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Kang H, Huang Y, Peng H, Zhang X, Liu Y, Liu Y, Xia Y, Liu S, Wu Y, Wang S, Lei T, Zhang H. Mesenchymal Stem Cell-Loaded Hydrogel Improves Surgical Treatment for Chronic Cerebral Ischemia. Transl Stroke Res 2025; 16:896-913. [PMID: 38977638 DOI: 10.1007/s12975-024-01274-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/11/2024] [Accepted: 06/25/2024] [Indexed: 07/10/2024]
Abstract
Chronic cerebral ischemia (CCI) results in a prolonged insufficient blood supply to the brain tissue, leading to impaired neuronal function and subsequent impairment of cognitive and motor abilities. Our previous research showed that in mice with bilateral carotid artery stenosis, the collateral neovascularization post Encephalo-myo-synangiosis (EMS) treatment could be facilitated by bone marrow mesenchymal stem cells (MSCs) transplantation. Considering the advantages of biomaterials, we synthesized and modified a gelatin hydrogel for MSCs encapsulation. We then applied this hydrogel on the brain surface during EMS operation in rats with CCI, and evaluated its impact on cognitive performance and collateral circulation. Consequently, MSCs encapsulated in hydrogel significantly augment the therapeutic effects of EMS, potentially by promoting neovascularization, facilitating neuronal differentiation, and suppressing neuroinflammation. Furthermore, taking advantage of multi-RNA-sequencing and in silico analysis, we revealed that MSCs loaded in hydrogel regulate PDCD4 and CASP2 through the overexpression of miR-183-5p and miR-96-5p, thereby downregulating the expression of apoptosis-related proteins and inhibiting early apoptosis. In conclusion, a gelatin hydrogel to enhance the functionality of MSCs has been developed, and its combination with EMS treatment can improve the therapeutic effect in rats with CCI, suggesting its potential clinical benefit.
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Affiliation(s)
- Huayu Kang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yimin Huang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Huan Peng
- Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China
| | - Xincheng Zhang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuan Liu
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yanchao Liu
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuze Xia
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shengwen Liu
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yaqi Wu
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Sheng Wang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ting Lei
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Huaqiu Zhang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, China.
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Liu J, Tian R, Chen X, Song Q, Sun C, Li D, Fang Y, Lv S, Li Y, Song X. MiR-493-5p functions as a tumour suppressor in head and neck squamous cell carcinoma progression by targeting HIF-1α. Discov Oncol 2025; 16:899. [PMID: 40411544 PMCID: PMC12103410 DOI: 10.1007/s12672-025-02690-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 05/12/2025] [Indexed: 05/26/2025] Open
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) demonstrates insidious onset, high prevalence, and low 5-year overall survival rate. While downregulation of miR-493-5p is implicated in the development of various cancers, its role in HNSCC remains unclear. Here, we explored the association of miR-493-5p with HNSCC progression and elucidated the underlying mechanisms. METHODS The miR-493-5p expression in HNSCC tissues and cells was verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation and migration were detected by Cell Counting Kit 8, colony formation, and wound-healing assay. Dual-luciferase reporter gene assay was used to verify that miR-493-5p targeted hypoxia-inducible factor (HIF)-1α. Cobalt chloride (CoCl2) was used to induce HIF-1α expression to perform rescue assays. SCC VII cells were used to construct the mouse model. After 15 days, the tumour volume was compared. The expression of HIF-1α, glycolysis, and epithelial-mesenchymal transition (EMT) proteins were verified by western blotting. RESULTS MiR-493-5p expression was low and beneficial to prognosis in HNSCC tumours. MiR-493-5p constrained HNSCC cell proliferation and migration and inhibited HIF-1α expression by targeting its 3' untranslated region directly. CoCl2 addition reduced miR-493-5p-induced cell proliferation, which may be related to the increased expression of HIF-1α. MiR-493-5p decelerated tumour cell growth in mice and was associated with glycolysis and EMT in HNSCC cells. CONCLUSIONS MiR-493-5p, which targets HIF-1α and inhibits glycolysis and EMT, may be a novel therapeutic target for HNSCC.
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Affiliation(s)
- Jiahui Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Ruxian Tian
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Xi Chen
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Qing Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yeda Hospital, Yantai, China
| | - Caiyu Sun
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Dongxian Li
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Yuhui Fang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
- The Second Medical College, Binzhou Medical University, Yantai, China
| | - Shijun Lv
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Yumei Li
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, China.
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China.
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China.
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China.
| | - Xicheng Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, China.
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China.
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China.
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China.
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Pulito C, Vaccarella S, Palcau AC, Ganci F, Brandi R, Frascolla C, Sacconi A, Canu V, Benedetti A, De Pascale V, Donzelli S, Fisch AS, Manciocco V, Covello R, Pimpinelli F, Morrone A, Fazi F, Pellini R, Muti P, Meens J, Karamboulas C, Nichols AC, Strano S, Klinghammer K, Tinhofer I, Ailles L, Fontemaggi G, Blandino G. MicroRNA-mediated PTEN downregulation as a novel non-genetic mechanism of acquired resistance to PI3Kα inhibitors of head & neck squamous cell carcinoma. Drug Resist Updat 2025; 81:101251. [PMID: 40382983 DOI: 10.1016/j.drup.2025.101251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 05/02/2025] [Accepted: 05/07/2025] [Indexed: 05/20/2025]
Abstract
AIMS Head and neck squamous cell carcinomas (HNSCCs) frequently harbor alterations in the PI3K signalling axis and, particularly, in the PIK3CA gene. The promising rationale of using PI3K inhibitors for the treatment of HNSCC has, however, clashed with the spontaneous development of resistance over time. METHODS To identify valuable targets for overcoming acquired resistance to PI3Kα inhibitors in HNSCC, we performed microRNA profiling on a cohort of HNSCC PDXs that were treated with alpelisib, including both responsive and resistant tumors. Using CRISPR/Cas9, siRNA, and PTEN-/- isogenic and alpelisib-resistant cell models, we examined the role of PTEN in resistance acquisition. Phospho-proteomic analysis identified PTEN-dependent phosphorylation events, while PI3Kα inhibitor-resistant organoids were used to assess PLK1 inhibitor efficacy. RESULTS We identified microRNAs altered in resistant PDXs, including members of the miR-17-92 cluster. Mechanistically, we observed that the hyperactive c-Myc was recruited to MIR17HG regulatory regions in alpelisib-resistant cells, sustaining miR-17-5p, miR-19b-3p, and miR-20a-5p expression, which downregulated PTEN. PTEN knockout or depletion conferred alpelisib resistance in HNSCC cells. We identified PTEN-dependent phosphorylation events, such as p-PLK1-T210, involved in resistance. Interestingly, pharmacological inhibition of PLK1 strongly reduced the viability of PI3Kα-resistant organoids derived from HNSCC PDXs and cell line models. CONCLUSION Overall, this study unveils a novel, microRNA-driven, non-genetic mechanism contributing to acquired resistance to PI3Kα inhibitors in HNSCC. Indeed, linking hyperactive c-Myc to sustain miR-17-92 expression and consequent PTEN downregulation, we also propose that targeting PTEN-dependent downstream effectors, such as PLK1, may offer a powerful therapeutic strategy for resistant HNSCC.
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Affiliation(s)
- Claudio Pulito
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Sebastiano Vaccarella
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Alina Catalina Palcau
- Microbiology and Virology Unit, San Gallicano Dermatological Institute IRCSS, Rome 00144, Italy
| | - Federica Ganci
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Renata Brandi
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Carlotta Frascolla
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Andrea Sacconi
- UOSD Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Valeria Canu
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Anna Benedetti
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Valentina De Pascale
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Sara Donzelli
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Anne-Sophie Fisch
- Department of Radiooncology and Radiotherapy, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Valentina Manciocco
- Department of Otorhinolaryngology, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Renato Covello
- Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Fulvia Pimpinelli
- Microbiology and Virology Unit, San Gallicano Dermatological Institute IRCSS, Rome 00144, Italy
| | - Aldo Morrone
- Scientific Director Office, IRCCS San Gallicano Dermatology Institute, Rome 00144, Italy
| | - Francesco Fazi
- Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology & Medical Embryology, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Raul Pellini
- Department of Otorhinolaryngology, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Paola Muti
- Department of Biomedical, Surgical and Dental Sciences, University of Milan La Statale, Milan 20122, Italy
| | - Jalna Meens
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Christina Karamboulas
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Anthony C Nichols
- Department of Otolaryngology - Head and Neck Surgery, Western University, London, Ontario, Canada
| | - Sabrina Strano
- SAFU Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Konrad Klinghammer
- Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ingeborg Tinhofer
- Department of Radiooncology and Radiotherapy, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Laurie Ailles
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Giulia Fontemaggi
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy.
| | - Giovanni Blandino
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy.
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Alrehaili JA. Association between the expression of specific microRNAs and prostate cancer progression- a systematic review and meta-analysis. Front Oncol 2025; 14:1481885. [PMID: 39991184 PMCID: PMC11842264 DOI: 10.3389/fonc.2024.1481885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 12/23/2024] [Indexed: 02/25/2025] Open
Abstract
Background This systematic review and metanalysis aimed to summarize the evidence supporting the significance of particular MiRNAs in PrCa progression and to thoroughly examine the body of prior research. Methods In accordance with the PRISMA guidelines, this review was conducted using a specifically design data extraction protocol and searching several online databases for relevant articles. The protocol was registered in the PROSPERO database (CRD42023428460). Results 8 studies were ultimately included in this review. MiRNAs significantly reduced PrCa proliferation, with an odds ratio (OR) of 0.28 (95% CI: 0.21-0.39) and a risk ratio (RR) of 0.51 (95% CI: 0.43-0.61), though moderate heterogeneity was observed (I² = 57%). For two studies investigating MiRNAs as biomarkers for predicting metastasis, the pooled OR was 0.60 (95% CI: 0.47-0.76) and the RR was 0.72 (95% CI: 0.62-0.84), both demonstrating significant predictive value with low heterogeneity (I² = 0%). Conclusion The results emphasize the potential of miRNAs as biomarkers for predicting PrCa metastasis and demonstrate that miRNAs have a discernible effect on PrCa proliferation. However, to improve our comprehension of MiRNA's function in this condition, additional studies are required to address the limitations and investigate how MiRNA acts in many areas of PrCa. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42023428460.
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Affiliation(s)
- Jihad Awadallah Alrehaili
- Department of Pathology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
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de Bakker T, Maes A, Dragan T, Martinive P, Penninckx S, Van Gestel D. Strategies to Overcome Intrinsic and Acquired Resistance to Chemoradiotherapy in Head and Neck Cancer. Cells 2024; 14:18. [PMID: 39791719 PMCID: PMC11719474 DOI: 10.3390/cells14010018] [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: 11/19/2024] [Revised: 12/18/2024] [Accepted: 12/25/2024] [Indexed: 01/12/2025] Open
Abstract
Definitive chemoradiotherapy (CRT) is a cornerstone of treatment for locoregionally advanced head and neck cancer (HNC). Research is ongoing on how to improve the tumor response to treatment and limit normal tissue toxicity. A major limitation in that regard is the growing occurrence of intrinsic or acquired treatment resistance in advanced cases. In this review, we will discuss how overexpression of efflux pumps, perturbation of apoptosis-related factors, increased expression of antioxidants, glucose metabolism, metallotheionein expression, increased DNA repair, cancer stem cells, epithelial-mesenchymal transition, non-coding RNA and the tumour microenvironment contribute towards resistance of HNC to chemotherapy and/or radiotherapy. These mechanisms have been investigated for years and been exploited for therapeutic gain in resistant patients, paving the way to the development of new promising drugs. Since in vitro studies on resistance requires a suitable model, we will also summarize published techniques and treatment schedules that have been shown to generate acquired resistance to chemo- and/or radiotherapy that most closely mimics the clinical scenario.
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Affiliation(s)
- Tycho de Bakker
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
| | - Anouk Maes
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
| | - Tatiana Dragan
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
| | - Philippe Martinive
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
| | - Sébastien Penninckx
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
- Medical Physics Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Dirk Van Gestel
- Radiotherapy Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium (S.P.)
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Santiago FE, Adige T, Mahmud S, Dong X, Niedernhofer LJ, Robbins PD. miR-96-5p expression is sufficient to induce and maintain the senescent cell fate in the absence of stress. Proc Natl Acad Sci U S A 2024; 121:e2321182121. [PMID: 39325426 PMCID: PMC11459134 DOI: 10.1073/pnas.2321182121] [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: 12/22/2023] [Accepted: 08/08/2024] [Indexed: 09/27/2024] Open
Abstract
Senescence is a cell fate driven by different types of stress that results in exit from the cell cycle and expression of an inflammatory senescence-associated secretory phenotype (SASP). Here, we demonstrate that stable overexpression of miR-96-5p was sufficient to induce cellular senescence in the absence of genotoxic stress, inducing expression of certain markers of early senescence including SASP factors while repressing markers of deep senescence including LINE-1 and type 1 interferons. Stable miR-96-5p overexpression led to genome-wide changes in heterochromatin followed by epigenetic activation of p16Ink4a, p21Cip1, and SASP expression, induction of a marker of DNA damage, and induction of a transcriptional signature similar to other senescent lung and endothelial cell types. Expression of miR-96-5p significantly increased following senescence induction in culture cells and with aging in tissues from naturally aged and Ercc1-/Δ progeroid mice. Mechanistically, miR-96-5p directly suppressed expression of SIN3B and SIN3 corepressor complex constituents KDM5A and MORF4L2, and siRNA-mediated knockdown of these transcriptional regulators recapitulated the senescent phenotype. In addition, pharmacologic inhibition of the SIN3 complex suppressed senescence and SASP markers. These results clearly demonstrate that a single microRNA is sufficient to drive early senescence in the absence of genotoxic stress through targeting epigenetic and transcriptional regulators, identifying novel targets for the development of senotherapeutics.
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Affiliation(s)
- Fernando E. Santiago
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minnesota, MN55455
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minnesota, MN55455
| | - Tanvi Adige
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minnesota, MN55455
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minnesota, MN55455
| | - Shamsed Mahmud
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minnesota, MN55455
- Department of Genetics, Cell Biology and Development, University of Minnesota, MinnesotaMN55455
| | - Xiao Dong
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minnesota, MN55455
- Department of Genetics, Cell Biology and Development, University of Minnesota, MinnesotaMN55455
| | - Laura J. Niedernhofer
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minnesota, MN55455
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minnesota, MN55455
| | - Paul D. Robbins
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minnesota, MN55455
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minnesota, MN55455
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Wen L, Li M, Yin J. PTEN Deficiency Induced by Extracellular Vesicle miRNAs from Clonorchis sinensis Potentiates Cholangiocarcinoma Development by Inhibiting Ferroptosis. Int J Mol Sci 2024; 25:10350. [PMID: 39408679 PMCID: PMC11477024 DOI: 10.3390/ijms251910350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/21/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
The human phosphatase and tensin homolog (PTEN) is a tumor suppressor. A slight deficiency in PTEN might cause cancer susceptibility and progression. Infection by the liver fluke Clonorchis sinensis could lead to persistent loss of PTEN in cholangiocarcinoma. However, the mechanism of PTEN loss and its malignant effect on cholangiocarcinoma have not yet been elucidated. Extracellular vesicles secreted by Clonorchis sinensis (CS-EVs) are rich in microRNAs (miRNAs) and can mediate communication between hosts and parasites. Herein, we delved into the miRNAs present in CS-EVs, specifically those that potentially target PTEN and modulate the progression of cholangiocarcinoma via ferroptosis mechanisms. CS-EVs were extracted by differential ultra-centrifugation for high-throughput sequencing of miRNA. Lentiviral vectors were used to construct stably transfected cell lines. Erastin was used to construct ferroptosis induction models. Finally, 36 miRNAs were identified from CS-EVs. Among them, csi-miR-96-5p inhibited PTEN expression according to the predictions and dual luciferase assay. The CCK-8 assay, xenograft tumor assays and transwell assay showed that csi-miR-96-5p overexpression and PTEN knockout significantly increased the proliferation and migration of cholangiocarcinoma cells and co-transfection of PTEN significantly reversed the effect. In the presence of erastin, the cell proliferation and migration ability of the negative transfection control group were significantly impaired, although they did not significantly change with transfection of csi-miR-96-5p and PTEN knockout, indicating that they obtained ferroptosis resistance. Mechanistically, csi-miR-96-5p and PTEN knockout significantly inhibited ferroptosis through a decrease in ferrous ion (Fe2+) and malondialdehyde (MDA), and an increase in glutathione reductase (GSH), Solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). In conclusion, loss of PTEN promoted the progression of cholangiocarcinoma via the ferroptosis pathway and csi-miR-96-5p delivered by CS-EVs may mediate this process.
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Affiliation(s)
| | | | - Jigang Yin
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China; (L.W.); (M.L.)
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8
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Gao Z, Luan X, Wang X, Han T, Li X, Li Z, Li P, Zhou Z. DNA damage response-related ncRNAs as regulators of therapy resistance in cancer. Front Pharmacol 2024; 15:1390300. [PMID: 39253383 PMCID: PMC11381396 DOI: 10.3389/fphar.2024.1390300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 08/14/2024] [Indexed: 09/11/2024] Open
Abstract
The DNA damage repair (DDR) pathway is a complex signaling cascade that can sense DNA damage and trigger cellular responses to DNA damage to maintain genome stability and integrity. A typical hallmark of cancer is genomic instability or nonintegrity, which is closely related to the accumulation of DNA damage within cancer cells. The treatment principles of radiotherapy and chemotherapy for cancer are based on their cytotoxic effects on DNA damage, which are accompanied by severe and unnecessary side effects on normal tissues, including dysregulation of the DDR and induced therapeutic tolerance. As a driving factor for oncogenes or tumor suppressor genes, noncoding RNA (ncRNA) have been shown to play an important role in cancer cell resistance to radiotherapy and chemotherapy. Recently, it has been found that ncRNA can regulate tumor treatment tolerance by altering the DDR induced by radiotherapy or chemotherapy in cancer cells, indicating that ncRNA are potential regulatory factors targeting the DDR to reverse tumor treatment tolerance. This review provides an overview of the basic information and functions of the DDR and ncRNAs in the tolerance or sensitivity of tumors to chemotherapy and radiation therapy. We focused on the impact of ncRNA (mainly microRNA [miRNA], long noncoding RNA [lncRNA], and circular RNA [circRNA]) on cancer treatment by regulating the DDR and the underlying molecular mechanisms of their effects. These findings provide a theoretical basis and new insights for tumor-targeted therapy and the development of novel drugs targeting the DDR or ncRNAs.
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Affiliation(s)
- Ziru Gao
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xinchi Luan
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xuezhe Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Tianyue Han
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiaoyuan Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Zeyang Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Zhixia Zhou
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
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9
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Krsek A, Baticic L, Sotosek V, Braut T. The Role of Biomarkers in HPV-Positive Head and Neck Squamous Cell Carcinoma: Towards Precision Medicine. Diagnostics (Basel) 2024; 14:1448. [PMID: 39001338 PMCID: PMC11241541 DOI: 10.3390/diagnostics14131448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/03/2024] [Accepted: 07/04/2024] [Indexed: 07/16/2024] Open
Abstract
Head and neck cancer (HNC) represents a significant global health challenge, with squamous cell carcinomas (SCCs) accounting for approximately 90% of all HNC cases. These malignancies, collectively referred to as head and neck squamous cell carcinoma (HNSCC), originate from the mucosal epithelium lining the larynx, pharynx, and oral cavity. The primary risk factors associated with HNSCC in economically disadvantaged nations have been chronic alcohol consumption and tobacco use. However, in more affluent countries, the landscape of HNSCC has shifted with the identification of human papillomavirus (HPV) infection, particularly HPV-16, as a major risk factor, especially among nonsmokers. Understanding the evolving risk factors and the distinct biological behaviors of HPV-positive and HPV-negative HNSCC is critical for developing targeted treatment strategies and improving patient outcomes in this complex and diverse group of cancers. Accurate diagnosis of HPV-positive HNSCC is essential for developing a comprehensive model that integrates the molecular characteristics, immune microenvironment, and clinical outcomes. The aim of this comprehensive review was to summarize the current knowledge and advances in the identification of DNA, RNA, and protein biomarkers in bodily fluids and tissues that have introduced new possibilities for minimally or non-invasive cancer diagnosis, monitoring, and assessment of therapeutic responses.
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Affiliation(s)
- Antea Krsek
- Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia;
| | - Lara Baticic
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Vlatka Sotosek
- Department of Clinical Medical Sciences I, Faculty of Health Studies, University of Rijeka, 51000 Rijeka, Croatia;
- Department of Anesthesiology, Reanimatology, Emergency and Intensive Care Medicine, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Tamara Braut
- Department of Otorhinolaryngology and Head and Neck Surgery, Clinical Hospital Centre Rijeka, 51000 Rijeka, Croatia;
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10
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Ganci F, Allegretti M, Frascolla C, Spinella F, Rollo F, Sacconi A, Valentina PD, Palcau AC, Manciocco V, Vescovo M, Cotroneo E, Blandino F, Benevolo M, Covello R, Muti P, Strano S, Vidiri A, Fontemaggi G, Pellini R, Blandino G. Combined TP53 status in tumor-free resection margins and circulating microRNA profiling predicts the risk of locoregional recurrence in head and neck cancer. Biomark Res 2024; 12:32. [PMID: 38444004 PMCID: PMC10916059 DOI: 10.1186/s40364-024-00576-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/15/2024] [Indexed: 03/07/2024] Open
Abstract
Locoregional recurrences represent a frequently unexpected problem in head and neck squamous cell carcinoma (HNSCC). Relapse often (10-30%) occurs in patients with histologically negative resection margins (RMs), probably due to residual tumor cells or hidden pre-cancerous lesions in normal mucosa, both missed by histopathological examination. Therefore, definition of a 'clean' or tumor-negative RM is controversial, demanding for novel approaches to be accurately explored. Here, we evaluated next generation sequencing (NGS) and digital PCR (dPCR) as tools to profile TP53 mutational status and circulating microRNA expression aiming at scoring the locoregional risk of recurrence by means of molecular analyses. Serial monitoring of these biomarkers allowed identifying patients at high risk, laying the ground for accurate tracking of disease evolution and potential intensification of post-operative treatments. Additionally, our pipeline demonstrated its applicability into the clinical routine, being cost-effective and feasible in terms of patient sampling, holding promise to accurately (re)-stage RMs in the era of precision medicine.
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Affiliation(s)
- Federica Ganci
- Translational Oncologic Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Matteo Allegretti
- Translational Oncologic Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Carlotta Frascolla
- Translational Oncologic Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Francesca Spinella
- Department of Research and Development, Eurofins Genoma Group, Rome, Italy
| | - Francesca Rollo
- Pathology, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Andrea Sacconi
- SAFU Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Pascale De Valentina
- Translational Oncologic Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Alina Catalina Palcau
- Translational Oncologic Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Valentina Manciocco
- Otolaryngology-Head and Neck Surgery, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Mariavittoria Vescovo
- Pathology, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Ettore Cotroneo
- Clinical and Technical Department Management, Eurofins Genoma Group, Rome, Italy
| | - Francesca Blandino
- Department of Research and Development, Eurofins Genoma Group, Rome, Italy
| | - Maria Benevolo
- Pathology, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Renato Covello
- Pathology, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Paola Muti
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Sabrina Strano
- SAFU Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Antonello Vidiri
- Radiology and Diagnostic Imaging, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Giulia Fontemaggi
- Translational Oncologic Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Raul Pellini
- Otolaryngology-Head and Neck Surgery, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Giovanni Blandino
- Translational Oncologic Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
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11
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Yang J, Gu Z. Ferroptosis in head and neck squamous cell carcinoma: from pathogenesis to treatment. Front Pharmacol 2024; 15:1283465. [PMID: 38313306 PMCID: PMC10834699 DOI: 10.3389/fphar.2024.1283465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 01/10/2024] [Indexed: 02/06/2024] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignant tumor worldwide, with high morbidity and mortality. Surgery and postoperative chemoradiotherapy have largely reduced the recurrence and fatality rates for most HNSCCs. Nonetheless, these therapeutic approaches result in poor prognoses owing to severe adverse reactions and the development of drug resistance. Ferroptosis is a kind of programmed cell death which is non-apoptotic. Ferroptosis of tumor cells can inhibit tumor development. Ferroptosis involves various biomolecules and signaling pathways, whose expressions can be adjusted to modulate the sensitivity of cells to ferroptosis. As a tool in the fight against cancer, the activation of ferroptosis is a treatment that has received much attention in recent years. Therefore, understanding the molecular mechanism of ferroptosis in HNSCC is an essential strategy with therapeutic potential. The most important thing to treat HNSCC is to choose the appropriate treatment method. In this review, we discuss the molecular and defense mechanisms of ferroptosis, analyze the role and mechanism of ferroptosis in the inhibition and immunity against HNSCC, and explore the therapeutic strategy for inducing ferroptosis in HNSCC including drug therapy, radiation therapy, immunotherapy, nanotherapy and comprehensive treatment. We find ferroptosis provides a new target for HNSCC treatment.
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Affiliation(s)
- Jing Yang
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhaowei Gu
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, China
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12
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Wen LJ, Yin JG, Wang YX, Liu K, Zhao JX. csi-miR-96-5p delivered by Clonorchis sinensis extracellular vesicles promotes intrahepatic cholangiocarcinoma proliferation and migration via the ferroptosis-related PTEN/SLC7A11/GPX4 axis. Parasit Vectors 2023; 16:465. [PMID: 38124152 PMCID: PMC10734124 DOI: 10.1186/s13071-023-06075-7] [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: 11/04/2023] [Accepted: 11/30/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Clonorchis sinensis (CS) is classified as a group 1 carcinogen and can cause intrahepatic cholangiocarcinoma (ICC). CS extracellular vesicles (CsEVs) play important roles in mediating communication between parasitic helminths and humans. Ferroptosis is a novel cell death mechanism that is mainly induced by lipid peroxidation and iron overload. However, the role of CsEVs in the regulation of ferroptosis in ICC remains unclear. This study aimed to explore the role of CS-secreted miR-96-5p (csi-miR-96-5p) delivered by CsEVs in ICC progression and ferroptosis. METHODS Tissue samples were collected from ICC patients with CS infection (CS-ICC) or without CS infection (NC-ICC). The levels of csi-miR-96-5p and PTEN gene were determined by quantitative polymerase chain reaction (qPCR) and western blotting, and survival analysis was performed. CsEVs were isolated and identified by ultracentrifugation and transmission electron microscopy. Lentiviruses were used to establish stable cell lines with csi-miR-96-5p mimic expression, PTEN overexpression (PTEN-EXO) and PTEN CRISPR/Cas9-based knockout (PTEN-KO) and their respective negative controls. Cell proliferation was assessed by performing Cell Counting Kit-8 assays in vitro and in a tumor xenograft model in vivo, and cell migration was assessed by performing Transwell assays. Erastin is used to induce ferroptosis. Ferroptosis levels were evaluated using biomarkers. RESULTS High csi-miR-96-5p and low PTEN expression was observed in CS-ICC tissues and was associated with poor overall survival. csi-miR-96-5p was highly enriched in CsEVs and was taken up by ICC cells. csi-miR-96-5p mimics or PTEN-KO significantly promoted the growth and migration of ICC cells in vitro and in vivo, whereas PTEN-EXO exerted the opposite effect. Mechanistically, csi-miR-96-5p mimics or PTEN-KO inhibited erastin-induced ferroptosis, including reducing the accumulation of Fe2+, lipid reactive oxygen species, and malondialdehyde, increasing the GSH/GSSG ratio and levels of SLC7A11 and GPX4, whereas PTEN-EXOs exerted the opposite effect. CONCLUSIONS csi-miR-96-5p delivered by CsEVs reduced ferroptosis by regulating the expression of the PTEN/SLC7A11/GPX4 axis, thereby promoting ICC proliferation and migration. For the first time to our knowledge, we found that CS miRNAs could promote tumor development through ferroptosis.
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Affiliation(s)
- Li-Jia Wen
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, China
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Ji-Gang Yin
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, China
| | - Yong-Xin Wang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Ji-Xue Zhao
- Department of Pediatric Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
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13
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Kozłowska-Masłoń J, Guglas K, Kolenda T, Lamperska K, Makałowska I. miRNA in head and neck squamous cell carcinomas: promising but still distant future of personalized oncology. Rep Pract Oncol Radiother 2023; 28:681-697. [PMID: 38179293 PMCID: PMC10764040 DOI: 10.5603/rpor.96666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 07/24/2023] [Indexed: 01/06/2024] Open
Abstract
Head and neck squamous cell carcinoma is one of the most common and fatal cancers worldwide. Lack of appropriate preventive screening tests, late detection, and high heterogeneity of these tumors are the main reasons for the unsatisfactory effects of therapy and, consequently, unfavorable outcomes for patients. An opportunity to improve the quality of diagnostics and treatment of this group of cancers are microRNAs (miRNAs) - molecules with a great potential both as biomarkers and therapeutic targets. This review aims to present the characteristics of these short non-coding RNAs (ncRNAs) and summarize the current reports on their use in oncology focused on medical strategies tailored to patients' needs.
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Affiliation(s)
- Joanna Kozłowska-Masłoń
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
| | - Kacper Guglas
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Kolenda
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Research and Implementation Unit, Greater Poland Cancer Centre, Poznan, Poland
| | - Katarzyna Lamperska
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Research and Implementation Unit, Greater Poland Cancer Centre, Poznan, Poland
| | - Izabela Makałowska
- Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
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14
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Li S, Meng W, Guo Z, Liu M, He Y, Li Y, Ma Z. The miR-183 Cluster: Biogenesis, Functions, and Cell Communication via Exosomes in Cancer. Cells 2023; 12:1315. [PMID: 37174715 PMCID: PMC10177187 DOI: 10.3390/cells12091315] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/18/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Cancer is one of the leading causes of human death. MicroRNAs have been found to be closely associated with cancer. The miR-183 cluster, comprising miR-183, miR-96, and miR-182, is transcribed as a polycistronic miRNA cluster. Importantly, in most cases, these clusters promote cancer development through different pathways. Exosomes, as extracellular vesicles, play an important role in cellular communication and the regulation of the tissue microenvironment. Interestingly, the miR-183 cluster can be detected in exosomes and plays a functional regulatory role in tumor development. Here, the biogenesis and functions of the miR-183 cluster in highly prevalent cancers and their relationship with other non-coding RNAs are summarized. In addition, the miR-183 cluster in exosomes has also been discussed. Finally, we discuss the miR-183 cluster as a promising target for cancer therapy. This review is expected to provide a new direction for cancer treatment.
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Affiliation(s)
- Shuhui Li
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Wei Meng
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Ziyi Guo
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Min Liu
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Yanyun He
- Experimental Center of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Yanli Li
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Zhongliang Ma
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai 200444, China
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15
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El-Mahdy HA, Mohamadin AM, Abulsoud AI, Khidr EG, El-Husseiny AA, Ismail A, Elsakka EGE, Mokhlis HA, El-Husseiny HM, Doghish AS. miRNAs as potential game-changers in head and neck cancer: Future clinical and medicinal uses. Pathol Res Pract 2023; 245:154457. [PMID: 37058745 DOI: 10.1016/j.prp.2023.154457] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/06/2023] [Accepted: 04/07/2023] [Indexed: 04/16/2023]
Abstract
Head and neck cancers (HNCs) are a group of heterogeneous tumors formed most frequently from epithelial cells of the larynx, lips, oropharynx, nasopharynx, and mouth. Numerous epigenetic components, including miRNAs, have been demonstrated to have an impact on HNCs characteristics like progression, angiogenesis, initiation, and resistance to therapeutic interventions. The miRNAs may control the production of numerous genes linked to HNCs pathogenesis. The roles that miRNAs play in angiogenesis, invasion, metastasis, cell cycle, proliferation, and apoptosis are responsible for this impact. The miRNAs also have an impact on crucial HNCs-related mechanistic networks like the WNT/β-catenin signaling, PTEN/Akt/mTOR pathway, TGFβ, and KRAS mutations. miRNAs may affect how the HNCs respond to treatments like radiation and chemotherapy in addition to pathophysiology. This review aims to demonstrate the relationship between miRNAs and HNCs with a particular emphasis on how miRNAs impact HNCs signaling networks.
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Affiliation(s)
- Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt.
| | - Ahmed M Mohamadin
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt; Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Emad Gamil Khidr
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt
| | - Ahmed A El-Husseiny
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt; Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr, Cairo 11829, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt
| | - Hamada Ahmed Mokhlis
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Nasr, Cairo 11231, Egypt
| | - Hussein M El-Husseiny
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai Cho, Fuchu-shi, Tokyo 183-8509, Japan; Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Al Qalyubia 13736, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt; Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt.
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16
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Guo D, Yang M, Li S, Zhu W, Chen M, Pan J, Long D, Liu Z, Zhang C. Expression and molecular regulation of non-coding RNAs in HPV-positive head and neck squamous cell carcinoma. Front Oncol 2023; 13:1122982. [PMID: 37064141 PMCID: PMC10090466 DOI: 10.3389/fonc.2023.1122982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 03/06/2023] [Indexed: 03/31/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignancy worldwide. Accumulating evidence suggests that persistent HPV infection is closely related to a subset of HNSCC types, and the incidence of human papillomavirus (HPV)-positive HNSCC has been annually increasing in recent decades. Although the carcinogenesis of HPV-positive HNSCC has not been completely elucidated, it has been well confirmed that E6 and E7, the main viral oncoproteins are responsible for the maintenance of malignant transformation, promotion of cell proliferation, and increase in tumor invasion. Moreover, compared with HPV-negative HNSCC, HPV-positive HNSCC shows some special clinical-pathological features, which are possibly related to HPV infection and their specific regulatory mechanisms. Non-coding RNA (ncRNA) is a class of RNA lacking the protein-coding function and playing a critical regulatory role via multiple complex molecular mechanisms. NcRNA is an important regulatory pattern of epigenetic modification, which can exert significant effects on HPV-induced tumorigenesis and progression by deregulating downstream genes. However, the knowledge of ncRNAs is still limited, hence, a better understanding of ncRNAs could provide some insights for exploring the carcinogenesis mechanism and identifying valuable biomarkers in HPV-positive HNSCC. Therefore, in this review, we mainly focused on the expression profile of ncRNAs (including lncRNA, miRNA, and circRNA) and explored their regulatory role in HPV-positive HNSCC, aiming to clarify the regulatory mechanism of ncRNAs and identify valuable biomarkers for HPV-positive HNSCC.
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17
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Vidotto T, Melo CM, Lautert-Dutra W, Chaves LP, Reis RB, Squire JA. Pan-cancer genomic analysis shows hemizygous PTEN loss tumors are associated with immune evasion and poor outcome. Sci Rep 2023; 13:5049. [PMID: 36977733 PMCID: PMC10050165 DOI: 10.1038/s41598-023-31759-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
In tumors, somatic mutations of the PTEN suppressor gene are associated with advanced disease, chemotherapy resistance, and poor survival. PTEN loss of function may occur by inactivating mutation, by deletion, either affecting one copy (hemizygous loss) leading to reduced gene expression or loss of both copies (homozygous) with expression absent. Various murine models have shown that minor reductions in PTEN protein levels strongly influence tumorigenesis. Most PTEN biomarker assays dichotomize PTEN (i.e. presence vs. absence) ignoring the role of one copy loss. We performed a PTEN copy number analysis of 9793 TCGA cases from 30 different tumor types. There were 419 (4.28%) homozygous and 2484 (25.37%) hemizygous PTEN losses. Hemizygous deletions led to reduced PTEN gene expression, accompanied by increased levels of instability and aneuploidy across tumor genomes. Outcome analysis of the pan-cancer cohort showed that losing one copy of PTEN reduced survival to comparable levels as complete loss, and was associated with transcriptomic changes controlling immune response and the tumor microenvironment. Immune cell abundances were significantly altered for PTEN loss, with changes in head and neck, cervix, stomach, prostate, brain, and colon more evident in hemizygous loss tumors. These data suggest that reduced expression of PTEN in tumors with hemizygous loss leads to tumor progression and influences anticancer immune response pathways.
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Affiliation(s)
- T Vidotto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - C M Melo
- Department of Genetics, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - W Lautert-Dutra
- Department of Genetics, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - L P Chaves
- Department of Genetics, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - R B Reis
- Division of Urology, Department of Surgery and Anatomy, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - J A Squire
- Department of Genetics, Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada.
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18
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Hashemi M, Mirdamadi MSA, Talebi Y, Khaniabad N, Banaei G, Daneii P, Gholami S, Ghorbani A, Tavakolpournegari A, Farsani ZM, Zarrabi A, Nabavi N, Zandieh MA, Rashidi M, Taheriazam A, Entezari M, Khan H. Pre-clinical and clinical importance of miR-21 in human cancers: Tumorigenesis, therapy response, delivery approaches and targeting agents. Pharmacol Res 2023; 187:106568. [PMID: 36423787 DOI: 10.1016/j.phrs.2022.106568] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/18/2022] [Accepted: 11/19/2022] [Indexed: 11/23/2022]
Abstract
The field of non-coding RNA (ncRNA) has made significant progress in understanding the pathogenesis of diseases and has broadened our knowledge towards their targeting, especially in cancer therapy. ncRNAs are a large family of RNAs with microRNAs (miRNAs) being one kind of endogenous RNA which lack encoded proteins. By now, miRNAs have been well-coined in pathogenesis and development of cancer. The current review focuses on the role of miR-21 in cancers and its association with tumor progression. miR-21 has both oncogenic and onco-suppressor functions and most of the experiments are in agreement with the tumor-promoting function of this miRNA. miR-21 primarily decreases PTEN expression to induce PI3K/Akt signaling in cancer progression. Overexpression of miR-21 inhibits apoptosis and is vital for inducing pro-survival autophagy. miR-21 is vital for metabolic reprogramming and can induce glycolysis to enhance tumor progression. miR-21 stimulates EMT mechanisms and increases expression of MMP-2 and MMP-9 thereby elevating tumor metastasis. miR-21 is a target of anti-cancer agents such as curcumin and curcumol and its down-regulation impairs tumor progression. Upregulation of miR-21 results in cancer resistance to chemotherapy and radiotherapy. Increasing evidence has revealed the role of miR-21 as a biomarker as it is present in both the serum and exosomes making them beneficial biomarkers for non-invasive diagnosis of cancer.
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Affiliation(s)
- 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
| | - Motahare Sadat Ayat Mirdamadi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Yasmin Talebi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Biology, Islamic Azad University Central Tehran Branch, Tehran, Iran
| | - Nasrin Khaniabad
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Gooya Banaei
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain
| | - Pouria Daneii
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Sadaf Gholami
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Amin Ghorbani
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Alireza Tavakolpournegari
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain
| | - Zoheir Mohammadian Farsani
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Industrial and Environmental Biotechnology, National Institute for Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey
| | - Noushin Nabavi
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of epidemiology, Faculty of Veterinary Medicine, University of Tehran, 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.
| | - 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.
| | - 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.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, 23200, Pakistan.
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Moghaddam M, Vivarelli S, Falzone L, Libra M, Bonavida B. Cancer resistance via the downregulation of the tumor suppressors RKIP and PTEN expressions: therapeutic implications. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:170-207. [PMID: 37205308 PMCID: PMC10185445 DOI: 10.37349/etat.2023.00128] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 12/12/2022] [Indexed: 05/21/2023] Open
Abstract
The Raf kinase inhibitor protein (RKIP) has been reported to be underexpressed in many cancers and plays a role in the regulation of tumor cells' survival, proliferation, invasion, and metastasis, hence, a tumor suppressor. RKIP also regulates tumor cell resistance to cytotoxic drugs/cells. Likewise, the tumor suppressor, phosphatase and tensin homolog (PTEN), which inhibits the phosphatidylinositol 3 kinase (PI3K)/AKT pathway, is either mutated, underexpressed, or deleted in many cancers and shares with RKIP its anti-tumor properties and its regulation in resistance. The transcriptional and posttranscriptional regulations of RKIP and PTEN expressions and their roles in resistance were reviewed. The underlying mechanism of the interrelationship between the signaling expressions of RKIP and PTEN in cancer is not clear. Several pathways are regulated by RKIP and PTEN and the transcriptional and post-transcriptional regulations of RKIP and PTEN is significantly altered in cancers. In addition, RKIP and PTEN play a key role in the regulation of tumor cells response to chemotherapy and immunotherapy. In addition, molecular and bioinformatic data revealed crosstalk signaling networks that regulate the expressions of both RKIP and PTEN. These crosstalks involved the mitogen-activated protein kinase (MAPK)/PI3K pathways and the dysregulated nuclear factor-kappaB (NF-κB)/Snail/Yin Yang 1 (YY1)/RKIP/PTEN loop in many cancers. Furthermore, further bioinformatic analyses were performed to investigate the correlations (positive or negative) and the prognostic significance of the expressions of RKIP or PTEN in 31 different human cancers. These analyses were not uniform and only revealed that there was a positive correlation between the expression of RKIP and PTEN only in few cancers. These findings demonstrated the existence of signaling cross-talks between RKIP and PTEN and both regulate resistance. Targeting either RKIP or PTEN (alone or in combination with other therapies) may be sufficient to therapeutically inhibit tumor growth and reverse the tumor resistance to cytotoxic therapies.
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Affiliation(s)
- Matthew Moghaddam
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), East Los Angeles, CA 90095, USA
| | - Silvia Vivarelli
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Occupational Medicine Section, University of Messina, 98125 Messina, Italy
| | - Luca Falzone
- Epidemiology and Biostatistics Unit, National Cancer Institute IRCCS Fondazione G. Pascale, 80131 Naples, Italy
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
- Research Centre for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
| | - Benjamin Bonavida
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), East Los Angeles, CA 90095, USA
- Correspondence: Benjamin Bonavida, Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), 1602 Molecular Sciences Building, 609 Charles E. Young Drive, East Los Angeles, CA 90095, USA.
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20
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Salivary miRNAs Expression in Potentially Malignant Disorders of the Oral Mucosa and Oral Squamous Cell Carcinoma: A Pilot Study on miR-21, miR-27b, and miR-181b. Cancers (Basel) 2022; 15:cancers15010291. [PMID: 36612284 PMCID: PMC9818333 DOI: 10.3390/cancers15010291] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/16/2022] [Accepted: 12/28/2022] [Indexed: 01/04/2023] Open
Abstract
(1) Background: Oral potentially malignant disorders (OPMD) represent a fundamental challenge for clinicians, considering the possibility of progression into oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). Several studies have examined the expression of miRNAs in humans as diagnostic and prognostic biomarkers. Among these, miR-21, miR-27b, and miR-181b proved to be promising. This cohort study evaluated the different expressions of those miRNAs in the saliva of patients with OPMD and OSCC. (2) Methods: Patients with a clinical diagnosis of OPMD and/or OSCC were enrolled; saliva samples were collected; miRNAs were extracted and quantified via qRT-PCR was performed. Data were analyzed by subgroups based on the histopathological diagnosis (OSCC and the grade of OED) using the ΔΔCt method. Saliva from 10 healthy donors was used as the control. One-way ANOVA and Kruskal-Wallis tests were performed to assess the differences between groups. (3) Results: 23 patients for the OPMD group (6 with no dysplasia, 7 with low-grade, and 10 with high-grade dysplasia) and 10 with OSCC were analyzed. MiR-21 did not show any variation among groups; miR-27b was under-expressed in dysplastic lesions (p = 0.046); miR-181b was upregulated in high-grade dysplasia (p = 0.006), increasing with the degree of dysplasia, and decreasing in OSCCs. (4) Conclusions: Salivary miR-27b and miR-181b could be promising biomarkers for oral dysplasia. Further studies are needed to clarify their feasibility.
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21
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Wu EY, Huang LP, Bao JH. miR-96-5p regulates cervical cancer cell resistance to cisplatin by inhibiting lncRNA TRIM52-AS1 and promoting IGF2BP2. Kaohsiung J Med Sci 2022; 38:1178-1189. [PMID: 36354205 DOI: 10.1002/kjm2.12593] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 08/02/2022] [Accepted: 08/16/2022] [Indexed: 11/11/2022] Open
Abstract
MicroRNA (miRNA) and long noncoding RNA (lncRNA) are both regulators of cancer progression. This study sought to discuss the functional mechanism of miR-96-5p/lncRNA TRIM52 antisense RNA 1 (head-to-head; TRIM52-AS1) in cervical cancer (CC) cell resistance to cisplatin (DDP). DDP-resistant CC cell line was established using increasing concentrations of DDP, followed by transfection with miR-96-5p inhibitor, or si-TRIM52-AS1, or insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) overexpression vector. Expression levels of miR-96-5p, TRIM52-AS1, and IGF2BP2 were determined. Changes in IC50 value to DDP, cell proliferation, and apoptosis rate were evaluated by cell-counting kit-8 assay, colony formation, and flow cytometry. The bindings of miR-96-5p to IGF2BP2 and TRIM52-AS1 to IGF2BP2 were verified by dual-luciferase or RNA pull-down assays. These experiments revealed an up-expression of miR-96-5p and IGF2BP2 while an under-expression of TRIM52-AS1 in CC cells. After DDP treatment, miR-96-5p inhibition increased apoptosis and decreased proliferation and DDP resistance. miR-96-5p bound to TRIM52-AS1 and downregulated TRIM52-AS1 expression, and TRIM52-AS1 bound to IGF2BP2 to inhibit IGF2BP2 expression. TRIM52-AS1 inhibition or IGF2BP2 overexpression neutralized the inhibition of silencing miR-96-5p on CC cell resistance to DDP. Overall, miR-96-5p improved CC cell resistance to DDP by inhibiting TRIM52-AS1 and promoting IGF2BP2.
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Affiliation(s)
- En Yuesu Wu
- Department of Gynecology II, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, Inner Mongolia, China
| | - Li-Ping Huang
- Department of Gynecology II, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, Inner Mongolia, China
| | - Jin-Hua Bao
- Department of Gynecology II, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, Inner Mongolia, China
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22
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MiR-29c-3p/C1QTNF6 Restrains the Angiogenesis and Cell Proliferation, Migration and Invasion in Head and Neck Squamous Cell Carcinoma. Mol Biotechnol 2022; 65:913-921. [DOI: 10.1007/s12033-022-00591-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 10/24/2022] [Indexed: 11/11/2022]
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23
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MiR-96-5p Facilitates Lung Adenocarcinoma Cell Phenotypes by Inhibiting FHL1. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:7891222. [PMID: 36017148 PMCID: PMC9398840 DOI: 10.1155/2022/7891222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/22/2022] [Accepted: 07/27/2022] [Indexed: 12/09/2022]
Abstract
Objective FHL1 is understood as a tumor repressor gene in various cancers and a possible target for cancer treatment. We investigated the influences of FHL1 on cell functions as well as its molecular mechanisms in lung adenocarcinoma (LUAD) cells. Methods The miRNA-mRNA modulatory axis was predicted by bioinformatics. The expression levels of FHL1 mRNA and protein in LUAD cells were, respectively, analyzed by qRT-PCR and western blot. Dual luciferase analysis was introduced to verify the interaction between miR-96-5p and FHL1. CCK-8, cell colony formation, and Transwell assays were utilized to analyze proliferation, colony formation, migration, and invasion of A549 cells. Results Expression of FHL1 mRNA and protein in LUAD tissue and cells was downregulated, which was linked with poor prognoses of patients. In addition, FHL1 overexpression could hamper colony formation, proliferation, invasion, and migration of LUAD cells. In addition, dual-luciferase analysis verified miR-96-5p as an upstream regulator of FHL1. Overexpression of miR-96-5p suppressed FHL1 expression in LUAD cells and promoted proliferation, invasion, and migration of LUAD cells, while overexpression of FHL1 could simultaneously restore the above-mentioned promoting effect. Conclusion MiR-96-5p fostered cell malignant behaviors by targeting FHL1. This research uncovered the regulatory mechanism of FHL1 in LUAD and offered optional therapeutic targets for LUAD patients.
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24
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Wu M, Qiu Q, Zhou Q, Li J, Yang J, Zheng C, Luo A, Li X, Zhang H, Cheng X, Lu W, Liu P, Lu B, Lu Y. circFBXO7/miR-96-5p/MTSS1 axis is an important regulator in the Wnt signaling pathway in ovarian cancer. Mol Cancer 2022; 21:137. [PMID: 35768865 PMCID: PMC9241180 DOI: 10.1186/s12943-022-01611-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 06/21/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND CircRNAs are a novel class of evolutionarily conserved noncoding RNA molecules that form covalently closed continuous loop structures without 5' caps and 3' poly(A) tails. Accumulating evidence suggests that circRNAs play important regulatory roles in cancer and are promising biomarkers for cancer diagnosis and prognosis, as well as targets for cancer therapy. In this study, we identify and explore the role of a novel circRNA, circFBXO7, in ovarian cancer. METHODS rRNA-depleted RNA-sequencing was performed to identify differentially expressed circRNAs between ovarian cancerous and normal tissues. qRT-PCR and single-molecule RNA in-situ hybridization was used to quantify circFBXO7 expression in tumor tissues. The association of circFBXO7 expression with patient prognosis was evaluated by Kaplan-Meier survival analysis. The biological function of circFBXO7 was also investigated using loss-of-function and gain-of-function assays in vivo and in vitro. Luciferase reporter and TOP/FOP-Flash reporter assays were then conducted together with RNA immunoprecipitation and western blot to assess the circFBXO7/miR-96-5p/MTSS1/Wnt/β-catenin axis. RESULTS circFBXO7 was downregulated in ovarian cancer which was associated with poor prognosis. Biologically, circFBXO7 overexpression significantly suppressed ovarian cancer cell proliferation, migration, and invasion in vitro, and inhibited tumor growth and metastasis in vivo, whereas its knockdown exerted an opposite role. Mechanistically, circFBXO7 functioned as a competing endogenous RNA for miR-96-5p to regulate the expression of MTSS1. Consequently, downregulation of MTSS1 led to excessive accumulation of β-catenin and increased phosphorylation of GSK3β, leading to the translocation of β-catenin to the nucleus, thereby activating the Wnt/β-catenin signaling pathway and ultimately promoting ovarian cancer progression. CONCLUSIONS Our findings indicate that circFBXO7 acts as a bone fide tumor suppressor in ovarian cancer and that the circFBXO7/miR-96-5p/MTSS1 axis is an important regulator in the Wnt/β-catenin signaling pathway which may provide a promising target for ovarian cancer therapy.
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Affiliation(s)
- Mengting Wu
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Qiongzi Qiu
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Qing Zhou
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Jia Li
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
| | - Juze Yang
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
| | - Chengcai Zheng
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Aoran Luo
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Xufan Li
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China
| | - Honghe Zhang
- Department of Pathology, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.,Cancer Center, Zhejiang University, Hangzhou, 310013, Zhejiang, China
| | - Xiaodong Cheng
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China.,Cancer Center, Zhejiang University, Hangzhou, 310013, Zhejiang, China
| | - Weiguo Lu
- Cancer Center, Zhejiang University, Hangzhou, 310013, Zhejiang, China.,Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Pengyuan Liu
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China. .,Cancer Center, Zhejiang University, Hangzhou, 310013, Zhejiang, China.
| | - Bingjian Lu
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China. .,Cancer Center, Zhejiang University, Hangzhou, 310013, Zhejiang, China.
| | - Yan Lu
- Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China. .,Cancer Center, Zhejiang University, Hangzhou, 310013, Zhejiang, China.
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25
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Chen C, Chang X, Zhang S, Zhao Q, Lei C. CircRNA CTNNB1 (circCTNNB1) ameliorates cerebral ischemia/reperfusion injury by sponging miR-96-5p to up-regulate scavenger receptor class B type 1 (SRB1) expression. Bioengineered 2022; 13:10258-10273. [PMID: 35435123 PMCID: PMC9162012 DOI: 10.1080/21655979.2022.2061304] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Emerging studies show that circRNA catenin beta 1 (circCTNNB1) plays a critical role in cancer. However, the expression and function of circCTNNB1 in cerebral ischemia/reperfusion injury (IRI) have not been reported. The present study discovered that circCTNNB1 and scavenger receptor class B type 1 (SRB1) expression levels were significantly down-regulated in mouse astrocytes (mAS) treated with oxygen glucose deprivation and reperfusion (OGD/R), and similar results were observed in a mouse middle cerebral artery occlusion model. Overexpression of circCTNNB1 alleviated cell apoptosis, oxidative stress and the inflammatory response induced by OGD/R in vitro. Up-regulation of circCTNNB1 increased SRB1 expression levels to protect mAS cells from OGD/R-induced damage. CircCTNNB1 and SRB1 interacted with miR-96-5p, and the overexpression of miR-96-5p efficiently reversed the function of circCTNNB1 in OGD/R-treated mAS cells. CircCTNNB1 protected against cerebral ischemia-reperfusion injury by up-regulating SRB1 in vivo. In conclusion, our findings suggest that circCTNNB1 acts as a competitive endogenous RNA for miR-96-5p to alleviate cerebral IRI, which provides novel evidence that circCTNNB1 and SRB1 may be biomarkers and therapeutic targets for cerebral IRI.
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Affiliation(s)
- Chun Chen
- Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xiaolong Chang
- Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Shifei Zhang
- Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qi Zhao
- Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chunyan Lei
- Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, China
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26
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Park SE, Kim W, Hong JY, Kang D, Park S, Suh J, You D, Park YY, Suh N, Hwang JJ, Kim CS. miR-96-5p targets PTEN to mediate sunitinib resistance in clear cell renal cell carcinoma. Sci Rep 2022; 12:3537. [PMID: 35241735 PMCID: PMC8894382 DOI: 10.1038/s41598-022-07468-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 02/14/2022] [Indexed: 11/18/2022] Open
Abstract
A multiple receptor tyrosine kinase inhibitor, sunitinib, is a first-line therapy for clear cell renal cell carcinoma (CCRCC). Unfortunately, it has the major challenges of low initial response rate and resistance after about one year of treatment. Here we evaluated a microRNA (miRNA) and its target responsible for sunitinib resistance. Using miRNA profiling, we identified miR-96-5p upregulation in tumors from sunitinib-resistant CCRCC patients. By bioinformatic analysis, PTEN was selected as a potential target of miR-96-5p, which showed low levels in tumors from sunitinib-resistant CCRCC patients. Furthermore, PTEN and miR-96-5p levels were negatively correlated in a large The Cancer Genome Atlas kidney renal clear cell carcinoma cohort and high miR-96 and low PTEN represented poor prognosis in this cohort. Additionally, four-week sunitinib treatment increased miR-96-5p and decreased PTEN only in tumors from a sunitinib-resistant patient-derived xenograft model. We found a novel miR-96-5p binding site in the PTEN 3′ UTR and confirmed direct repression by luciferase reporter assay. Furthermore, we demonstrated that repression of PTEN by miR-96-5p increased cell proliferation and migration in sunitinib-treated cell lines. These results highlight the direct suppression of PTEN by miR-96-5p and that high miR-96-5p and low PTEN are partially responsible for sunitinib resistance and poor prognosis in CCRCC.
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Affiliation(s)
- Sang Eun Park
- Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Wonju Kim
- Department of Pharmaceutical Engineering, College of Medical Sciences, Soon Chun Hyang University, 22, Soonchunhyang-ro, Shinchang, Asan, Chungnam, 31538, Republic of Korea.,Department of Medical Sciences, General Graduate School, Soon Chun Hyang University, Asan, Chungnam, 31538, Republic of Korea
| | - Ji-Ye Hong
- Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Dayeon Kang
- Department of Medical Sciences, General Graduate School, Soon Chun Hyang University, Asan, Chungnam, 31538, Republic of Korea
| | - Seulki Park
- Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.,Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Jungyo Suh
- Department of Urology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Dalsan You
- Department of Urology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Yun-Yong Park
- Department of Life Science, Chung-Ang University, Seoul, 06911, Republic of Korea
| | - Nayoung Suh
- Department of Pharmaceutical Engineering, College of Medical Sciences, Soon Chun Hyang University, 22, Soonchunhyang-ro, Shinchang, Asan, Chungnam, 31538, Republic of Korea. .,Department of Medical Sciences, General Graduate School, Soon Chun Hyang University, Asan, Chungnam, 31538, Republic of Korea.
| | - Jung Jin Hwang
- Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
| | - Choung-Soo Kim
- Department of Urology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
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27
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Schitcu VH, Raduly L, Nutu A, Zanoaga O, Ciocan C, Munteanu VC, Cojocneanu R, Petrut B, Coman I, Braicu C, Berindan-Neagoe I. MicroRNA Dysregulation in Prostate Cancer. Pharmgenomics Pers Med 2022; 15:177-193. [PMID: 35300057 PMCID: PMC8923686 DOI: 10.2147/pgpm.s348565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/17/2022] [Indexed: 12/17/2022] Open
Abstract
Prostate cancer biology is complex, and needs to be deciphered. The latest evidence reveals the significant role of non-coding RNAs, particularly microRNAs (miRNAs), as key regulatory factors in cancer. Therefore, the identification of altered miRNA patterns involved in prostate cancer will allow them to be used for development of novel diagnostic and prognostic biomarkers. Patients and Methods: We performed a miRNAs transcriptomic analysis, using microarray (10 matched pairs tumor tissue versus normal adjacent tissue, selected based on inclusion criteria), followed by overlapping with TCGA data. A total of 292 miRNAs were differentially expressed, with 125 upregulated and 167 downregulated in TCGA patients’ cohort with PRAD (prostate adenocarcinoma), respectively for the microarray experiments; 16 upregulated and 44 downregulated miRNAs were found in our cohort. To confirm our results obtained for tumor tissue, we performed validation with qRT-PCR at the tissue and plasma level of two selected transcripts, and finally, we focused on the identification of altered miRNAs involved in key biological processes. Results: A common signature identified a panel of 12 upregulated and 1 downregulated miRNA, targeting and interconnected in a network with the TP53, AGO2, BIRC5 gene and EGFR as a core element. Among this signature, the overexpressed transcripts (miR-20b-5p, miR-96-5p, miR-183-5p) and the downregulated miR-542-5p were validated by qRT-PCR in an additional patients’ cohort of 34 matched tumor and normal adjacent paired samples. Further, we performed the validation of the expression level for miR-20b-5p, miR-96-5p, miR-183-5p plasma, on the same patients’ cohort versus a healthy control group, confirming the overexpression of these transcripts in the PRAD group, demonstrating the liquid biopsy as a potential investigational tool in prostate cancer. Conclusion: In this pilot study, we provide evidence on miRNA dysregulation and its association with key functional components of the PRAD landscape, where an important role is acted by miR-20b-5p, miR-542-5p, or the oncogenic cluster miR-183-96-182.
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Affiliation(s)
- Vlad Horia Schitcu
- Research Center for Functional Genomics, Biomedicine, and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
- Department of Urology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400012, Romania
- Department of Urology, “Prof. Dr. Ion Chiricuta” Oncology Institute, Cluj-Napoca, Romania
| | - Lajos Raduly
- Research Center for Functional Genomics, Biomedicine, and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
| | - Andreea Nutu
- Research Center for Functional Genomics, Biomedicine, and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
| | - Oana Zanoaga
- Research Center for Functional Genomics, Biomedicine, and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
| | - Cristina Ciocan
- Research Center for Functional Genomics, Biomedicine, and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
| | - Vlad Cristian Munteanu
- Department of Urology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400012, Romania
- Department of Urology, “Prof. Dr. Ion Chiricuta” Oncology Institute, Cluj-Napoca, Romania
| | - Roxana Cojocneanu
- Research Center for Functional Genomics, Biomedicine, and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
| | - Bogdan Petrut
- Department of Urology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400012, Romania
- Department of Urology, “Prof. Dr. Ion Chiricuta” Oncology Institute, Cluj-Napoca, Romania
| | - Ioan Coman
- Department of Urology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400012, Romania
| | - Cornelia Braicu
- Research Center for Functional Genomics, Biomedicine, and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
- Correspondence: Cornelia Braicu, Research Center for Functional Genomics, Biomedicine, and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 23 Gh. Marinescu Street, Cluj-Napoca, 400337, Romania, Tel +40-264-597-256, Fax +40-264-597-257, Email ;
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine, and Translational Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
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Rahimi HR, Mojarrad M, Moghbeli M. MicroRNA-96: A therapeutic and diagnostic tumor marker. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:3-13. [PMID: 35656454 DOI: 10.22038/ijbms.2021.59604.13226] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/19/2021] [Indexed: 12/17/2022]
Abstract
Cancer has been always considered as one of the main human health challenges worldwide. One of the main causes of cancer-related mortality is late diagnosis in the advanced stages of the disease, which reduces the therapeutic efficiency. Therefore, novel non-invasive diagnostic methods are required for the early detection of tumors and improving the quality of life and survival in cancer patients. MicroRNAs (miRNAs) have pivotal roles in various cellular processes such as cell proliferation, motility, and neoplastic transformation. Since circulating miRNAs have high stability in body fluids, they can be suggested as efficient noninvasive tumor markers. MiR-96 belongs to the miR-183-96-182 cluster that regulates cell migration and tumor progression as an oncogene or tumor suppressor by targeting various genes in solid tumors. In the present review, we have summarized all of the studies that assessed the role of miR-96 during tumor progression. This review clarifies the molecular mechanisms and target genes recruited by miR-96 to regulate tumor progression and metastasis. It was observed that miR-96 mainly affects tumorigenesis by targeting the structural proteins and FOXO transcription factors.
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Affiliation(s)
- Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Mojarrad
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Dong Q, Long X, Cheng J, Wang W, Tian Q, Di W. LncRNA GAS5 suppresses ovarian cancer progression by targeting the miR-96-5p/PTEN axis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1770. [PMID: 35071464 PMCID: PMC8756204 DOI: 10.21037/atm-21-6134] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/08/2021] [Indexed: 12/03/2022]
Abstract
Background Long non-coding RNAs (lncRNAs) play critical roles in the occurrence and progression of various tumors, including ovarian cancer (OC). The lncRNA growth arrest-specific transcript 5 (GAS5) has been shown to be an important modulator in the growth and metastasis of OC cells. Our previous studies confirmed that GAS5 was down-regulated in OC; however, the potential underlying molecular mechanism underlying has not yet been elucidated. Methods We screened the Gene Expression Profiling Interactive Analysis (GEPIA) database for the expression of the lncRNA GAS5 in OC. Cell Counting Kit-8 (CCK-8), transwell assay, colony formation assay, flow cytometry analysis, and western blotting were applied to determine the various functions of GAS5 in OC progression. The competing endogenous RNA (ceRNA) mechanism was verified through bioinformatics analysis, dual-spectral luciferase reporter gene assay, and RNA immunoprecipitation assay (RIPA). Finally, the expression interactions between microRNA-96-5p, phosphatase and tensin homolog deleted on chromosome ten (PTEN), and GAS5 were measured. Results Our results demonstrated decreased expression levels of GAS5 and PTEN in OC samples and cell lines, while miR-96-5p was up-regulated when compared with the controls. GAS5 overexpression could significantly reduce OC cell proliferation and invasion ability via suppression of miR-96-5p expression. Moreover, GAS5 could influence the PTEN/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Conclusions Our study identified GAS5 as a ceRNA that can regulate the PTEN/AKT/mTOR axis by sponging miR-96-5p in OC.
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Affiliation(s)
- Qian Dong
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoran Long
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Cheng
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenjing Wang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qi Tian
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wen Di
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Kashani B, Zandi Z, Kaveh V, Pourbagheri-Sigaroodi A, Ghaffari SH, Bashash D. Small molecules with huge impacts: the role of miRNA-regulated PI3K pathway in human malignancies. Mol Biol Rep 2021; 48:8045-8059. [PMID: 34689281 DOI: 10.1007/s11033-021-06739-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 09/15/2021] [Indexed: 11/28/2022]
Abstract
Along with evolution, a considerable number of signaling cascades have evolved within cells to meet their multifaceted needs. Among transmitting molecules, phosphoinositide 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) have teamed up to build a signaling axis that effectively regulates various cellular processes including cell proliferation and migration. Given the extensive output of the PI3K/Akt/mTOR signaling axis, its aberrancy could subsequently lead to the formation of a wide range of human cancers spanning from hematologic malignancies to different types of solid tumors. Despite the high frequency of the PI3K pathway over-activation in most malignancies, mutations in the DNA sequence are not equally common. Such incompatibility sheds light on the possible effects of post-translational modification mechanisms that may take control of this pathway, some of the most important ones of which are through microRNAs (miRNAs or miRs). The present review is designed to take off the veil from the regulatory role of these small non-coding RNAs on the PI3K/Akt/mTOR signaling axis in carcinogenesis.
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Affiliation(s)
- Bahareh Kashani
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Zandi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Kaveh
- Department of Medical Oncology and Hematology, Iran University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Mazilu L, Suceveanu AI, Stanculeanu DL, Gheorghe AD, Fricatel G, Negru SM. Tumor microenvironment is not an 'innocent bystander' in the resistance to treatment of head and neck cancers (Review). Exp Ther Med 2021; 22:1128. [PMID: 34466142 PMCID: PMC8383332 DOI: 10.3892/etm.2021.10562] [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: 06/08/2021] [Accepted: 07/08/2021] [Indexed: 12/24/2022] Open
Abstract
Head and neck cancers are still one of the most common types of cancer in the world. They rank in the leading sixth place in terms of incidence globally, and the incidence continues to rise. The mortality rates remain at high levels. Pathological subclassification places squamous cell carcinoma of the head and neck (HNSCC) in the first place concerning the histological forms of head and neck cancers; a tumor with extremely aggressive behavior and high mortality rates. The tumor microenvironment is a very complex ecosystem of cellular and non-cellular components, characterized by unique features, that contribute to the appearance of immunosuppression and diminished anticancer immunity, impacting patient prognosis and treatment outcome. Despite many important advances in therapy, resistance to therapy represents a difficult challenge in HNSCC patients. Tumor progression, metastasis, and response to therapy are all influenced by the complex ecosystem represented by the tumor microenvironment and by the interactions between cellular and non-cellular components of this system. Therefore, the tumor microenvironment, in the light of recent data, is not an innocent bystander. In the last few years, there has been a sustained effort to characterize the tumor microenvironment, to identify targets of response and identify other mechanisms of tumor-specific immune responses, or to discover other biomarkers of response. There is an urgent need to understand how to properly select patients, the therapy sequence, and how to use feasible biomarkers that can help to identify the patient who may obtain the most benefit from available therapies.
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Affiliation(s)
- Laura Mazilu
- Department of Oncology, ‘Ovidius’ University, 900527 Constanţa, Romania
| | | | - Dana-Lucia Stanculeanu
- Department of Oncology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | | | - Gabriela Fricatel
- Department of Oncology, ‘Ovidius’ University, 900527 Constanţa, Romania
| | - Serban-Mircea Negru
- Department of Oncology, ‘Victor Babes’ University of Medicine and Pharmacy, 300041 Timisoara, Romania
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Wu F, Wu B, Zhang X, Yang C, Zhou C, Ren S, Wang J, Yang Y, Wang G. Screening of MicroRNA Related to Irradiation Response and the Regulation Mechanism of miRNA-96-5p in Rectal Cancer Cells. Front Oncol 2021; 11:699475. [PMID: 34458143 PMCID: PMC8386172 DOI: 10.3389/fonc.2021.699475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/13/2021] [Indexed: 01/03/2023] Open
Abstract
Neoadjuvant chemoradiotherapy has been widely used in the treatment of locally advanced rectal cancer due to the excellent advantages of irradiation in cancer therapy. Unfortunately, not every patient can benefit from this treatment, therefore, it is of great significance to explore biomarkers that can predict irradiation sensitivity. In this study, we screened microRNAs (miRNAs) which were positively correlated with irradiation resistance and found that miRNA-552 and miRNA-183 families were positively correlated with the irradiation resistance of rectal cancer, and found that high expression of miRNA-96-5p enhanced the irradiation resistance of rectal cancer cells through direct regulation of the GPC3 gene and abnormal activation of the canonical Wnt signal transduction pathway. Based on the radioreactivity results of patient-derived xenograft models, this is the first screening report for radio-resistant biomarkers in rectal cancer. Our results suggest that miRNA-96-5p expression is an important factor affecting the radiation response of colorectal cancer cells.
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Affiliation(s)
- Fengpeng Wu
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bingyue Wu
- Department of Oncology, Hebei Provincial People's Hospital, Graduate School of Hebei Medical University, Shijiazhuang, China
| | - Xiaoxiao Zhang
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Congrong Yang
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chaoxi Zhou
- Department of General Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shuguang Ren
- Laboratory Animal Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jun Wang
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yafan Yang
- Department of General Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Guiying Wang
- Department of General Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.,Department of General Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, China
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Hu W, Zhao Y, Su L, Wu Z, Jiang W, Jiang X, Liu M. Silencing the lncRNA NORAD inhibits EMT of head and neck squamous cell carcinoma stem cells via miR‑26a‑5p. Mol Med Rep 2021; 24:743. [PMID: 34435652 PMCID: PMC8430304 DOI: 10.3892/mmr.2021.12383] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 12/03/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells are closely associated with tumor metastasis or recurrence. According to previous literature reports, microRNA (miR)‑26a has an inhibitory effect on head and neck squamous cell carcinoma (HNSCC), and the long non‑coding RNA (lncRNA) non‑coding RNA activated by DNA damage (NORAD) has been found to interact with miR‑26a‑5p. The present study aimed to investigate the regulation and mechanism of NORAD and miR‑26a‑5p in the epithelial‑mesenchymal transition (EMT) of HNSCC stem cells. An ALDEFLUOR stem cell detection kit, a flow cytometer, a self‑renewal ability test and western blotting were used to sort and identify HNSCC stem cells. The ENCORI website and a dual‑luciferase assay were used to assess the relationship between genes. The mRNA and protein expression levels of NORAD, miR‑26a‑5p and EMT‑related genes were detected via reverse transcription‑quantitative PCR and western blotting. Functional experiments (MTT assay, flow cytometry, wound healing assay and Transwell assay) were conducted to analyze the effects of NORAD and miR‑26a‑5p on HNSCC stem cells. The successfully sorted aldehyde dehydrogenase (ALDH)+ cells had a self‑renewal capacity and displayed upregulated expression levels of CD44, Oct‑4 and Nanog. NORAD knockdown, achieved using small interfering (si)RNA, downregulated the expression levels of tumor markers in ALDH+ cells. siNORAD inhibited cell vitality, migration and invasion, as well as promoted apoptosis, increased the expression of epithelial cell markers and decreased the expression of interstitial cell markers in HNSCC stem cells. miR‑26a‑5p was a downstream gene of NORAD, and knockdown of miR‑26a‑5p partially offset the regulatory effect of siNORAD on HNSCC stem cells. Collectively, the present study demonstrated that NORAD knockdown attenuated the migration, invasion and EMT of HNSCC stem cells via miR‑26a‑5p.
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Affiliation(s)
- Weiming Hu
- Department of Otorhinolaryngology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Yong Zhao
- Department of Otorhinolaryngology, XIXI Hospital of Hangzhou, Hangzhou, Zhejiang 310012, P.R. China
| | - Lizhong Su
- Department of Otorhinolaryngology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Zuliang Wu
- Department of Otorhinolaryngology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Wenjing Jiang
- Department of Otorhinolaryngology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Xiaoze Jiang
- Department of Otorhinolaryngology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Ming Liu
- Department of Otorhinolaryngology, Zhejiang Hospital, Hangzhou, Zhejiang 310012, P.R. China
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Piotrowski I, Zhu X, Saccon TD, Ashiqueali S, Schneider A, de Carvalho Nunes AD, Noureddine S, Sobecka A, Barczak W, Szewczyk M, Golusiński W, Masternak MM, Golusiński P. miRNAs as Biomarkers for Diagnosing and Predicting Survival of Head and Neck Squamous Cell Carcinoma Patients. Cancers (Basel) 2021; 13:cancers13163980. [PMID: 34439138 PMCID: PMC8392400 DOI: 10.3390/cancers13163980] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/30/2021] [Accepted: 08/03/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. It arises from the epithelium of the upper aerodigestive tract. Increasing evidence suggests that there is a significant role of microRNAs in HNSCC formation and progression. The aim of this study was to explore and compare the expression of HNSCC related miRNAs in tumor vs neighboring healthy tissue of HNSCC patients with tumors located in either the oral cavity, oropharynx, or larynx. Our results demonstrated that expression of these miRNAs was significantly different not only between healthy and tumor tissues, but also among tumor locations. Further analysis indicated that microRNA expression could be used to distinguish between tumor and healthy tissues, and prognose the overall survival of patients. Abstract Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. These tumors originate from epithelial cells of the upper aerodigestive tract. HNSCC tumors in different regions can have significantly different molecular characteristics. While many microRNAs (miRNAs) have been found to be involved in the regulation of the carcinogenesis and pathogenesis of HNSCC, new HNSCC related miRNAs are still being discovered. The aim of this study was to explore potential miRNA biomarkers that can be used to diagnose HNSCC and prognose survival of HNSCC patients. For this purpose, we chose a panel of 12 miRNAs: miR-146a-5p, miR-449a, miR-126-5p, miR-34a-5p, miR-34b-5p, miR-34c-5p, miR-217-5p, miR-378c, miR-6510-3p, miR-96-5p, miR-149-5p, and miR-133a-5p. Expression of these miRNAs was measured in tumor tissue and neighboring healthy tissue collected from patients diagnosed with HNSCC (n = 79) in either the oral cavity, oropharynx, or larynx. We observed a pattern of differentially expressed miRNAs at each of these cancer locations. Our study showed that some of these miRNAs, separately or in combination, could serve as biomarkers distinguishing between healthy and tumor tissue, and their expression correlated with patients’ overall survival.
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Affiliation(s)
- Igor Piotrowski
- Radiobiology Lab, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland; (I.P.); (A.S.); (W.B.)
- Department of Electroradiology, Poznan University of Medical Sciences, ul. Garbary 15, 61-866 Poznan, Poland
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA; (X.Z.); (S.A.); (A.D.d.C.N.); (S.N.); (M.M.M.)
| | - Xiang Zhu
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA; (X.Z.); (S.A.); (A.D.d.C.N.); (S.N.); (M.M.M.)
| | - Tatiana Dandolini Saccon
- Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas 96010-610, Brazil;
| | - Sarah Ashiqueali
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA; (X.Z.); (S.A.); (A.D.d.C.N.); (S.N.); (M.M.M.)
| | - Augusto Schneider
- Faculdade de Nutrição, Universidade Federal de Pelotas, Pelotas 96010-610, Brazil;
| | - Allancer Divino de Carvalho Nunes
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA; (X.Z.); (S.A.); (A.D.d.C.N.); (S.N.); (M.M.M.)
| | - Sarah Noureddine
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA; (X.Z.); (S.A.); (A.D.d.C.N.); (S.N.); (M.M.M.)
| | - Agnieszka Sobecka
- Radiobiology Lab, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland; (I.P.); (A.S.); (W.B.)
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (M.S.); (W.G.)
| | - Wojciech Barczak
- Radiobiology Lab, Department of Medical Physics, Greater Poland Cancer Centre, 61-866 Poznan, Poland; (I.P.); (A.S.); (W.B.)
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (M.S.); (W.G.)
| | - Mateusz Szewczyk
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (M.S.); (W.G.)
- Department of Head and Neck Surgery, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Wojciech Golusiński
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (M.S.); (W.G.)
- Department of Head and Neck Surgery, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Michal M. Masternak
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA; (X.Z.); (S.A.); (A.D.d.C.N.); (S.N.); (M.M.M.)
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (M.S.); (W.G.)
| | - Paweł Golusiński
- Department of Otolaryngology and Maxillofacial Surgery, University of Zielona Gora, 65-417 Zielona Gora, Poland
- Department of Maxillofacial Surgery, Poznan University of Medical Sciences, 61-701 Poznan, Poland
- Correspondence:
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Overview of Oral Potentially Malignant Disorders: From Risk Factors to Specific Therapies. Cancers (Basel) 2021; 13:cancers13153696. [PMID: 34359597 PMCID: PMC8345150 DOI: 10.3390/cancers13153696] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/09/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a very aggressive cancer, representing one of the most common malignancies worldwide. Oral potentially malignant disorders (OPMDs) regroup a variegate set of different histological lesions, characterized by the potential capacity to transform in OSCC. Most of the risk factors associated with OSCC are present also in OPMDs' development; however, the molecular mechanisms and steps of malignant transformation are still unknown. Treatment of OSCC, including surgery, systemic therapy and radiotherapy (alone or in combination), has suffered a dramatic change in last years, especially with the introduction of immunotherapy. However, most cases are diagnosed during the advanced stage of the disease, decreasing drastically the survival rate of the patients. Hence, early diagnosis of premalignant conditions (OPMDs) is a priority in oral cancer, as well as a massive education about risk factors, the understanding of mechanisms involved in malignant progression and the development of specific and more efficient therapies. The aim of this article is to review epidemiological, clinical, morphological and molecular features of OPMDs, with the purpose to lay the foundation for an exhaustive comprehension of these lesions and their ability of malignant transformation and for the development of more effective and personalized treatments.
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Tang G, Liu L, Xiao Z, Wen S, Chen L, Yang P. CircRAB3IP upregulates twist family BHLH transcription factor (TWIST1) to promote osteosarcoma progression by sponging miR-580-3p. Bioengineered 2021; 12:3385-3397. [PMID: 34224315 PMCID: PMC8806556 DOI: 10.1080/21655979.2021.1948487] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Circular RNAs (circ RNAs) have been found to play an important role in cancer development. However, the role of circRAB3IP in osteosarcoma (OS) is unclear. In the present study, We found that circRAB3IP was highly expressed in OS tissues and OS cells. High levels of circRAB3IP was correlated with advanced TNM stage, distant metastasis. CircRAB3IP knockdown inhibited cell proliferation, migration, and invasion. Moreover, circRAB3IP directly binds to miR-580-3p. TWIST1 is directly targeted by miR-580-3p. We also demonstrated that circRAB3IP act as the sponge of miR-580-3p to promote TWIST1 expression. CircRAB3IP promotes OS cells proliferation, migration, and invasion through modulating miR-580-3p/TWIST1 axis. Moreover, circRAB3IP facilitated tumor formation in vivo. Our findings suggested that circRAB3IP acts as an oncogene in OS by regulating miR-580-3p/TWIST1 axis.
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Affiliation(s)
- Guojun Tang
- Department of Spine Surgery, The Second Affiliated Hospital, University of South China, Hengyang, Hunan, P.R. China
| | - Linghua Liu
- Department of Nursing, Hubei College of Chinese Medicine, Jingzhou, Hubei, P.R. China
| | - Zhihong Xiao
- Department of Spine Surgery, The Second Affiliated Hospital, University of South China, Hengyang, Hunan, P.R. China
| | - Shuo Wen
- Department of Breast and Thyroid Surgery, Union Hospital West Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Liangyuan Chen
- Department of Spine Surgery, The Second Affiliated Hospital, University of South China, Hengyang, Hunan, P.R. China
| | - Peng Yang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
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Vahabi M, Blandino G, Di Agostino S. MicroRNAs in head and neck squamous cell carcinoma: a possible challenge as biomarkers, determinants for the choice of therapy and targets for personalized molecular therapies. Transl Cancer Res 2021; 10:3090-3110. [PMID: 35116619 PMCID: PMC8797920 DOI: 10.21037/tcr-20-2530] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/10/2020] [Indexed: 12/11/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) are referred to a group of heterogeneous cancers that include structures of aerodigestive tract such as oral and nasal cavity, salivary glands, oropharynx, pharynx, larynx, paranasal sinuses, and local lymph nodes. HNSCC is characterized by frequent alterations of several genes such as TP53, PIK3CA, CDKN2A, NOTCH1, and MET as well as copy number increase in EGFR, CCND1, and PIK3CA. These genomic alterations play a role in terms of resistance to chemotherapy, molecular targeted therapy, and prediction of patient outcome. MicroRNAs (miRNAs) are small single-stranded noncoding RNAs which are about 19-25 nucleotides. They are involved in the tumorigenesis of HNSCC including dysregulation of cell survival, proliferation, cellular differentiation, adhesion, and invasion. The discovery of the stable presence of the miRNAs in all human body made them attractive biomarkers for diagnosis and prognosis or as targets for novel therapeutic ways, enabling personalized treatment for HNSCC. In recent times the number of papers concerning the characterization of miRNAs in the HNSCC tumorigenesis has grown a lot. In this review, we discuss the very recent studies on different aspects of miRNA dysregulation with their clinical significance and we apologize for the many past and most recent works that have not been mentioned. We also discuss miRNA-based therapy that are being tested on patients by clinical trials.
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Affiliation(s)
- Mahrou Vahabi
- IRCCS Regina Elena National Cancer Institute, Oncogenomic and Epigenetic Laboratory, via Elio Chianesi, Rome, Italy
| | - Giovanni Blandino
- IRCCS Regina Elena National Cancer Institute, Oncogenomic and Epigenetic Laboratory, via Elio Chianesi, Rome, Italy
| | - Silvia Di Agostino
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, viale Europa, Catanzaro, Italy
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Micro-RNA 122 and micro-RNA 96 affected human osteosarcoma biological behavior and associated with prognosis of patients with osteosarcoma. Biosci Rep 2021; 40:226707. [PMID: 33078195 PMCID: PMC7736625 DOI: 10.1042/bsr20201529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/20/2020] [Accepted: 07/29/2020] [Indexed: 11/17/2022] Open
Abstract
Osteosarcoma (OS) is the most common bone malignancy in both children and adolescents. In the present study, we aimed to explore the association of miRNA-122 and miRNA-96 expression with the clinical characteristics and prognosis of patients with osteosarcoma. The expression of miRNA-122 and miRNA-96 in human osteosarcoma cell lines and tissues were detected in the present study. Reverse transcriptase-PCR (RT-PCR) was used to determine the expression levels of miRNA-122 and miRNA-96 in 68 human OS samples. We found that MiRNA-122 and miRNA-96 were widely up-regulated in osteosarcoma, gastric cancer and pancreatic cancer. In HOS, Saos-2 and U2OS osteosarcoma cells, miRNA-122 and miRNA-96 were up-regulated significantly, while down-regulated in MG-63 cells. After further investigation, we found that miRNA-122 and miRNA-96 concentrations were significantly higher in the tumor tissues than those in the normal tissues (P<0.01). Moreover, the cell proliferation of LV-miRNA-122-RNAi and LV-miRNA-96-RNAi transfected SaOS2 was significantly decreased compared with the LV- miRNA-122-RNAi-CN and LV- miRNA-96-RNAi group. After adjusting for competing risk factors, we found combined high miRNA-122 and miRNA-96 expression was identified as independent predictor of overall survival.
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Chen Y, Cui J, Gong Y, Wei S, Wei Y, Yi L. MicroRNA: a novel implication for damage and protection against ionizing radiation. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:15584-15596. [PMID: 33533004 PMCID: PMC7854028 DOI: 10.1007/s11356-021-12509-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 01/12/2021] [Indexed: 04/16/2023]
Abstract
Ionizing radiation (IR) is a form of high energy. It poses a serious threat to organisms, but radiotherapy is a key therapeutic strategy for various cancers. It is significant to reduce radiation injury but maximize the effect of radiotherapy. MicroRNAs (miRNAs) are posttranscriptionally regulatory factors involved in cellular radioresponse. In this review, we show how miRNAs regulate important genes on cellular response to IR-induced damage and how miRNAs participate in IR-induced carcinogenesis. Additionally, we summarize the experimental and clinical evidence for miRNA involvement in radiotherapy and discuss their potential for improvement of radiotherapy. Finally, we highlight the role that miRNAs play in accident exposure to IR or radiotherapy as predictive biomarker. miRNA therapeutics have shown great perspective in radiobiology; miRNA may become a novel strategy for damage and protection against IR.
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Affiliation(s)
- Yonglin Chen
- Hengyang Medical College, Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, University of South China, Hengyang, 421001, Hunan Province, People's Republic of China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Jian Cui
- Hengyang Medical College, Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, University of South China, Hengyang, 421001, Hunan Province, People's Republic of China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Yaqi Gong
- Hengyang Medical College, Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, University of South China, Hengyang, 421001, Hunan Province, People's Republic of China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Shuang Wei
- Hengyang Medical College, Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, University of South China, Hengyang, 421001, Hunan Province, People's Republic of China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Yuanyun Wei
- Hengyang Medical College, Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, University of South China, Hengyang, 421001, Hunan Province, People's Republic of China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Lan Yi
- Hengyang Medical College, Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, University of South China, Hengyang, 421001, Hunan Province, People's Republic of China.
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, 421001, Hunan Province, People's Republic of China.
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Circulating Exosomal miR-96 as a Novel Biomarker for Radioresistant Non-Small-Cell Lung Cancer. JOURNAL OF ONCOLOGY 2021; 2021:5893981. [PMID: 33727921 PMCID: PMC7937465 DOI: 10.1155/2021/5893981] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 01/24/2021] [Accepted: 01/31/2021] [Indexed: 12/17/2022]
Abstract
Patients with non-small-cell lung cancer (NSCLC) frequently develop radioresistance, resulting in poor response to radiation and unfavourable prognosis. Early detection of radioresistance hence can guide the adjustment of treatment regimens in time. Exosomes are lipid bilayer-enclosed vesicles with sub-micrometer size that are released by various cells. Exosomes contain a tissue-specific signature wherein a variety of proteins and nucleic acids are selectively packaged. Growing evidence shows exosomes are involved in cancer pathophysiology and exosomes as the latest addition to the liquid biopsy portfolio have been used in cancer diagnosis. Compared to cell free RNA, exosomal lipid envelope can effectively protect RNA cargo against degradation. Therefore, exosomes may hold great promise for the identification of radioresistance. Here, we report six plasma exosomal miRNAs could be used to distinguish radioresistant NSCLC patients from radiosensitive NSCLC patients and to evaluate the prognosis of NSCLC. Samples were obtained from 52 NSCLC patients with or without radioresistance and 45 age-matched healthy volunteers. Exosomes in 1 ml plasma were isolated followed by extraction of small RNA. The expression levels of miRNAs were determined by quantitative real-time PCR. Potential miRNA markers were further evaluated in additional 52 NSCLC patients. We found exosomal miR-1246 and miR-96 are significantly overexpressed in NSCLC patients. Moreover, exosomal miR-96 in patients with radioresistant NSCLC is significantly higher than that of controls. Exosomal miR-96 also demonstrates a significant correlation with vascular invasion and poor overall survival. Altogether, our results indicate that exosomal miR-96 could be a non-invasive diagnostic and prognostic marker of radioresistant NSCLC.
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Ortiz-Cuaran S, Bouaoud J, Karabajakian A, Fayette J, Saintigny P. Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers. Front Oncol 2021; 11:614332. [PMID: 33718169 PMCID: PMC7947611 DOI: 10.3389/fonc.2021.614332] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 01/08/2021] [Indexed: 12/24/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most incident cancer worldwide. More than half of HNSCC patients experience locoregional or distant relapse to treatment despite aggressive multimodal therapeutic approaches that include surgical resection, radiation therapy, and adjuvant chemotherapy. Before the arrival of immunotherapy, systemic chemotherapy was previously employed as the standard first-line protocol with an association of cisplatin or carboplatin plus 5-fluorouracil plus cetuximab (anti-EFGR antibody). Unfortunately, acquisition of therapy resistance is common in patients with HNSCC and often results in local and distant failure. Despite our better understanding of HNSCC biology, no other molecular-targeted agent has been approved for HNSCC. In this review, we outline the mechanisms of resistance to the therapeutic strategies currently used in HNSCC, discuss combination treatment strategies to overcome them, and summarize the therapeutic regimens that are presently being evaluated in early- and late-phase clinical trials.
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Affiliation(s)
- Sandra Ortiz-Cuaran
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
| | - Jebrane Bouaoud
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
- Department of Maxillofacial Surgery and Stomatology, Pitié-Salpêtrière University Hospital, Pierre et Marie Curie University, Sorbonne University, Paris, France
| | - Andy Karabajakian
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Jérôme Fayette
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Pierre Saintigny
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
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Qi CL, Sheng JF, Huang ML, Zou Y, Wang YP, Wang F, Zeng F, Hua QQ, Chen SM. Integrated analysis of deregulation microRNA expression in head and neck squamous cell carcinoma. Medicine (Baltimore) 2021; 100:e24618. [PMID: 33578572 PMCID: PMC7886409 DOI: 10.1097/md.0000000000024618] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 01/08/2021] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) play critical roles in carcinogenesis and development of cancers. In this study, we analyzed the eccentrically expressed miRNAs in head and neck squamous cell carcinoma (HNSCC) tissues based on the miRNA-Seq data of HNSCC patients available in the Cancer Genome Atlas database. Aberrant expression of 2589 miRNAs was detected in HNSCC tissues (1128 downregulated and 1461 upregulated). The differential expression levels of the miRNAs were further validated by analysis of 25 HNSCC samples and paired control tissues and compared with the Gene Expression Omnibus database to determine the candidate miRNAs. Quantitative reverse transcription polymerase chain reaction was used to compare the expression of these candidate miRNAs between 22 fresh HNSCC tissue samples and 11 control samples. In addition, the relationship between the expression of these candidate miRNAs and Tumor, Node, Metastases staging of HNSCC was analyzed. Compared with the expression in control tissues, the levels of hsa-miR-410-3p, hsa-miR-411-5p, hsa-miR-125b-2-3p, and hsa-miR-99a-3p were significantly lower in HNSCC. According to the Cancer Genome Atlas dataset analyzed, all 4 miRNAs were shown to inhibit tumor progression (T stage), positive lymph node metastasis (N stage), and distant metastasis (M stage) in HNSCC. Kyoto Encyclopedia of Genes and Genomes analysis showed that genes regulated by these 4 miRNAs were enriched in certain pathways, including the transforming growth factor-β signaling pathway and the Hippo pathway. Enriched gene ontology terms mainly included regulation of transcription, cell proliferation, and apoptosis, which are well-characterized functions of miRNAs. Moreover, all 4 miRNAs inhibited the progression of primary tumors (T stage) and metastasis of regional lymph nodes (N stage). The top 4 aberrantly expressed miRNAs identified in this study have great clinical value in developing strategies for early diagnosis and treatment of HNSCC. More intensive studies are required to elucidate the mechanism underlying the roles of these miRNAs in HNSCC.
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Affiliation(s)
- Cheng-Lin Qi
- Department of Otolaryngology-Head and Neck Surgery
| | | | | | - You Zou
- Department of Otolaryngology-Head and Neck Surgery
| | | | - Fei Wang
- Department of Otolaryngology-Head and Neck Surgery
| | - Feng Zeng
- Department of Otolaryngology-Head and Neck Surgery
| | - Qing-Quan Hua
- Department of Otolaryngology-Head and Neck Surgery
- Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. China
| | - Shi-Ming Chen
- Department of Otolaryngology-Head and Neck Surgery
- Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. China
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Zhang X, Yang J. Role of Non-coding RNAs on the Radiotherapy Sensitivity and Resistance of Head and Neck Cancer: From Basic Research to Clinical Application. Front Cell Dev Biol 2021; 8:637435. [PMID: 33644038 PMCID: PMC7905100 DOI: 10.3389/fcell.2020.637435] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 12/23/2020] [Indexed: 12/14/2022] Open
Abstract
Head and neck cancers (HNCs) rank as the sixth common and the seventh leading cause of cancer-related death worldwide, with an estimated incidence of 600,000 cases and 40-50% mortality rate every year. Radiotherapy is a common local therapeutic modality for HNC mainly through the function of ionizing radiation, with approximately 60% of patients treated with radiotherapy or chemoradiotherapy. Although radiotherapy is more advanced and widely used in clinical practice, the 5-year overall survival rates of locally advanced HNCs are still less than 40%. HNC cell resistance to radiotherapy remains one of the major challenges to improve the overall survival in HNC patients. Non-coding RNAs (ncRNAs) are newly discovered functional small RNA molecules that are different from messenger RNAs, which can be translated into a protein. Many previous studies have reported the dysregulation and function of ncRNAs in HNC. Importantly, researchers reported that several ncRNAs were also dysregulated in radiotherapy-sensitive or radiotherapy-resistant HNC tissues compared with the normal cancer tissues. They found that ectopically elevating or knocking down expression of some ncRNAs could significantly influence the response of HNC cancer cells to radiotherapy, indicating that ncRNAs could regulate the sensitivity of cancer cells to radiotherapy. The implying mechanism for ncRNAs in regulating radiotherapy sensitivity may be due to its roles on affecting DNA damage sensation, inducing cell cycle arrest, regulating DNA damage repair, modulating cell apoptosis, etc. Additionally, clinical studies reported that in situ ncRNA expression in HNC tissues may predict the response of radiotherapy, and circulating ncRNA from body liquid serves as minimally invasive therapy-responsive and prognostic biomarkers in HNC. In this review, we aimed to summarize the current function and mechanism of ncRNAs in regulating the sensitivity of HNC cancer cells to radiotherapy and comprehensively described the state of the art on the role of ncRNAs in the prognosis prediction, therapy monitoring, and prediction of response to radiotherapy in HNC.
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Affiliation(s)
- Xixia Zhang
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jing Yang
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, China
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Ding L, Fang Y, Li Y, Hu Q, Ai M, Deng K, Huang X, Xin H. AIMP3 inhibits cell growth and metastasis of lung adenocarcinoma through activating a miR-96-5p-AIMP3-p53 axis. J Cell Mol Med 2021; 25:3019-3030. [PMID: 33538115 PMCID: PMC7957209 DOI: 10.1111/jcmm.16344] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 12/24/2020] [Accepted: 01/15/2021] [Indexed: 12/18/2022] Open
Abstract
Aminoacyl‐tRNA synthetase‐interacting multifunctional protein‐3 (AIMP3) is a tumour suppressor, however, the roles of AIMP3 in non‐small cell lung cancer (NSCLC) are not explored yet. Here, we reported that AIMP3 significantly inhibited the cell growth and metastasis of NSCLC (lung adenocarcinoma) in vitro and in vivo. We have firstly identified that AIMP3 was down‐regulated in human NSCLC tissues compared with adjacent normal lung tissues using immunohistochemistry and western blot assays. Overexpression of AIMP3 markedly suppressed the proliferation and migration of cancer cells in a p53‐dependent manner. Furthermore, we observed that AIMP3 significantly suppressed tumour growth and metastasis of A549 cells in xenograft nude mice. Mechanically, we identified that AIMP3 was a direct target of miR‐96‐5p, and we also observed that there was a negative correlation between AIMP3 and miR‐96‐5p expression in paired NSCLC clinic samples. Ectopic miR‐96‐5p expression promoted the proliferation and migration of cancer cells in vitro and tumour growth and metastasis in vivo which partially depended on AIMP3. Taken together, our results demonstrated that the axis of miR‐96‐5p‐AIMP3‐p53 played an important role in lung adenocarcinoma, which may provide a new strategy for the diagnosis and treatment of NSCLC.
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Affiliation(s)
- Liting Ding
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, the Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Yang Fang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, the Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Yong Li
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qinghua Hu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, the Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Meiling Ai
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, the Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Keyu Deng
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, the Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Xuan Huang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, the Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Hongbo Xin
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, the Institute of Translational Medicine, Nanchang University, Nanchang, China
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Zhan JB, Zheng J, Zeng LY, Fu Z, Huang QJ, Wei X, Zeng M. Downregulation of miR-96-5p Inhibits mTOR/NF-κb Signaling Pathway via DEPTOR in Allergic Rhinitis. Int Arch Allergy Immunol 2021; 182:210-219. [PMID: 33477144 DOI: 10.1159/000509403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 06/14/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND This study aims to investigate the regulatory effect of microRNA-96-5p (miR-96-5p) in the pathophysiological process of allergic rhinitis (AR). METHODS Nasal mucosal tissue samples were collected from AR patients and healthy controls. An in vitro AR model was established by stimulating human nasal epithelial cells (HNECs) with interleukin (IL)-13. The expressions of target genes and proteins were measured by qPCR, Western blot, or ELISA. Dual-luciferase reporter assay and pull-down assay were performed to confirm the interaction between miR-96-5p and DEP domain-containing mammalian target of rapamycin-interacting protein (DEPTOR). RESULTS The level of miR-96-5p was increased while the expression of DEPTOR was decreased in AR patients. The expressions of proinflammatory cytokines were markedly increased and the mammalian target of rapamycin (mTOR)/NF-κB pathway was activated in HNECs following IL-13 stimulation. miR-96-5p downregulation alleviated the stimulated function by IL-13. DEPTOR was the target of miR-96-5p. Knockdown of DEPTOR reversed the function of miR-96-5p inhibitor on IL-13-stimulated HNECs. CONCLUSIONS The current study showed that miR-96-5p and DEPTOR were aberrantly expressed in AR nasal mucosa. miR-96-5p knockdown inhibited the production of inflammatory cytokines and the activation of mTOR/NF-κB pathway via targeting DEPTOR. These findings suggested that miR-96-5p might be used as a diagnostic marker and therapeutic target for the treatment of AR.
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Affiliation(s)
- Jia-Bin Zhan
- Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China
| | - Jing Zheng
- Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China
| | - Lian-Ya Zeng
- Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China
| | - Zhi Fu
- Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China
| | - Qiu-Ju Huang
- Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China
| | - Xin Wei
- Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China,
| | - Min Zeng
- Medical Center, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China
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Bhat AA, Yousuf P, Wani NA, Rizwan A, Chauhan SS, Siddiqi MA, Bedognetti D, El-Rifai W, Frenneaux MP, Batra SK, Haris M, Macha MA. Tumor microenvironment: an evil nexus promoting aggressive head and neck squamous cell carcinoma and avenue for targeted therapy. Signal Transduct Target Ther 2021; 6:12. [PMID: 33436555 PMCID: PMC7804459 DOI: 10.1038/s41392-020-00419-w] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/02/2020] [Accepted: 10/15/2020] [Indexed: 12/17/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a very aggressive disease with a poor prognosis for advanced-stage tumors. Recent clinical, genomic, and cellular studies have revealed the highly heterogeneous and immunosuppressive nature of HNSCC. Despite significant advances in multimodal therapeutic interventions, failure to cure and recurrence are common and account for most deaths. It is becoming increasingly apparent that tumor microenvironment (TME) plays a critical role in HNSCC tumorigenesis, promotes the evolution of aggressive tumors and resistance to therapy, and thereby adversely affects the prognosis. A complete understanding of the TME factors, together with the highly complex tumor-stromal interactions, can lead to new therapeutic interventions in HNSCC. Interestingly, different molecular and immune landscapes between HPV+ve and HPV-ve (human papillomavirus) HNSCC tumors offer new opportunities for developing individualized, targeted chemoimmunotherapy (CIT) regimen. This review highlights the current understanding of the complexity between HPV+ve and HPV-ve HNSCC TME and various tumor-stromal cross-talk modulating processes, including epithelial-mesenchymal transition (EMT), anoikis resistance, angiogenesis, immune surveillance, metastatic niche, therapeutic resistance, and development of an aggressive tumor phenotype. Furthermore, we summarize the recent developments and the rationale behind CIT strategies and their clinical applications in HPV+ve and HPV-ve HNSCC.
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Affiliation(s)
- Ajaz A Bhat
- Functional and Molecular Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Parvaiz Yousuf
- Department of Zoology, School of Life Sciences, Central University of Kashmir, Ganderbal, Jammu & Kashmir, India
| | - Nissar A Wani
- Functional and Molecular Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Arshi Rizwan
- Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
| | - Shyam S Chauhan
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Mushtaq A Siddiqi
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Jammu & Kashmir, India
| | - Davide Bedognetti
- Laboratory of Cancer Immunogenomics, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Wael El-Rifai
- Department of Surgery, University of Miami, Miami, FL, USA
| | | | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.,Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Mohammad Haris
- Functional and Molecular Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar. .,Laboratory Animal Research Center, Qatar University, Doha, Qatar.
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Jammu & Kashmir, India.
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Ebahimzadeh K, Shoorei H, Mousavinejad SA, Anamag FT, Dinger ME, Taheri M, Ghafouri-Fard S. Emerging role of non-coding RNAs in response of cancer cells to radiotherapy. Pathol Res Pract 2020; 218:153327. [PMID: 33422780 DOI: 10.1016/j.prp.2020.153327] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 12/23/2020] [Accepted: 12/23/2020] [Indexed: 01/03/2023]
Abstract
Radiotherapy is an effective method for treatment of a large proportion of human cancers. Yet, the efficacy of this method is precluded by the induction of radioresistance in tumor cells and the radiation-associated injury of normal cells surrounding the field of radiation. These restrictions necessitate the introduction of modalities for either radiosensitization of cancer cells or protection of normal cells against adverse effects of radiation. Non-coding RNAs (ncRNAs) have essential roles in the determination of radiosensitivity. Moreover, ncRNAs can modulate radiation-induced side effects in normal cells. Several microRNAs (miRNAs) such as miR-620, miR-21 and miR-96-5p confer radioresistance, while other miRNAs including miR-340/ 429 confer radiosensitivity. The expression levels of a number of miRNAs are associated with radiation-induced complications such as lung fibrosis or oral mucositis. The expression patterns of several long non-coding RNAs (lncRNAs) such as MALAT1, LINC00630, HOTAIR, UCA1 and TINCR are associated with response to radiotherapy. Taken together, lncRNAs and miRNAs contribute both in modulation of response of cancer cells to radiotherapy and in protection of normal cells from the associated side effects. The current review provides an overview of the roles of these transcripts in these aspects.
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Affiliation(s)
- Kaveh Ebahimzadeh
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Seyed Ali Mousavinejad
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Marcel E Dinger
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Soudeh Ghafouri-Fard
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Romanowska K, Sobecka A, Rawłuszko-Wieczorek AA, Suchorska WM, Golusiński W. Head and Neck Squamous Cell Carcinoma: Epigenetic Landscape. Diagnostics (Basel) 2020; 11:diagnostics11010034. [PMID: 33375464 PMCID: PMC7823717 DOI: 10.3390/diagnostics11010034] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/21/2020] [Accepted: 12/24/2020] [Indexed: 02/06/2023] Open
Abstract
Head and neck squamous carcinoma (HNSCC) constitutes the sixth most prevalent cancer worldwide. The molecular pathogenesis of HNSCC includes disorders in cell cycle, intercellular signaling, proliferation, squamous cell differentiation and apoptosis. In addition to the genetic mutations, changes in HNSCC are also characterized by the accumulation of epigenetic alterations such as DNA methylation, histone modifications, non-coding RNA activity and RNA methylation. In fact, some of them may promote cancer formation and progression by controlling the gene expression machinery, hence, they could be used as biomarkers in the clinical surveillance of HNSCC or as targets for therapeutic strategies. In this review, we focus on the current knowledge regarding epigenetic modifications observed in HNSCC and its predictive value for cancer development.
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Affiliation(s)
- Kamila Romanowska
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, 61-866 Poznan, Poland; (A.S.); (W.G.)
- Department of Medical Physics, Radiobiology Laboratory, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, 61-866 Poznan, Poland;
- Correspondence:
| | - Agnieszka Sobecka
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, 61-866 Poznan, Poland; (A.S.); (W.G.)
- Department of Medical Physics, Radiobiology Laboratory, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, 61-866 Poznan, Poland;
| | | | - Wiktoria M. Suchorska
- Department of Medical Physics, Radiobiology Laboratory, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, 61-866 Poznan, Poland;
| | - Wojciech Golusiński
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, 61-866 Poznan, Poland; (A.S.); (W.G.)
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Zhao L, Tian C, Xiao E, Du J, Liang J, Chen X, Chi W. Clinical significance and potential mechanisms of miR-223-3p and miR-204-5p in squamous cell carcinoma of head and neck: a study based on TCGA and GEO. Open Med (Wars) 2020; 15:728-738. [PMID: 33336030 PMCID: PMC7712329 DOI: 10.1515/med-2020-0146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/10/2020] [Accepted: 06/21/2020] [Indexed: 01/13/2023] Open
Abstract
Objective To explore the clinical significance and mechanisms of altered miRNAs in squamous cell carcinoma of head and neck (SCCHN) and provide references for SCCHN diagnosis and prognosis. Method Differential expressed miRNAs (DEMs) in SCCHN were screened through gene expression omnibus (GEO) DataSets and verified by the cancer genome atlas (TCGA) database. Next, the overall survival analysis, receiver operating characteristics, and clinical correlation analysis were adopted to filter the miRNAs with diagnostic and prognostic values. Finally, functional enrichment analyses were conducted for inquiring into the mechanisms of miRNAs. Results Total 103 DEMs (p < 0.05, fold change ≥ 2) in SCCHN were screened out from GSE124566. Partly, the expression levels of the selected (12/17) miRNAs were verified by TCGA. Followed, of the 12 miRNAs, two miRNA expression levels were associated with the overall survival, and five miRNAs showed diagnostic values (AUC ≥ 0.85). Besides, miR-223-3p and miR-204-5p expression levels were correlated to certain clinical features. Epithelial–mesenchymal transition (EMT) related biological process and energy metabolism controlling related AMPK signaling pathway might mediate the roles of miR-223-3p and miR-204-5p, respectively. Conclusion With diagnostic and prognostic values, miR-223-3p and miR-204-5p may be involved in the progression of SCCHN through EMT-related biological process and energy balance related AMPK signaling pathway, respectively.
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Affiliation(s)
- Lei Zhao
- Department of Otorhinolaryngology, The Affiliated Hospital of Hebei University, Baoding, No. 212 Yuhua Road, Hebei Province, 071000, China
| | - Congzhe Tian
- Department of Otorhinolaryngology, The Affiliated Hospital of Hebei University, Baoding, No. 212 Yuhua Road, Hebei Province, 071000, China
| | - Erbin Xiao
- Department of Otorhinolaryngology, The Affiliated Hospital of Hebei University, Baoding, No. 212 Yuhua Road, Hebei Province, 071000, China
| | - Jinduo Du
- Department of Otorhinolaryngology, The Affiliated Hospital of Hebei University, Baoding, No. 212 Yuhua Road, Hebei Province, 071000, China
| | - Jingwei Liang
- Department of Otorhinolaryngology, The Affiliated Hospital of Hebei University, Baoding, No. 212 Yuhua Road, Hebei Province, 071000, China
| | - Xianghong Chen
- Department of Otorhinolaryngology, The Affiliated Hospital of Hebei University, Baoding, No. 212 Yuhua Road, Hebei Province, 071000, China
| | - Weiwei Chi
- Department of Otorhinolaryngology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, 050031, China
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50
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Carron J, Torricelli C, Silva JK, Queiroz GSR, Ortega MM, Lima CSP, Lourenço GJ. microRNAs deregulation in head and neck squamous cell carcinoma. Head Neck 2020; 43:645-667. [PMID: 33159410 DOI: 10.1002/hed.26533] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 09/30/2020] [Accepted: 10/23/2020] [Indexed: 12/24/2022] Open
Abstract
Head and neck (HN) squamous cell carcinoma (SCC) is the eighth most common human cancer worldwide. Besides tobacco and alcohol consumption, genetic and epigenetic alterations play an important role in HNSCC occurrence and progression. microRNAs (miRNAs) are small noncoding RNAs that regulate cell cycle, proliferation, development, differentiation, and apoptosis by interfering in gene expression. Expression profiling of miRNAs showed that some miRNAs are upregulated or downregulated in tumor cells when compared with the normal cells. The present review focuses on the role of miRNAs deregulations in HNSCC, enrolled in risk, development, outcome, and therapy sensitivity. Moreover, the influence of single nucleotide variants in miRNAs target sites, miRNAs seed sites, and miRNAs-processing genes in HNSCC was also revised. Due to its potential for cancer diagnosis, progression, and as a therapeutic target, miRNAs may bring new perspectives in HNSCC understanding and therapy, especially for those patients with no or insufficient treatment options.
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Affiliation(s)
- Juliana Carron
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Caroline Torricelli
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Janet K Silva
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Gabriela S R Queiroz
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Manoela M Ortega
- Laboratory of Cell and Molecular Tumor Biology and Bioactive Compounds, São Francisco University, Bragança Paulista, Brazil
| | - Carmen S P Lima
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Gustavo J Lourenço
- Laboratory of Cancer Genetics, School of Medical Sciences, University of Campinas, Campinas, Brazil
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