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1
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Zhao N, Xiong Q, Li P, Chen G, Xiao H, Wu C. TSC complex decrease the expression of mTOR by regulated miR-199b-3p. Sci Rep 2025; 15:1892. [PMID: 39806027 PMCID: PMC11730325 DOI: 10.1038/s41598-025-85706-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025] Open
Abstract
The TSC complex formed by TSC1 and TSC2 is the most important upstream negative regulator of mTORC1. Genetic variations in either TSC1 or TSC2 cause tuberous sclerosis complex (TSC) disease which is a rare autosomal dominant disorder resulting in impairment of multiple organ systems. In this study, besides a reported variation, c.2509_2512del (p.Asn837Valfs*11, p.N837fs) in TSC1, we found a de novo TSC2 variation c.1113delG (p.Gln371Hisfs*18, p.Q371fs), which these two mutation influence the formation of TSC complex. We found that the decrease of TSC complex with the appearance of the decreased miR-199b-3p expression. At the same time, the reduction of miR-199b-3p increased the expression of mTOR and the activation of mTORC1 and mTORC2, the additional miR-199b-3p caused the decrease the expression of mTOR and the activation of mTORC1 and mTORC2. In brief, our results may illustrate a novel mechanism of TSC caused by variations in either TSC1 or TSC2, and a new mTOR expression regulator, miR-199b-3p.
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Affiliation(s)
- Na Zhao
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
- Department of Pathology, The Second Hospital of ShanXi Medical University, No.382 WuYi Road, Tai Yuan, ShanXi, Taiyuan, 030000, China
| | - Qiuhong Xiong
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Ping Li
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Guangxin Chen
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Han Xiao
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
| | - Changxin Wu
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
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2
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Zhou T, Qiu JM, Han XJ, Zhang X, Wang P, Xie SY, Xie N. The application of nanoparticles in delivering small RNAs for cancer therapy. Discov Oncol 2024; 15:500. [PMID: 39331172 PMCID: PMC11436575 DOI: 10.1007/s12672-024-01341-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 09/11/2024] [Indexed: 09/28/2024] Open
Abstract
Small molecular RNAs, including microRNA (miRNA) and small interfering RNA (siRNA), participate in the regulation of gene expression. As powerful regulators, miRNAs, take part in posttranscriptional regulation of gene expression and play important roles in the diagnosis and treatment of cancer. Meanwhile, siRNA can induce sequence-specific gene silencing, thus being able to inhibit tumorigenesis by suppressing the expression of their targeted proto-oncogenes. Small RNAs (including naked miRNAs and siRNAs) are easily degraded by circulating RNAase, which can be retarded through the package of nanoparticles. Therefore, nanoparticles help tumor therapy by regulating targeted genes of small RNAs. Here, we reviewed the effects of small RNAs on gene expression; the advantages, disadvantages, and targeted modification of nanoparticles as carriers transporting small RNAs; and the application of nanocarriers delivering small RNA for cancer-targeted therapy.
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Affiliation(s)
- Tong Zhou
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, 264003, People's Republic of China
- Shandong Laboratory of Advanced Materials and Green Manufacturing (Yantai), Shandong, 264000, People's Republic of China
| | - Jun-Ming Qiu
- Department of Anesthesiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264000, People's Republic of China
| | - Xue-Jia Han
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, 264003, People's Republic of China
| | - Xia Zhang
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, 264003, People's Republic of China
| | - Pingyu Wang
- Department of Epidemiology, Binzhou Medical University, YanTai, ShanDong, 264003, People's Republic of China
| | - Shu-Yang Xie
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, 264003, People's Republic of China.
- Shandong Laboratory of Advanced Materials and Green Manufacturing (Yantai), Shandong, 264000, People's Republic of China.
| | - Ning Xie
- Department of Breast and Thyroid Surgery, Affiliated Yantaishan Hospital of Binzhou Medical University, Yantai, Shandong, 264000, People's Republic of China.
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3
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Mahboobnia K, Beveridge DJ, Yeoh GC, Kabir TD, Leedman PJ. MicroRNAs in Hepatocellular Carcinoma Pathogenesis: Insights into Mechanisms and Therapeutic Opportunities. Int J Mol Sci 2024; 25:9393. [PMID: 39273339 PMCID: PMC11395074 DOI: 10.3390/ijms25179393] [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: 07/21/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets.
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Affiliation(s)
- Khadijeh Mahboobnia
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Dianne J Beveridge
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - George C Yeoh
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - Tasnuva D Kabir
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Peter J Leedman
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
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Yin R, Lu H, Cao Y, Zhang J, Liu G, Guo Q, Kai X, Zhao J, Wei Y. The Mechanisms of miRNAs on Target Regulation and their Recent Advances in Atherosclerosis. Curr Med Chem 2024; 31:5779-5804. [PMID: 37807413 DOI: 10.2174/0109298673253678230920054220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/25/2023] [Accepted: 08/18/2023] [Indexed: 10/10/2023]
Abstract
miRNAs are crucial regulators in a variety of physiological and pathological processes, while their regulation mechanisms were usually described as negatively regulating gene expression by targeting the 3'-untranslated region(3'-UTR) of target gene miRNAs through seed sequence in tremendous studies. However, recent evidence indicated the existence of non-canonical mechanisms mediated by binding other molecules besides mRNAs. Additionally, accumulating evidence showed that functions of intracellular and intercellular miRNAs exhibited spatiotemporal patterns. Considering that detailed knowledge of the miRNA regulating mechanism is essential for understanding the roles and further clinical applications associated with their dysfunction and dysregulation, which is complicated and not fully clarified. Based on that, we summarized the recently reported regulation mechanisms of miRNAs, including recognitions, patterns of actions, and chemical modifications. And we also highlight the novel findings of miRNAs in atherosclerosis progression researches to provide new insights for non-coding RNA-based therapy in intractable diseases.
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Affiliation(s)
- Runting Yin
- School of Pharmacy, Jiangsu University, No. 301, Xuefu Road, Zhenjiang, 212000, China
| | - Hongyu Lu
- School of Pharmacy, Jiangsu University, No. 301, Xuefu Road, Zhenjiang, 212000, China
| | - Yixin Cao
- Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Jia Zhang
- School of Pharmacy, Jiangsu University, No. 301, Xuefu Road, Zhenjiang, 212000, China
| | - Geng Liu
- School of Pharmacy, Jiangsu University, No. 301, Xuefu Road, Zhenjiang, 212000, China
| | - Qian Guo
- School of Pharmacy, Jiangsu University, No. 301, Xuefu Road, Zhenjiang, 212000, China
| | - Xinyu Kai
- School of Pharmacy, Jiangsu University, No. 301, Xuefu Road, Zhenjiang, 212000, China
| | - Jiemin Zhao
- School of Pharmacy, Jiangsu University, No. 301, Xuefu Road, Zhenjiang, 212000, China
| | - Yuan Wei
- School of Pharmacy, Jiangsu University, No. 301, Xuefu Road, Zhenjiang, 212000, China
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5
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Liu Y, Xiao X, Wang J, Wang Y, Yu Y. Silencing CircEIF3I/miR-526b-5p Axis Epigenetically Targets HGF/c-Met Signal to Hinder the Malignant Growth, Metastasis and Angiogenesis of Hepatocellular Carcinoma. Biochem Genet 2023; 61:48-68. [PMID: 35723810 DOI: 10.1007/s10528-022-10239-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 05/25/2022] [Indexed: 01/24/2023]
Abstract
BACKGROUND Hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition factor (c-Met) is important for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Circular RNAs (circRNAs) are key regulators of HCC progression, and this study focused on circRNA eukaryotic translation initiation factor 3 subunit I (circEIF3I) with HGF/c-Met in HCC. METHODS Levels of circEIF3I, microRNA (miR)-526b-5p, HGF, E-cadherin, N-cadherin, and Vimentin were detected by Gene Expression Omnibus database, quantitative PCR and western blotting. Cell functions were measured by detecting cell growth (cell proliferation assay with WST-1 and EdU, colony formation assay, flow cytometry, caspase 3 activity assay, and nude mouse tumorigenicity assay), metastasis (transwell assay and western blotting), angiogenesis (endothelial tube formation assay). Molecular interaction was determined dual-luciferase reporter assay, RNA immunoprecipitation, and Pearson correlation analysis. RESULTS Expression of circEIF3I was upregulated in HCC tissues. Knockdown of circEIF3I suppressed cell proliferation epithelial-mesenchymal transition, migration, invasion and tube formation ability but promoted apoptosis of HCC cells. CircEIF3I could sponge miR-526b-5pto regulate downstream HGF. Functionally, circEIF3I regulation in HCC cell progression was associated with miR-526b-5p sponging function and HGF upregulation could attenuate tumor-inhibiting roles of miR-526b-5p. HCC tumor growth was delayed by interfering circEIF3I. CONCLUSION CircEIF3I was an oncogenic circRNA in HCC-, and interfering circEIF3I exhibited anti-HCC activity via circEIF3I-miR-526b-5p-HGF/c-Met pathway.
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Affiliation(s)
- Yang Liu
- Department of Radiological, The Second Hospital of Jilin University, Changchun City, Jilin Province, China
| | - Xia Xiao
- Department of Clinical Laboratory, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130001, Jilin Province, China
| | - Jingying Wang
- Department of Laboratory, China-Japan Union Hospital of Jilin University, Changchun City, Jilin Province, China
| | - Yitong Wang
- Department of Clinical Laboratory, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130001, Jilin Province, China
| | - Yanhui Yu
- Department of Clinical Laboratory, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130001, Jilin Province, China.
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6
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Singh AK, Singh SV, Kumar R, Kumar S, Senapati S, Pandey AK. Current therapeutic modalities and chemopreventive role of natural products in liver cancer: Progress and promise. World J Hepatol 2023; 15:1-18. [PMID: 36744169 PMCID: PMC9896505 DOI: 10.4254/wjh.v15.i1.1] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/02/2022] [Accepted: 12/21/2022] [Indexed: 01/16/2023] Open
Abstract
Liver cancer is a severe concern for public health officials since the clinical cases are increasing each year, with an estimated 5-year survival rate of 30%-35% after diagnosis. Hepatocellular carcinoma (HCC) constitutes a significant subtype of liver cancer (approximate75%) and is considered primary liver cancer. Treatment for liver cancer mainly depends on the stage of its progression, where surgery including, hepatectomy and liver transplantation, and ablation and radiotherapy are the prime choice. For advanced liver cancer, various drugs and immunotherapy are used as first-line treatment, whereas second-line treatment includes chemotherapeutic drugs from natural and synthetic origins. Sorafenib and lenvatinib are first-line therapies, while regorafenib and ramucirumab are second-line therapy. Various metabolic and signaling pathways such as Notch, JAK/ STAT, Hippo, TGF-β, and Wnt have played a critical role during HCC progression. Dysbiosis has also been implicated in liver cancer. Drug-induced toxicity is a key obstacle in the treatment of liver cancer, necessitating the development of effective and safe medications, with natural compounds such as resveratrol, curcumin, diallyl sulfide, and others emerging as promising anticancer agents. This review highlights the current status of liver cancer research, signaling pathways, therapeutic targets, current treatment strategies and the chemopreventive role of various natural products in managing liver cancer.
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Affiliation(s)
- Amit Kumar Singh
- Department of Botany, Government Naveen Girls College, Balod (Hemchand Yadav University), Durg, Chattisgarh, India
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India
| | - Shiv Vardan Singh
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India
| | - Ramesh Kumar
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India
- Department of Biochemistry, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Shashank Kumar
- Department of Biochemistry, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Sabyasachi Senapati
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Abhay K Pandey
- Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India.
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7
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Qiu X, Xu H, Wang K, Gao F, Xu X, He H. P-21 Activated Kinases in Liver Disorders. Cancers (Basel) 2023; 15:cancers15020551. [PMID: 36672500 PMCID: PMC9857091 DOI: 10.3390/cancers15020551] [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: 12/14/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 01/18/2023] Open
Abstract
The p21 Activated Kinases (PAKs) are serine threonine kinases and play important roles in many biological processes, including cell growth, survival, cytoskeletal organization, migration, and morphology. Recently, PAKs have emerged in the process of liver disorders, including liver cancer, hepatic ischemia-reperfusion injury, hepatitis, and liver fibrosis, owing to their effects in multiple signaling pathways in various cell types. Activation of PAKs promotes liver cancer growth and metastasis and contributes to the resistance of liver cancer to radiotherapy and chemotherapy, leading to poor survival of patients. PAKs also play important roles in the development and progression of hepatitis and other pathological processes of the liver such as fibrosis and ischemia-reperfusion injury. In this review, we have summarized the currently available studies about the role of PAKs in liver disorders and the mechanisms involved, and further explored the potential therapeutic application of PAK inhibitors in liver disorders, with the aim to provide a comprehensive overview on current progress and perspectives of PAKs in liver disorders.
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Affiliation(s)
- Xun Qiu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Hanzhi Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Kai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China
- Correspondence: (K.W.); (H.H.)
| | - Fengqiang Gao
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Hong He
- Department of Surgery, University of Melbourne, Austin Health, 145 Studley Rd., Heidelberg, VIC 3084, Australia
- Correspondence: (K.W.); (H.H.)
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8
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Chiu CH. CRISPR/Cas9 genetic screens in hepatocellular carcinoma gene discovery. CURRENT RESEARCH IN BIOTECHNOLOGY 2023; 5:100127. [DOI: 10.1016/j.crbiot.2023.100127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
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9
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Khanbabaei H, Ebrahimi S, García-Rodríguez JL, Ghasemi Z, Pourghadamyari H, Mohammadi M, Kristensen LS. Non-coding RNAs and epithelial mesenchymal transition in cancer: molecular mechanisms and clinical implications. J Exp Clin Cancer Res 2022; 41:278. [PMID: 36114510 PMCID: PMC9479306 DOI: 10.1186/s13046-022-02488-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/06/2022] [Indexed: 11/30/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a fundamental process for embryonic development during which epithelial cells acquire mesenchymal characteristics, and the underlying mechanisms confer malignant features to carcinoma cells such as dissemination throughout the organism and resistance to anticancer treatments. During the past decades, an entire class of molecules, called non-coding RNA (ncRNA), has been characterized as a key regulator of almost every cellular process, including EMT. Like protein-coding genes, ncRNAs can be deregulated in cancer, acting as oncogenes or tumor suppressors. The various forms of ncRNAs, including microRNAs, PIWI-interacting RNAs, small nucleolar RNAs, transfer RNA-derived RNA fragments, long non-coding RNAs, and circular RNAs can orchestrate the complex regulatory networks of EMT at multiple levels. Understanding the molecular mechanism underlying ncRNAs in EMT can provide fundamental insights into cancer metastasis and may lead to novel therapeutic approaches. In this review, we describe recent advances in the understanding of ncRNAs in EMT and provide an overview of recent ncRNA applications in the clinic.
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10
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Callegari E, Guerriero P, Bassi C, D’Abundo L, Frassoldati A, Simoni E, Astolfi L, Silini EM, Sabbioni S, Negrini M. miR-199a-3p increases the anti-tumor activity of palbociclib in liver cancer models. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 29:538-549. [PMID: 36035756 PMCID: PMC9395755 DOI: 10.1016/j.omtn.2022.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 07/15/2022] [Indexed: 02/07/2023]
Abstract
Palbociclib is in early-stage clinical testing in advanced hepatocellular carcinoma (HCC). Here, we investigated whether the anti-tumor activity of palbociclib, which prevents the CDK4/6-mediated phosphorylation of RB1 but simultaneously activates AKT signaling, could be improved by its combination with a PI3K/AKT/mTOR inhibitor in liver cancer models. The selective pan-AKT inhibitor, MK-2206, or the microRNA-199a-3p were tested in combination with palbociclib in HCC cell lines and in the TG221 HCC transgenic mouse model. The combination palbociclib/MK-2206 was highly effective, but too toxic to be tolerated by mice. Conversely, the combination miR-199a-3p mimics/palbociclib not only induced a complete or partial regression of tumor lesions, but was also well tolerated. After 3 weeks of treatment, the combination produced a significant reduction in number and size of tumor nodules in comparison with palbociclib or miR-199a-3p mimics used as single agents. Moreover, we also reported the efficacy of this combination against sorafenib-resistant cells in vitro and in vivo. At the molecular level, the combination caused the simultaneous decrease of the phosphorylation of both RB1 and of AKT. Our findings provide pre-clinical evidence for the efficacy of the combination miR-199a-3p/palbociclib as anti-HCC treatment or as a new approach to overcome sorafenib resistance.
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11
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Kara G, Arun B, Calin GA, Ozpolat B. miRacle of microRNA-Driven Cancer Nanotherapeutics. Cancers (Basel) 2022; 14:3818. [PMID: 35954481 PMCID: PMC9367393 DOI: 10.3390/cancers14153818] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/28/2022] [Accepted: 08/04/2022] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs (miRNAs) are non-protein-coding RNA molecules 20-25 nucleotides in length that can suppress the expression of genes involved in numerous physiological processes in cells. Accumulating evidence has shown that dysregulation of miRNA expression is related to the pathogenesis of various human diseases and cancers. Thus, stragegies involving either restoring the expression of tumor suppressor miRNAs or inhibiting overexpressed oncogenic miRNAs hold potential for targeted cancer therapies. However, delivery of miRNAs to tumor tissues is a challenging task. Recent advances in nanotechnology have enabled successful tumor-targeted delivery of miRNA therapeutics through newly designed nanoparticle-based carrier systems. As a result, miRNA therapeutics have entered human clinical trials with promising results, and they are expected to accelerate the transition of miRNAs from the bench to the bedside in the next decade. Here, we present recent perspectives and the newest developments, describing several engineered natural and synthetic novel miRNA nanocarrier formulations and their key in vivo applications and clinical trials.
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Affiliation(s)
- Goknur Kara
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Chemistry, Biochemistry Division, Ordu University, Ordu 52200, Turkey
| | - Banu Arun
- Department of Breast Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA
| | - George A. Calin
- Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA
| | - Bulent Ozpolat
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
- Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
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12
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Ren Z, Liao T, Li C, Kuang Y. Drug Delivery Systems with a "Tumor-Triggered" Targeting or Intracellular Drug Release Property Based on DePEGylation. MATERIALS (BASEL, SWITZERLAND) 2022; 15:5290. [PMID: 35955225 PMCID: PMC9369796 DOI: 10.3390/ma15155290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 12/10/2022]
Abstract
Coating nanosized anticancer drug delivery systems (DDSs) with poly(ethylene glycol) (PEG), the so-called PEGylation, has been proven an effective method to enhance hydrophilicity, aqueous dispersivity, and stability of DDSs. What is more, as PEG has the lowest level of protein absorption of any known polymer, PEGylation can reduce the clearance of DDSs by the mononuclear phagocyte system (MPS) and prolong their blood circulation time in vivo. However, the "stealthy" characteristic of PEG also diminishes the uptake of DDSs by cancer cells, which may reduce drug utilization. Therefore, dynamic protection strategies have been widely researched in the past years. Coating DDSs with PEG through dynamic covalent or noncovalent bonds that are stable in blood and normal tissues, but can be broken in the tumor microenvironment (TME), can achieve a DePEGylation-based "tumor-triggered" targeting or intracellular drug release, which can effectively improve the utilization of drugs and reduce their side effects. In this review, the stimuli and methods of "tumor-triggered" targeting or intracellular drug release, based on DePEGylation, are summarized. Additionally, the targeting and intracellular controlled release behaviors of the DDSs are briefly introduced.
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Affiliation(s)
- Zhe Ren
- Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei Key Laboratory of Polymer Materials, Hubei University, Wuhan 430062, China; (Z.R.); (T.L.)
| | - Tao Liao
- Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei Key Laboratory of Polymer Materials, Hubei University, Wuhan 430062, China; (Z.R.); (T.L.)
| | - Cao Li
- Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei Key Laboratory of Polymer Materials, Hubei University, Wuhan 430062, China; (Z.R.); (T.L.)
| | - Ying Kuang
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, China
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13
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Yoshioka H, Suzuki A, Iwaya C, Iwata J. Suppression of microRNA 124-3p and microRNA 340-5p ameliorates retinoic acid-induced cleft palate in mice. Development 2022; 149:275062. [PMID: 35420127 PMCID: PMC9148563 DOI: 10.1242/dev.200476] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/25/2022] [Indexed: 11/20/2022]
Abstract
ABSTRACT
The etiology of cleft lip with or without cleft palate (CL/P), a common congenital birth defect, is complex, with genetic and epigenetic, as well as environmental, contributing factors. Recent studies suggest that fetal development is affected by maternal conditions through microRNAs (miRNAs), a group of short noncoding RNAs. Here, we show that miR-129-5p and miR-340-5p suppress cell proliferation in both primary mouse embryonic palatal mesenchymal cells and O9-1 cells, a neural crest cell line, through the regulation of Sox5 and Trp53 by miR-129-5p, and the regulation of Chd7, Fign and Tgfbr1 by miR-340-5p. Notably, miR-340-5p, but not miR-129-5p, was upregulated following all-trans retinoic acid (atRA; tretinoin) administration, and a miR-340-5p inhibitor rescued the cleft palate (CP) phenotype in 47% of atRA-induced CP mice. We have previously reported that a miR-124-3p inhibitor can also partially rescue the CP phenotype in atRA-induced CP mouse model. In this study, we found that a cocktail of miR-124-3p and miR-340-5p inhibitors rescued atRA-induced CP with almost complete penetrance. Taken together, our results suggest that normalization of pathological miRNA expression can be a preventive intervention for CP.
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Affiliation(s)
- Hiroki Yoshioka
- Department of Diagnostic & Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
| | - Akiko Suzuki
- Department of Diagnostic & Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
| | - Chihiro Iwaya
- Department of Diagnostic & Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
| | - Junichi Iwata
- Department of Diagnostic & Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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The Use of Nanomedicine to Target Signaling by the PAK Kinases for Disease Treatment. Cells 2021; 10:cells10123565. [PMID: 34944073 PMCID: PMC8700304 DOI: 10.3390/cells10123565] [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: 11/23/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 12/11/2022] Open
Abstract
P21-activated kinases (PAKs) are serine/threonine kinases involved in the regulation of cell survival, proliferation, inhibition of apoptosis, and the regulation of cell morphology. Some members of the PAK family are highly expressed in several types of cancer, and they have also been implicated in several other medical disorders. They are thus considered to be good targets for treatment of cancer and other diseases. Although there are several inhibitors of the PAKs, the utility of some of these inhibitors is reduced for several reasons, including limited metabolic stability. One way to overcome this problem is the use of nanoparticles, which have the potential to increase drug delivery. The overall goals of this review are to describe the roles for PAK kinases in cell signaling and disease, and to describe how the use of nanomedicine is a promising new method for administering PAK inhibitors for the purpose of disease treatment and research. We discuss some of the basic mechanisms behind nanomedicine technology, and we then describe how these techniques are being used to package and deliver PAK inhibitors.
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Lou Y, Jiang Y, Liang Z, Liu B, Li T, Zhang D. Role of RhoC in cancer cell migration. Cancer Cell Int 2021; 21:527. [PMID: 34627249 PMCID: PMC8502390 DOI: 10.1186/s12935-021-02234-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/27/2021] [Indexed: 12/20/2022] Open
Abstract
Migration is one of the five major behaviors of cells. Although RhoC-a classic member of the Rho gene family-was first identified in 1985, functional RhoC data have only been widely reported in recent years. Cell migration involves highly complex signaling mechanisms, in which RhoC plays an essential role. Cell migration regulated by RhoC-of which the most well-known function is its role in cancer metastasis-has been widely reported in breast, gastric, colon, bladder, prostate, lung, pancreatic, liver, and other cancers. Our review describes the role of RhoC in various types of cell migration. The classic two-dimensional cell migration cycle constitutes cell polarization, adhesion regulation, cell contraction and tail retraction, most of which are modulated by RhoC. In the three-dimensional cell migration model, amoeboid migration is the most classic and well-studied model. Here, RhoC modulates the formation of membrane vesicles by regulating myosin II, thereby affecting the rate and persistence of amoeba-like migration. To the best of our knowledge, this review is the first to describe the role of RhoC in all cell migration processes. We believe that understanding the detail of RhoC-regulated migration processes will help us better comprehend the mechanism of cancer metastasis. This will contribute to the study of anti-metastatic treatment approaches, aiding in the identification of new intervention targets for therapeutic or genetic transformational purposes.
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Affiliation(s)
- Yingyue Lou
- Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yuhan Jiang
- Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhen Liang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Bingzhang Liu
- Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Tian Li
- Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University, Changchun, Jilin, China.
| | - Duo Zhang
- Department of Plastic and Reconstructive Surgery, The First Hospital of Jilin University, Changchun, Jilin, China.
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Epigenetic Changes Affecting the Development of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13164237. [PMID: 34439391 PMCID: PMC8392268 DOI: 10.3390/cancers13164237] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/15/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma is a life-threatening disease. Despite many efforts to understand the exact pathogenesis and the signaling pathways involved in its formation, treatment remains unsatisfactory. Currently, an important function in the development of neoplastic diseases and treatment effects is attributed to changes taking place at the epigenetic level. Epigenetic studies revealed modified methylation patterns in HCC, dysfunction of enzymes engaged in the DNA methylation process, the aberrant function of non-coding RNAs, and a set of histone modifications that influence gene expression. The aim of this review is to summarize the current knowledge on the role of epigenetics in the formation of hepatocellular carcinoma. Abstract Hepatocellular carcinoma (HCC) remains a serious oncologic issue with still a dismal prognosis. So far, no key molecular mechanism that underlies its pathogenesis has been identified. Recently, by specific molecular approaches, many genetic and epigenetic changes arising during HCC pathogenesis were detected. Epigenetic studies revealed modified methylation patterns in HCC tumors, dysfunction of enzymes engaged in the DNA methylation process, and a set of histone modifications that influence gene expression. HCC cells are also influenced by the disrupted function of non-coding RNAs, such as micro RNAs and long non-coding RNAs. Moreover, a role of liver cancer stem cells in HCC development is becoming evident. The reversibility of epigenetic changes offers the possibility of influencing them and regulating their undesirable effects. All these data can be used not only to identify new therapeutic targets but also to predict treatment response. This review focuses on epigenetic changes in hepatocellular carcinoma and their possible implications in HCC therapy.
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Shiu TY, Lin HH, Shih YL, Feng AC, Huang HH, Huang TY, Hsieh CB, Chang WK, Hsieh TY. CRNDE-h transcript/miR-136-5p axis regulates interleukin enhancer binding factor 2 expression to promote hepatocellular carcinoma cell proliferation. Life Sci 2021; 284:119708. [PMID: 34153299 DOI: 10.1016/j.lfs.2021.119708] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/27/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022]
Abstract
AIMS Hepatocellular carcinoma (HCC) is a primary malignancy of the hepatocyte. Interleukin enhancer binding factor 2 (ILF2) plays a role in the development of HCC. However, the regulatory mechanisms of ILF2 expression in HCC remain unclear. In this study, we aimed to identify ILF2-targeting microRNAs (miRNAs) and to explore how they affect ILF2 expression in HCC. MAIN METHODS The tissue specimens were collected from 25 HCC patients. The underlying regulatory mechanism of ILF2 expression in HCC progression was determined using luciferase reporter assay, quantitative real-time PCR, Western blotting, and BrdU incorporation assay. KEY FINDINGS Of predicted miRNA candidates (miR-122-5p, miR-425-5p, miR-136-5p, miR-7-5p, miR-421 and miR-543), a statistically significant inverse correlation by linear correlation analysis was observed between miR-136-5p and ILF2 mRNA expressions in patients with HCC (r = -0.627, P < 0.001). Further analysis demonstrated that ILF2 was directly regulated by miR-136-5p. In addition, we showed that long noncoding RNA colorectal neoplasia differentially expressed-h (lncRNA CRNDE-h) transcript expression was significantly up-regulated in HCC, and a miR-136-5p binding site was newly found in the lncRNA CRNDE-h transcript sequence using IntaRNA tool. In terms of mechanism, highly-expressed lncRNA CRNDE-h transcript can sponge miR-136-5p, thereby preventing it from interacting with target ILF2 mRNA while promoting the proliferation of HCC cells. SIGNIFICANCE The lncRNA CRNDE-h/miR-136-5p/ILF2 axis plays a significant regulatory role in HCC progression, which may partly explain the pathogenic mechanisms of HCC and may provide promising potential targets for the diagnosis, treatment, and prognosis of HCC.
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Affiliation(s)
- Tzu-Yue Shiu
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Hsuan-Hwai Lin
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
| | - Yu-Lueng Shih
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - An-Chieh Feng
- Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Hsin-Hung Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Tien-Yu Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chung-Bao Hsieh
- Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Wei-Kuo Chang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Tsai-Yuan Hsieh
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
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Reda El Sayed S, Cristante J, Guyon L, Denis J, Chabre O, Cherradi N. MicroRNA Therapeutics in Cancer: Current Advances and Challenges. Cancers (Basel) 2021; 13:cancers13112680. [PMID: 34072348 PMCID: PMC8198729 DOI: 10.3390/cancers13112680] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/21/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Cancer is a complex disease associated with deregulation of numerous genes. In addition, redundant cellular pathways limit efficiency of monotarget drugs in cancer therapy. MicroRNAs are a class of gene expression regulators, which often function by targeting multiple genes. This feature makes them a double-edged sword (a) as attractive targets for anti-tumor therapy and concomitantly (b) as risky targets due to their potential side effects on healthy tissues. As for conventional antitumor drugs, nanocarriers have been developed to circumvent the problems associated with miRNA delivery to tumors. In this review, we highlight studies that have established the pre-clinical proof-of concept of miRNAs as relevant therapeutic targets in oncology. Particular attention was brought to new strategies based on nanovectorization of miRNAs as well as to the perspectives for their applications. Abstract The discovery of microRNAs (miRNAs) in 1993 has challenged the dogma of gene expression regulation. MiRNAs affect most of cellular processes from metabolism, through cell proliferation and differentiation, to cell death. In cancer, deregulated miRNA expression leads to tumor development and progression by promoting acquisition of cancer hallmark traits. The multi-target action of miRNAs, which enable regulation of entire signaling networks, makes them attractive tools for the development of anti-cancer therapies. Hence, supplementing downregulated miRNA by synthetic oligonucleotides or silencing overexpressed miRNAs through artificial antagonists became a common strategy in cancer research. However, the ultimate success of miRNA therapeutics will depend on solving pharmacokinetic and targeted delivery issues. The development of a number of nanocarrier-based platforms holds significant promises to enhance the cell specific controlled delivery and safety profile of miRNA-based therapies. In this review, we provide among the most comprehensive assessments to date of promising nanomedicine platforms that have been tested preclinically, pertaining to the treatment of selected solid tumors including lung, liver, breast, and glioblastoma tumors as well as endocrine malignancies. The future challenges and potential applications in clinical oncology are discussed.
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Affiliation(s)
- Soha Reda El Sayed
- University Grenoble Alpes, INSERM, CEA, Interdisciplinary Research Institute of Grenoble (IRIG), Biology and Biotechnologies for Health UMR_1292, F-38000 Grenoble, France; (S.R.E.S.); (J.C.); (L.G.); (J.D.); (O.C.)
| | - Justine Cristante
- University Grenoble Alpes, INSERM, CEA, Interdisciplinary Research Institute of Grenoble (IRIG), Biology and Biotechnologies for Health UMR_1292, F-38000 Grenoble, France; (S.R.E.S.); (J.C.); (L.G.); (J.D.); (O.C.)
- Centre Hospitalier Universitaire Grenoble Alpes, Service d’Endocrinologie, F-38000 Grenoble, France
| | - Laurent Guyon
- University Grenoble Alpes, INSERM, CEA, Interdisciplinary Research Institute of Grenoble (IRIG), Biology and Biotechnologies for Health UMR_1292, F-38000 Grenoble, France; (S.R.E.S.); (J.C.); (L.G.); (J.D.); (O.C.)
| | - Josiane Denis
- University Grenoble Alpes, INSERM, CEA, Interdisciplinary Research Institute of Grenoble (IRIG), Biology and Biotechnologies for Health UMR_1292, F-38000 Grenoble, France; (S.R.E.S.); (J.C.); (L.G.); (J.D.); (O.C.)
| | - Olivier Chabre
- University Grenoble Alpes, INSERM, CEA, Interdisciplinary Research Institute of Grenoble (IRIG), Biology and Biotechnologies for Health UMR_1292, F-38000 Grenoble, France; (S.R.E.S.); (J.C.); (L.G.); (J.D.); (O.C.)
- Centre Hospitalier Universitaire Grenoble Alpes, Service d’Endocrinologie, F-38000 Grenoble, France
| | - Nadia Cherradi
- University Grenoble Alpes, INSERM, CEA, Interdisciplinary Research Institute of Grenoble (IRIG), Biology and Biotechnologies for Health UMR_1292, F-38000 Grenoble, France; (S.R.E.S.); (J.C.); (L.G.); (J.D.); (O.C.)
- Correspondence: ; Tel.: +33-(0)4-38783501; Fax: +33-(0)4-38785058
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