 07/25/2017] [Accepted: 08/24/2017] [Indexed: 12/31/2022] Open
Abstract
PURPOSE Many breast cancer patients use natural compounds in their battle against breast cancer. Active Hexose Correlated Compound (AHCC®) is a cultured mushroom mycelium extract shown to favorably modulate the immune system and alleviate cancer burden. Cancer Stem cells (CSCs) are a subset of highly tumorigenic cancer cells that are thought to be responsible for recurrence. CSCs can be epigenetically regulated by microRNAs (miRNAs). We hypothesized that AHCC may influence CSCs by modulating tumor-suppressor or oncogenic miRNAs. METHODS Functionally-enriched stem and progenitor pools (FESPP) were isolated in the form of mammospheres from MDA-MB-231, MCF-7, and 4T1 cells, exposed to AHCC in both regular and primary culture from Balb/c mice, and analyzed by visual counting and flow cytometry. Cell motility was also observed in MDA-MB-231 cells. Profiling and RT-qPCR were performed to determine AHCC influence on miRNAs in MDA-MB-231 mammospheres. Additionally, Balb/c mice were orally gavaged with AHCC, and tumor growth parameters and miR-335 expression were analyzed. MDA-MB-231 cells were transfected with miR-335 and analyzed by western blot. RESULTS We demonstrated that AHCC reduced mammosphere growth in three cell lines and in primary culture, prevented cell migration, and upregulated miR-335 expression in MDA-MB-231 cells and mouse tumor samples. Among the differentially regulated miRNAs in CSCs, we focused on tumor suppressor miR-335, known to target extracellular matrix protein Tenascin C (TNC). TNC is involved in CSC immune evasion pathways. In MDA-MB-231, inhibition of miR-335 increased TNC protein expression. CONCLUSIONS These results support that AHCC limits FESPP growth, partly by targeting miRNA pathways.
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Affiliation(s)
- Émilie A. Graham
- Interdisciplinary Health Sciences, University of Ottawa, Ottawa, Canada
| | - Jean-François Mallet
- Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Majed Jambi
- Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | | | - Kohei Homma
- R&D Division Amino Up Chemical Co, Ltd, Sapporo, Japan
| | - Chantal Matar
- Interdisciplinary Health Sciences, University of Ottawa, Ottawa, Canada
- Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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34
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Drak Alsibai K, Meseure D. Tumor microenvironment and noncoding RNAs as co-drivers of epithelial-mesenchymal transition and cancer metastasis. Dev Dyn 2017; 247:405-431. [PMID: 28691356 DOI: 10.1002/dvdy.24548] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 05/31/2017] [Accepted: 06/29/2017] [Indexed: 12/13/2022] Open
Abstract
Reciprocal interactions between cancer cells and tumor microenvironment (TME) are crucial events in tumor progression and metastasis. Pervasive stromal reprogramming of TME modifies numerous cellular functions, including extracellular matrix (ECM) stiffness, inflammation, and immunity. These environmental factors allow selection of more aggressive cells that develop adaptive strategies associating plasticity and epithelial-mesenchymal transition (EMT), stem-like phenotype, invasion, immunosuppression, and resistance to therapies. EMT is a morphomolecular process that endows epithelial tumor cells with mesenchymal properties, including reduced adhesion and increased motility. Numerous studies have demonstrated involvement of noncoding RNAs (ncRNAs), such as miRNAs and lncRNAs, in tumor initiation, progression, and metastasis. NcRNAs regulate every hallmark of cancer and have now emerged as new players in induction and regulation of EMT. The reciprocal regulatory interactions between ncRNAs, TME components, and cancer cells increase the complexity of gene expression and protein translation in cancer. Thus, deeper understanding of molecular mechanisms controlling EMT will not only shed light on metastatic processes of cancer cells, but enhance development of new therapies targeting metastasis. In this review, we will provide recent findings on the role of known ncRNAs relevant to EMT and cancer metastasis and discuss the role of the interaction between ncRNAs and TME as co-drivers of EMT. Developmental Dynamics 247:405-431, 2018. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
| | - Didier Meseure
- Platform of Investigative Pathology, Curie Institute, Paris, France.,Department of Pathology, Curie Institute, Paris, France
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35
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Zhang K, Zhang L, Zhang M, Zhang Y, Fan D, Jiang J, Ye L, Fang X, Chen X, Fan S, Chao M, Liang C. Prognostic value of high-expression of miR-17-92 cluster in various tumors: evidence from a meta-analysis. Sci Rep 2017; 7:8375. [PMID: 28827775 PMCID: PMC5567103 DOI: 10.1038/s41598-017-08349-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 07/10/2017] [Indexed: 12/18/2022] Open
Abstract
The prognostic value of miR-17-92 cluster high-expression in various tumors remains controversial. Therefore, we conducted this meta-analysis by searching literatures in PubMed, Embase, Cochrane Library, China Biology Medicine disc, China National Knowledge Infrastructure to identify eligible studies. Eventually, we analyzed 36 articles that examined 17 tumor types from 4965 patients. Consequently, high-expression of miR-17-92 cluster in various tumors was associated with unfavorable overall survival in both univariate (HR = 2.05, 95%CI: 1.58-2.65, P<0.001) and multivariate (HR = 2.14, 95%CI: 1.75-2.61, P<0.001) analyses. Likewise, similar results were found in different subgroups of country, test method, miR-17-92 cluster component, sample source and size. Additionally, high-expression of miR-17-92 cluster was linked with poor disease-free survival (Univariate: HR = 1.96, 95%CI: 1.55-2.48, P<0.001; Multivariate: HR = 2.18, 95%CI: 1.63-2.91, P<0.001), favorable progression-free survival (Univariate: HR = 0.36, 95%CI: 0.16-0.80, P = 0.012; Multivariate: HR = 1.55, 95%CI: 0.79-3.05, P = 0.201) and poor cancer specific survival in univariate rather than multivariate analyses (Univariate: HR = 1.77, 95%CI: 1.21-2.60, P = 0.004; Multivariate: HR = 1.77, 95%CI: 0.80-3.92, P = 0.160). However, no association of miR-17-92 cluster high-expression was detected with recurrence or relapse-free survival. In summary, this meta-analysis towards high-expression of miR-17-92 cluster has indicated poor prognosis of various cancers. Notably, future studies comprising large cohort size from multicenter are required to confirm our conclusions.
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Affiliation(s)
- Kaiping Zhang
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Li Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University (AHMU) and Institute of Urology, AHMU, Hefei, China
| | - Meng Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University (AHMU) and Institute of Urology, AHMU, Hefei, China
| | - Yin Zhang
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Dengxin Fan
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Jiabin Jiang
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Liqin Ye
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Xiang Fang
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China
| | - Xianguo Chen
- Department of Urology, The First Affiliated Hospital of Anhui Medical University (AHMU) and Institute of Urology, AHMU, Hefei, China
| | - Song Fan
- Department of Urology, The First Affiliated Hospital of Anhui Medical University (AHMU) and Institute of Urology, AHMU, Hefei, China
| | - Min Chao
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, China.
| | - Chaozhao Liang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University (AHMU) and Institute of Urology, AHMU, Hefei, China.
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36
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Gu Y, Si J, Xiao X, Tian Y, Yang S. miR-92a Inhibits Proliferation and Induces Apoptosis by Regulating Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) Expression in Acute Myeloid Leukemia. Oncol Res 2017; 25:1069-1079. [PMID: 28059050 PMCID: PMC7841081 DOI: 10.3727/096504016x14829256525028] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Aberrant expression of microRNA-92a (miR-92a) has been investigated in various cancers. However, the function and mechanism of miR-92a in acute myeloid leukemia (AML) remain to be elucidated. Our data showed that miR-92a was evidently downregulated and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) was remarkably upregulated in AML cell lines HL-60 and THP-1. Dual luciferase reporter assay revealed that MTHFD2 was a direct target of miR-92a. Gain- and loss-of-function analysis demonstrated that MTHFD2 knockdown or miR-92a overexpression notably inhibited proliferation and promoted apoptosis of AML cell lines. Restoration of MTHFD2 expression reversed proliferation inhibition and apoptosis induction of AML cells triggered by miR-92a. Moreover, an implanted tumor model in mice indicated that miR-92a overexpression dramatically decreased tumor growth and MTHFD2 expression in vivo. Taken together, our results suggest that miR-92a inhibits proliferation and induces apoptosis by directly regulating MTHFD2 expression in AML. miR-92a may act as a tumor suppressor in AML, providing a promising therapeutic target for AML patients.
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Affiliation(s)
- Yueli Gu
- *Department of Hematology, Shangqiu First People’s Hospital, Shangqiu, P.R. China
| | - Jinchun Si
- †Department of Surgery Teaching and Research Section, Shangqiu Medical College, Shangqiu, P.R. China
| | - Xichun Xiao
- *Department of Hematology, Shangqiu First People’s Hospital, Shangqiu, P.R. China
| | - Ying Tian
- *Department of Hematology, Shangqiu First People’s Hospital, Shangqiu, P.R. China
| | - Shuo Yang
- *Department of Hematology, Shangqiu First People’s Hospital, Shangqiu, P.R. China
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Prognostic role of miR-17-92 family in human cancers: evaluation of multiple prognostic outcomes. Oncotarget 2017; 8:69125-69138. [PMID: 28978185 PMCID: PMC5620325 DOI: 10.18632/oncotarget.19096] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 06/20/2017] [Indexed: 12/31/2022] Open
Abstract
Recent evidence indicates that miR-17–92 family might be an essential prognostic biomarker for human cancers. However, results are still inconsistent. We therefore performed a meta-analysis to evaluate the predictive role of miR-17–92 family in human cancer prognosis. We searched literatures published before March 31th, 2017 inPubMed, Cochrane and Embase databases. Twenty six studies were included in our analyses. The overall hazard ratios (HRs) showed that high expression level of miR-17-92 family was a predictor of poor overall survival (OS): adjusted HRs = 1.71, 95% confidence intervals (CIs): 1.39–2.11, p < 0.00001, and poor disease-free survival (DFS): adjusted HRs = 2.29, 95% CIs: 1.41–3.72, p = 0.0008. However, no association between miR-17-92 family expression and cancer progress-free survival (PFS) was found (p > 0.05). Subgroup analyses showed that high expression of miR-17-92 family was associated with poor OS (adjusted HRs = 1.89, 95% CIs: 1.43–2.49, p < 0.00001) and DFS (adjusted HRs = 2.83, 95% CIs: 1.59–5.04, p = 0.0003) among the Asian, and no association was found for the Caucasian (p > 0.05). Besides, the HRs of miR-17-92 family high expression in tissue and serum samples was 1.68 (1.35–2.09) and 2.20 (1.08–4.46) for OS, and 1.73 (0.80–3.74) and 3.37 (2.25–5.02) for DFS. It also found that high expression of miR-17-92 family predicted a poor OS in breast cancer, esophageal squamous cell carcinoma, lymphoma and other cancers. Findings suggest that miR-17-92 family can be an effective predictor for prognosis prediction in cancer patients.
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38
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Lai YC, Fujikawa T, Ando T, Kitahara G, Koiwa M, Kubota C, Miura N. Rapid Communication: MiR-92a as a housekeeping gene for analysis of bovine mastitis-related microRNA in milk1. J Anim Sci 2017; 95:2732-2735. [DOI: 10.2527/jas.2017.1384] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
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39
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Differential Maturation of miR-17 ~ 92 Cluster Members in Human Cancer Cell Lines. Appl Biochem Biotechnol 2017; 182:1540-1547. [DOI: 10.1007/s12010-017-2416-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 01/16/2017] [Indexed: 12/13/2022]
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40
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Mungle T, Tewary S, Arun I, Basak B, Agarwal S, Ahmed R, Chatterjee S, Maity AK, Chakraborty C. Automated characterization and counting of Ki-67 protein for breast cancer prognosis: A quantitative immunohistochemistry approach. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2017; 139:149-161. [PMID: 28187885 DOI: 10.1016/j.cmpb.2016.11.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 10/21/2016] [Accepted: 11/03/2016] [Indexed: 06/06/2023]
Abstract
Ki-67 protein expression plays an important role in predicting the proliferative status of tumour cells and deciding the future course of therapy in breast cancer. Immunohistochemical (IHC) determination of Ki-67 score or labelling index, by estimating the fraction of Ki67 positively stained tumour cells, is the most widely practiced method to assess tumour proliferation (Dowsett et al. 2011). Accurate manual counting of these cells (specifically nuclei) due to complex and dense distribution of cells, therefore, becomes critical and presents a major challenge to pathologists. In this paper, we suggest a hybrid clustering algorithm to quantify the proliferative index of breast cancer cells based on automated counting of Ki-67 nuclei. The proposed methodology initially pre-processes the IHC images of Ki-67 stained slides of breast cancer. The RGB images are converted to grey, L*a*b*, HSI, YCbCr, YIQ and XYZ colour space. All the stained cells are then characterized by two stage segmentation process. Fuzzy C-means quantifies all the stained cells as one cluster. The blue channel of the first stage output is given as input to k-means algorithm, which provides separate cluster for Ki-67 positive and negative cells. The count of positive and negative nuclei is used to calculate the F-measure for each colour space. A comparative study of our work with the expert opinion is studied to evaluate the error rate. The positive and negative nuclei detection results for all colour spaces are compared with the ground truth for validation and F-measure is calculated. The F-measure for L*a*b* colour space (0.8847) provides the best statistical result as compared to grey, HSI, YCbCr, YIQ and XYZ colour space. Further, a study is carried out to count nuclei manually and automatically from the proposed algorithm with an average error rate of 6.84% which is significant. The study provides an automated count of positive and negative nuclei using L*a*b*colour space and hybrid segmentation technique. Computerized evaluation of proliferation index can aid pathologist in assessing breast cancer severity. The proposed methodology, further, has the potential advantage of saving time and assisting in decision making over the present manual procedure and could evolve as an assistive pathological decision support system.
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Affiliation(s)
- Tushar Mungle
- School of Medical Science & Technology, IIT Kharagpur, Kharagpur, West Bengal, India
| | - Suman Tewary
- School of Medical Science & Technology, IIT Kharagpur, Kharagpur, West Bengal, India
| | - Indu Arun
- Tata Medical Center, New Town, Rajarhat, Kolkata, West Bengal, India
| | - Bijan Basak
- Tata Medical Center, New Town, Rajarhat, Kolkata, West Bengal, India
| | - Sanjit Agarwal
- Tata Medical Center, New Town, Rajarhat, Kolkata, West Bengal, India
| | - Rosina Ahmed
- Tata Medical Center, New Town, Rajarhat, Kolkata, West Bengal, India
| | - Sanjoy Chatterjee
- Tata Medical Center, New Town, Rajarhat, Kolkata, West Bengal, India
| | - Asok Kumar Maity
- Midnapur Medical College and Hospital, Midnapur, West Bengal, India
| | - Chandan Chakraborty
- School of Medical Science & Technology, IIT Kharagpur, Kharagpur, West Bengal, India.
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41
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Wang H, Ke C, Ma X, Zhao Q, Yang M, Zhang W, Wang J. MicroRNA-92 promotes invasion and chemoresistance by targeting GSK3β and activating Wnt signaling in bladder cancer cells. Tumour Biol 2016; 37:16295–16304. [PMID: 27830467 DOI: 10.1007/s13277-016-5460-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 09/23/2016] [Indexed: 12/27/2022] Open
Abstract
miR-92 has been reported to be upregulated in several human cancers. Until now, its expression pattern and biological roles in human bladder cancer still remains unexplored. The present study aims to clarify its expression, function, and potential molecular mechanisms in bladder cancer. Using real-time PCR, we found that miR-92 was upregulated in bladder cancer tissues compared with normal bladder tissues. We transfected miR-92 mimic and inhibitor in T24 and 5637 bladder cancer cells separately. We found that miR-92 mimic promoted T24 proliferation and invasion, with increased expression of cyclin D1, c-myc, and MMP7 at both mRNA and protein levels. Further investigation found that miR-92 could also promote epithelial-mesenchymal transition by downregulating E-cadherin protein and upregulating vimentin. In addition, miR-92 mimic also promoted activation of Wnt signaling. Meanwhile, miR-92 inhibitor displayed the opposite effects in 5637 cell line. By use of bioinformatic prediction software and luciferase reporter assay, we discovered that GSK3β acted as a direct target of miR-92. Additionally, GSK3β siRNA abrogated the effects of miR-92 mimic on cyclin D1 and MMP7. Moreover, we observed a negative correlation between GSK3β and miR-92 in bladder cancer tissues. In conclusion, our study demonstrated that upregulation of miR-92 is closely related with malignant progression of bladder cancer and miR-92 promotes proliferation, invasion, and Wnt/c-myc/MMP7 signaling by targeting GSK3β.
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Affiliation(s)
- Haifeng Wang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China
| | - Changxing Ke
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China
| | - Xingyong Ma
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China
| | - Qinghua Zhao
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China
| | - Mingying Yang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China
| | - Wei Zhang
- Department of Urology, Affiliated Hospital of Hebei University, Baoding, 071000, China.
| | - Jiansong Wang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, China.
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42
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Zhang H, Cao H, Xu D, Zhu K. MicroRNA-92a promotes metastasis of nasopharyngeal carcinoma by targeting the PTEN/AKT pathway. Onco Targets Ther 2016; 9:3579-88. [PMID: 27366095 PMCID: PMC4913974 DOI: 10.2147/ott.s105470] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
MicroRNAs have been confirmed to be a group of important regulators during the pathogenesis of nasopharyngeal carcinoma (NPC). This study confirmed that the expression of microRNA-92a (miR-92a) was significantly upregulated in NPC as compared to noncancerous nasopharyngeal epithelial tissues. Furthermore, high expression of miR-92a was observed in all NPC cell lines, especially in high metastatic cell lines. Clinical analysis indicated that high expression of miR-92a was associated with adverse clinicopathological features including the advanced tumor-node-metastasis stage and distant metastasis, and conferred poor prognosis of patients. In vitro assays showed that miR-92a overexpression potentiated the migration and invasion of 6-10B cells, and miR-92a silencing reduced the number of migrated and invaded 5-8F cells. Phosphatase and tensin homolog (PTEN) was confirmed as a direct downstream target of miR-92a in NPC cells. Otherwise, alteration of miR-92a expression regulated PTEN/AKT pathway in NPC cells. Mechanistically, miR-92a exerted its promoting effects on the metastatic behaviors of NPC cells through suppressing PTEN/AKT pathway. Taken together, this study demonstrates that miR-92a is a promising prognostic biomarker for patients with NPC, and may be a potential therapeutic target to prevent the metastasis of NPC.
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Affiliation(s)
- Haixiong Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, the First Affiliated Hospital of Xi'an Medical College, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Hui Cao
- Department of Otorhinolaryngology, Head and Neck Surgery, the First Affiliated Hospital of Xi'an Medical College, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Dadao Xu
- Department of Otorhinolaryngology, Head and Neck Surgery, the First Affiliated Hospital of Xi'an Medical College, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Kang Zhu
- Department of Otorhinolaryngology, Head and Neck Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
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43
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Frediani JN, Fabbri M. Essential role of miRNAs in orchestrating the biology of the tumor microenvironment. Mol Cancer 2016; 15:42. [PMID: 27231010 PMCID: PMC4882787 DOI: 10.1186/s12943-016-0525-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 05/12/2016] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs) are emerging as central players in shaping the biology of the Tumor Microenvironment (TME). They do so both by modulating their expression levels within the different cells of the TME and by being shuttled among different cell populations within exosomes and other extracellular vesicles. This review focuses on the state-of-the-art knowledge of the role of miRNAs in the complexity of the TME and highlights limitations and challenges in the field. A better understanding of the mechanisms of action of these fascinating micro molecules will lead to the development of new therapeutic weapons and most importantly, to an improvement in the clinical outcome of cancer patients.
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Affiliation(s)
- Jamie N Frediani
- Children's Center for Cancer and Blood Diseases and The Saban Research Institute, Children's Hospital, Los Angeles, Los Angeles, CA, USA
| | - Muller Fabbri
- Children's Center for Cancer and Blood Diseases and The Saban Research Institute, Children's Hospital, Los Angeles, Los Angeles, CA, USA. .,Departments of Pediatrics and Molecular Microbiology & Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. .,, 4650 Sunset Blvd MS #57, Los Angeles, CA, 90027, USA.
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44
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Ren C, Wang W, Han C, Chen H, Fu D, Luo Y, Yao H, Wang D, Ma L, Zhou L, Han D, Shen M. Expression and prognostic value of miR-92a in patients with gastric cancer. Tumour Biol 2016; 37:9483-91. [PMID: 26790436 DOI: 10.1007/s13277-016-4865-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 01/13/2016] [Indexed: 12/12/2022] Open
Abstract
MicroRNA (miR)-92 expression is often aberrant in human cancers. However, its expression in gastric carcinoma and its relation to clinicopathological features and prognosis are unclear.Tissue microarrays were constructed from 180 patients with gastric cancer (GC), who were undergoing radical resection. MiR-92a expression was detected using miRNA-locked nucleic acid in situ hybridization, and its correlation with clinicopathological features and overall survival was analyzed. MiR-92a expression was decreased in 13.9 % (25/180) of GC, increased in 81.1 % (146/180), and unchanged in 5.0 % (9/180), compared with paracancerous normal tissue (P < 0.001). Univariate analysis showed that high miR-92a expression, tumor stage, tumor status, node status, and tumor size were significant negative prognostic predictors for overall survival in patients with GC (P < 0.001, P < 0.001, P = 0.008, P < 0.001, and P = 0.001, respectively). High miR-92a expression still remained a significant predictor of shorter survival in stage II (n = 56, P = 0.001) and stage III (n = 92, P = 0.009) GC. Multivariate regression analysis demonstrated that tumor status (hazard ratio [HR], 3.10; 95 % confidence interval [CI], 1.51-6.37; P = 0.002), stage (HR, 3.54; 95 % CI, 1.65-7.63; P = 0.000), lymph node metastasis (HR, 2.83; 95 % CI, 1.88-4.28; P = 0.000), high expression of miR-92a (HR, 2.94; 95 % CI, 2.01-4.31; P = 0.000), and tumor size (HR, 2.34; 95 % CI, 1.45-3.79; P = 0.002) predicted shorter OS.High expression of miR-92a compared with adjacent normal tissues was associated with shorter OS. MiR-92a may thus be useful for evaluating prognosis and may provide a novel treatment target in patients with GC.
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Affiliation(s)
- Chuanli Ren
- Clinical Medical Testing Laboratory, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, No. 98 Western Nantong Road, Yangzhou, 225001, China. .,Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
| | - Wenshu Wang
- Department of Physical Chemistry, Yangzhou University, Yangzhou, China
| | - Chongxu Han
- Clinical Medical Testing Laboratory, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, No. 98 Western Nantong Road, Yangzhou, 225001, China
| | - Hui Chen
- Geriatric Medicine, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Deyuan Fu
- Breast Oncology Surgery, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Yulin Luo
- Breast Oncology Surgery, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Hanyu Yao
- Breast Oncology Surgery, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Daxin Wang
- Clinical Medical Testing Laboratory, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, No. 98 Western Nantong Road, Yangzhou, 225001, China
| | - Li Ma
- Lab of Hematology, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Lin Zhou
- Clinical Medical Testing Laboratory, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, No. 98 Western Nantong Road, Yangzhou, 225001, China
| | - Dongsheng Han
- Clinical Medical Testing Laboratory, Northern Jiangsu People's Hospital and Clinical Medical College of Yangzhou University, No. 98 Western Nantong Road, Yangzhou, 225001, China
| | - Ming Shen
- Department of Physical Chemistry, Yangzhou University, Yangzhou, China
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45
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Egeland NG, Lunde S, Jonsdottir K, Lende TH, Cronin-Fenton D, Gilje B, Janssen EAM, Søiland H. The Role of MicroRNAs as Predictors of Response to Tamoxifen Treatment in Breast Cancer Patients. Int J Mol Sci 2015; 16:24243-75. [PMID: 26473850 PMCID: PMC4632748 DOI: 10.3390/ijms161024243] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 09/28/2015] [Accepted: 09/30/2015] [Indexed: 12/13/2022] Open
Abstract
Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. However, resistance to endocrine therapy leads to breast cancer relapse. The recent extension of adjuvant tamoxifen treatment up to 10 years actualizes the need for identifying biological markers that may be used to monitor predictors of treatment response. MicroRNAs are promising biomarkers that may fill the gap between preclinical knowledge and clinical observations regarding endocrine resistance. MicroRNAs regulate gene expression by posttranscriptional repression or degradation of mRNA, most often leading to gene silencing. MicroRNAs have been identified directly in the primary tumor, but also in the circulation of breast cancer patients. The few available studies investigating microRNA in patients suggest that seven microRNAs (miR-10a, miR-26, miR-30c, miR-126a, miR-210, miR-342 and miR-519a) play a role in tamoxifen resistance. Ingenuity Pathway Analysis (IPA) reveals that these seven microRNAs interact more readily with estrogen receptor (ER)-independent pathways than ER-related signaling pathways. Some of these pathways are targetable (e.g., PIK3CA), suggesting that microRNAs as biomarkers of endocrine resistance may have clinical value. Validation of the role of these candidate microRNAs in large prospective studies is warranted.
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Affiliation(s)
- Nina G Egeland
- Department of Pathology, Stavanger University Hospital, Gerd Ragna Bloch Thorsens Gate 8, 4011 Stavanger, Norway.
- Department of Mathematics and Natural Sciences, University of Stavanger, 4036 Stavanger, Norway.
| | - Siri Lunde
- Department of Breast and Endocrine Surgery, Stavanger University Hospital, 4011 Stavanger, Norway.
| | - Kristin Jonsdottir
- Department of Pathology, Stavanger University Hospital, Gerd Ragna Bloch Thorsens Gate 8, 4011 Stavanger, Norway.
| | - Tone H Lende
- Department of Breast and Endocrine Surgery, Stavanger University Hospital, 4011 Stavanger, Norway.
- Department of Clinical Science, University of Bergen, Postboks 7804, 5020 Bergen, Norway.
| | - Deirdre Cronin-Fenton
- Department of Clinical Epidemiology, Aarhus University, Science Center Skejby, Olof Palmes Allé 43, Aarhus N, 8200 Aarhus, Denmark.
| | - Bjørnar Gilje
- Department of Haematology and Oncology, Stavanger University Hospital, Gerd Ragna Bloch Thorsens Gate 8, 4011 Stavanger, Norway.
| | - Emiel A M Janssen
- Department of Pathology, Stavanger University Hospital, Gerd Ragna Bloch Thorsens Gate 8, 4011 Stavanger, Norway.
- Department of Mathematics and Natural Sciences, University of Stavanger, 4036 Stavanger, Norway.
| | - Håvard Søiland
- Department of Breast and Endocrine Surgery, Stavanger University Hospital, 4011 Stavanger, Norway.
- Department of Clinical Science, University of Bergen, Postboks 7804, 5020 Bergen, Norway.
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Smith L, Baxter EW, Chambers PA, Green CA, Hanby AM, Hughes TA, Nash CE, Millican-Slater RA, Stead LF, Verghese ET, Speirs V. Down-Regulation of miR-92 in Breast Epithelial Cells and in Normal but Not Tumour Fibroblasts Contributes to Breast Carcinogenesis. PLoS One 2015; 10:e0139698. [PMID: 26437339 PMCID: PMC4593575 DOI: 10.1371/journal.pone.0139698] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 09/16/2015] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND MicroRNA (miR) expression is commonly dysregulated in many cancers, including breast. MiR-92 is one of six miRs encoded by the miR-17-92 cluster, one of the best-characterised oncogenic miR clusters. We examined expression of miR-92 in the breast epithelium and stroma during breast cancer progression. We also investigated the role of miR-92 in fibroblasts in vitro and showed that down-regulation in normal fibroblasts enhances the invasion of breast cancer epithelial cells. METHODOLOGY/PRINCIPAL FINDINGS We used laser microdissection (LMD) to isolate epithelial cells from matched normal, DCIS and invasive tissue from 9 breast cancer patients and analysed miR-92 expression by qRT-PCR. Expression of ERβ1, a direct miR-92 target, was concurrently analysed for each case by immunohistochemistry. LMD was also used to isolate matched normal (NFs) and cancer-associated fibroblasts (CAFs) from 14 further cases. Effects of miR-92 inhibition in fibroblasts on epithelial cell invasion in vitro was examined using a Matrigel™ assay. miR-92 levels decreased in microdissected epithelial cells during breast cancer progression with highest levels in normal breast epithelium, decreasing in DCIS (p<0.01) and being lowest in invasive breast tissue (p<0.01). This was accompanied by a shift in cell localisation of ERβ1 from nuclear expression in normal breast epithelium to increased cytoplasmic expression during progression to DCIS (p = 0.0078) and invasive breast cancer (p = 0.031). ERβ1 immunoreactivity was also seen in stromal fibroblasts in tissues. Where miR-92 expression was low in microdissected NFs this increased in matched CAFs; a trend also seen in cultured primary fibroblasts. Down-regulation of miR-92 levels in NFs but not CAFs enhanced invasion of both MCF-7 and MDA-MB-231 breast cancer epithelial cells. CONCLUSIONS miR-92 is gradually lost in breast epithelial cells during cancer progression correlating with a shift in ERβ1 immunoreactivity from nuclei to the cytoplasm. Our data support a functional role in fibroblasts where modification of miR-92 expression can influence the invasive capacity of breast cancer epithelial cells. However in silico analysis suggests that ERβ1 may not be the most important miR-92 target in breast cancer.
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Affiliation(s)
- Laura Smith
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Euan W. Baxter
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Philip A. Chambers
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Caroline A. Green
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Andrew M. Hanby
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Thomas A. Hughes
- Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, United Kingdom
| | - Claire E. Nash
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | | | - Lucy F. Stead
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Eldo T. Verghese
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Valerie Speirs
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
- * E-mail:
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MicroRNA-92a promotes growth, metastasis, and chemoresistance in non-small cell lung cancer cells by targeting PTEN. Tumour Biol 2015; 37:3215-25. [PMID: 26432332 DOI: 10.1007/s13277-015-4150-3] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 09/23/2015] [Indexed: 01/01/2023] Open
Abstract
MicroRNA-92a (miR-92a) has been reported to play important roles in tumorigenesis of human various cancers. However, the roles and underlying molecular mechanism of miR-92a in non-small cell lung cancer (NSCLC) have not been totally elucidated. Therefore, the aims of this study were to determine the role of miR-92a and to elucidate its regulatory mechanism in NSCLC. We found that miR-92a was significantly upregulated in NSCLC tissues compared to matched adjacent normal lung tissues, and its expression is significantly associated with clinical characteristics of patients, including tumor, node, and metastasis (TNM) stage; tumor size; and lymph node metastasis (all P < 0.01). Function assays demonstrated that upregulation of miR-92a in NSCLC cells promoted cell proliferation, migration, and invasion, decreased apoptosis and caspase-3 activity, and enhanced chemoresistance of NSCLC cells, whereas downregulation of miR-92a showed the opposite effects. Moreover, phosphatase and tensin homolog (PTEN), a unique tumor suppressor gene, was confirmed as a direct target of miR-92a, and PTEN messenger RNA (mRNA) expression was decreased in NSCLC tissues and was inversely correlated with miR-92a. Downregulation of PTEN could mimic the same effects of miR-92a mimic in NSCLC cells and rescue the effects on NSCLC cells induced by miR-92a inhibitor. Taken together, these findings suggested that miR-92a could promote growth, metastasis, and chemoresistance in NSCLC cells at least partially by targeting PTEN.
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48
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Dang TM, Wong WC, Ong SM, Li P, Lum J, Chen J, Poidinger M, Zolezzi F, Wong SC. MicroRNA expression profiling of human blood monocyte subsets highlights functional differences. Immunology 2015; 145:404-16. [PMID: 25707426 DOI: 10.1111/imm.12456] [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: 06/19/2014] [Revised: 02/12/2015] [Accepted: 02/17/2015] [Indexed: 12/14/2022] Open
Abstract
Within human blood there are two subsets of monocytes that can be identified by differential expression of CD16. Although numerous phenotypic and functional differences between the subsets have been described, little is known of the mechanisms underlying the distinctive properties of the two subsets. MicroRNAs (miRNAs) are small non-coding RNAs that can regulate gene expression through promoting mRNA degradation or repressing translation, leading to alterations in cellular processes. Their potential influence on the functions of monocyte subsets has not been investigated. In this study, we employed microarray analysis to define the miRNA expression profile of human monocyte subsets. We identified 66 miRNAs that were differentially expressed (DE) between CD16(+) and CD16(-) monocytes. Gene ontology analysis revealed that the predicted targets of the DE miRNAs were predominantly associated with cell death and cellular movement. We validated the functional impacts of selected DE miRNAs in CD16(-) monocytes, over-expression of miR-432 significantly increases apoptosis, and inhibiting miR-19a significantly reduces cell motility. Furthermore, we found that miR-345, another DE miRNA directly targets the transcription factor RelA in monocytes, which resulted in the differential expression of RelA in monocyte subsets. This implicates miR-345 indirect regulation of many genes downstream of RelA, including important inflammatory mediators. Together, our data show that DE miRNAs could contribute substantially to regulating the functions of human blood monocytes.
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Affiliation(s)
- Truong-Minh Dang
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Wing-Cheong Wong
- Bioinformatic Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Siew-Min Ong
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Peng Li
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Josephine Lum
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Jinmiao Chen
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Michael Poidinger
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Francesca Zolezzi
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Siew-Cheng Wong
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
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Yang W, Dou C, Wang Y, Jia Y, Li C, Zheng X, Tu K. MicroRNA-92a contributes to tumor growth of human hepatocellular carcinoma by targeting FBXW7. Oncol Rep 2015; 34:2576-84. [PMID: 26323375 DOI: 10.3892/or.2015.4210] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 06/24/2015] [Indexed: 11/05/2022] Open
Abstract
Deregulation of microRNA-92a (miR-92a) has been reported in several human cancers and is associated with prognosis of patients. However, the clinical significance of miR-92a and the underlying mechanisms involved in hepatocarcinogenesis remain to be determined. The aim of the present study was to determine the role of miR-92a in hepatocellular carcinoma (HCC). The results showed that the expression of miR-92a was upregulated in HCC tissues as compared with matched tumor-adjacent tissues. A high expression of miR-92a was observed in HCC cell lines as compared with a non-transformed hepatic cell line. The gain- and loss-of-function studies revealed that miR-92a significantly promoted proliferation and cell cycle transition from G1 to S phase, and inhibited apoptosis of HCC cell in vitro. In tumor‑bearing nude mice, the downregulation of miR-92a suppressed tumor growth of HCC in vivo. miR-92a was inversely correlated with F-box and WD repeat domain-containing 7 (FBXW7) expression in HCC tissues. Furthermore, miR-92a negatively regulated FBXW7 abundance in HCC cells. In the present study, FBXW7 was identified as a direct target of miR-92a. Notably, alterations of FBXW7 expression abrogated the effects of miR-92a on HCC cell proliferation, cell cycle and apoptosis. Clinical association analysis revealed that a high expression of miR-92a was correlated with poor prognostic characteristics of HCC. Notably, the high expression of miR-92a conferred a reduced 5-year overall survival (OS) and recurrence-free survival (RFS) of HCC patients. The multivariate Cox regression analysis demonstrated that miR-92a expression was an independent prognostic marker for predicting survival of HCC patients. In conclusion, the results of the present study suggested that miR-92a promotes the tumor growth of HCC by targeting FBXW7 and may serve as a novel prognostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Wei Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Changwei Dou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yufeng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yuli Jia
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Chao Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xin Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Kangsheng Tu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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50
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Su X, Wang H, Ge W, Yang M, Hou J, Chen T, Li N, Cao X. An In Vivo Method to Identify microRNA Targets Not Predicted by Computation Algorithms: p21 Targeting by miR-92a in Cancer. Cancer Res 2015; 75:2875-85. [DOI: 10.1158/0008-5472.can-14-2218] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Accepted: 04/10/2015] [Indexed: 11/16/2022]
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