|
1
|
Xu L, Li C, Zhao C, Wang Z, Zhang Z, Shu X, Cao X, Xia S, Bao X, Shao P, Xu Y. Shionone protects cerebral ischemic injury through alleviating microglia-mediated neuroinflammation. Chin J Nat Med 2025; 23:471-479. [PMID: 40274349 DOI: 10.1016/s1875-5364(25)60812-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 03/15/2025] [Accepted: 04/03/2025] [Indexed: 04/26/2025]
Abstract
Microglia, the resident immune cells in the central nervous system (CNS), rapidly transition from a resting to an active state in the acute phase of ischemic brain injury. This active state mediates a pro-inflammatory response that can exacerbate the injury. Targeting the pro-inflammatory response of microglia in the semi-dark band during this acute phase may effectively reduce brain injury. Shionone (SH), an active ingredient extracted from the dried roots and rhizomes of the genus Aster (Asteraceae), has been reported to regulate the inflammatory response of macrophages in sepsis-induced acute lung injury. However, its function in post-stroke neuroinflammation, particularly microglia-mediated neuroinflammation, remains uninvestigated. This study found that SH significantly inhibited lipopolysaccharide (LPS)-induced elevation of inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS), in microglia in vitro. Furthermore, the results demonstrated that SH alleviated infarct volume and improved behavioral performance in middle cerebral artery occlusion (MCAO) mice, which may be attributed to the inhibition of the microglial inflammatory response induced by SH treatment. Mechanistically, SH potently inhibited the phosphorylation of serine-threonine protein kinase B (AKT), mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 (STAT3). These findings suggest that SH may be a potential therapeutic agent for relieving ischemic stroke (IS) by alleviating microglia-associated neuroinflammation.
Collapse
Affiliation(s)
- Lushan Xu
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China
| | - Chenggang Li
- School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China
| | - ChenChen Zhao
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China; Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing 210008, China
| | - Zibu Wang
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China; Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing 210008, China
| | - Zhi Zhang
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China; Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing 210008, China
| | - Xin Shu
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China; Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing 210008, China
| | - Xiang Cao
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Provincial Key Discipline of Neurology, Nanjing 210008, China
| | - Shengnan Xia
- Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China
| | - Xinyu Bao
- Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China
| | - Pengfei Shao
- Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China
| | - Yun Xu
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China; School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China; Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Provincial Key Discipline of Neurology, Nanjing 210008, China.
| |
Collapse
|
|
2
|
Li W, Li K, Chen Y, Wang S, Xu K, Ye S, Zhao B, Yuan H, Li Z, Shen Y, Mou T, Wang Y, Zhou W, Ma W. IRF1 transcriptionally up-regulates CXCL10 which increases CD8 + T cells infiltration in colorectal cancer. Int Immunopharmacol 2025; 144:113678. [PMID: 39591825 DOI: 10.1016/j.intimp.2024.113678] [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: 08/14/2024] [Revised: 11/17/2024] [Accepted: 11/18/2024] [Indexed: 11/28/2024]
Abstract
Tumor-infiltrating CD8+ T cell is a robust predictor of outcome and immunotherapy response in patients with CRC. However, limited introduction of intratumoral CD8+ T cells remains a barrier for treatment of CRC. One of the most effective but difficult therapy for CD8+ T cells entering the tumor is activating chemokine receptors. This study observed a decrease in the expression level of interferon regulator factor 1(IRF1) in CRC tumor tissues compared to matched non-tumor tissues. Furthermore, it found a positive correlation between low IRF1 expression and unfavorable prognosis in CRC patients. The present study also demonstrated that overexpression of IRF1 attenuated tumor growth by promoting the accumulation of facilitating CD8+T cells at the tumor site in mouse models. Additionally, this study identified IRF1 response elements in the promoter region of CXCL10 and show that the binding of IRF1 promoted the transcription of CXCL10. Of note, it was discovered that an increase in CXCL10 was positively associated with improved survival in CRC. These findings strongly suggest that IRF1 serves as a key transcription factor for CXCL10, highlighting its potential as a therapeutic target for CRC.
Collapse
Affiliation(s)
- Wenyi Li
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Kejun Li
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Yuehong Chen
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Shunyi Wang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Ke Xu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Shengzhi Ye
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Bohou Zhao
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Haitao Yuan
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Zhenghao Li
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Yunhao Shen
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Tingyu Mou
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China; State Key Laboratory of Organ Failure Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China
| | - Yanan Wang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China; State Key Laboratory of Organ Failure Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China; Department of Gastrointestinal and Hernia Surgery, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, Jiangxi 341000, China.
| | - Weijie Zhou
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China; State Key Laboratory of Organ Failure Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China; Department of Gastrointestinal and Hernia Surgery, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, Jiangxi 341000, China.
| | - Wenhui Ma
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China; Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Clinical Research Academy of Chinese Medicine, Jichang Road No. 16, Guangzhou 510405, China; State Key Laboratory of Organ Failure Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou 510515, China; Department of Gastrointestinal and Hernia Surgery, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, Jiangxi 341000, China.
| |
Collapse
|
|
3
|
Rahdan F, Saberi A, Saraygord-Afshari N, Hadizadeh M, Fayeghi T, Ghanbari E, Dianat-Moghadam H, Alizadeh E. Deciphering the multifaceted role of microRNAs in hepatocellular carcinoma: Integrating literature review and bioinformatics analysis for therapeutic insights. Heliyon 2024; 10:e39489. [PMID: 39498055 PMCID: PMC11532857 DOI: 10.1016/j.heliyon.2024.e39489] [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: 05/15/2024] [Revised: 08/06/2024] [Accepted: 10/15/2024] [Indexed: 11/07/2024] Open
Abstract
Hepatocellular carcinoma (HCC) poses a significant global health challenge, necessitating innovative therapeutic strategies. MicroRNAs (miRNAs) have emerged as pivotal regulators of HCC pathogenesis, influencing key processes such as self-renewal, angiogenesis, glycolysis, autophagy, and metastasis. This article integrates findings from a comprehensive literature review and bioinformatics analysis to elucidate the role of miRNAs in HCC. We discuss how dysregulation of miRNAs can drive HCC initiation, progression, and metastasis by modulating various signaling pathways and target genes. Moreover, leveraging high-throughput technology and bioinformatics tools, we identify key miRNAs involved in multiple cancer hallmarks, offering insights into potential combinatorial therapeutic strategies. Through our analysis considering p-values and signaling pathways associated with key features, we unveil miRNAs with simultaneous roles across critical cancer characteristics, providing a basis for the development of high-performance biomarkers. The microRNAs, miR-34a-5p, miR-373-3p, miR-21-5p, miR-214-5p, miR-195-5p, miR-139-5p were identified to be shared microRNAs in stemness, angiogenesis, glycolysis, autophagy, EMT, and metastasis of HCC. However, challenges such as miRNA stability and delivery hinder the translation of miRNA-based therapeutics into clinical practice. This review underscores the importance of further research to overcome existing barriers and realize the full potential of miRNA-based interventions for HCC management.
Collapse
Affiliation(s)
- Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alihossein Saberi
- Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Neda Saraygord-Afshari
- Department of Medical Biotechnology, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, 1449614535, Iran
| | - Morteza Hadizadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Tahura Fayeghi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Ghanbari
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
4
|
Wang L, Zhu Y, Zhang N, Xian Y, Tang Y, Ye J, Reza F, He G, Wen X, Jiang X. The multiple roles of interferon regulatory factor family in health and disease. Signal Transduct Target Ther 2024; 9:282. [PMID: 39384770 PMCID: PMC11486635 DOI: 10.1038/s41392-024-01980-4] [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: 04/26/2024] [Revised: 08/12/2024] [Accepted: 09/10/2024] [Indexed: 10/11/2024] Open
Abstract
Interferon Regulatory Factors (IRFs), a family of transcription factors, profoundly influence the immune system, impacting both physiological and pathological processes. This review explores the diverse functions of nine mammalian IRF members, each featuring conserved domains essential for interactions with other transcription factors and cofactors. These interactions allow IRFs to modulate a broad spectrum of physiological processes, encompassing host defense, immune response, and cell development. Conversely, their pivotal role in immune regulation implicates them in the pathophysiology of various diseases, such as infectious diseases, autoimmune disorders, metabolic diseases, and cancers. In this context, IRFs display a dichotomous nature, functioning as both tumor suppressors and promoters, contingent upon the specific disease milieu. Post-translational modifications of IRFs, including phosphorylation and ubiquitination, play a crucial role in modulating their function, stability, and activation. As prospective biomarkers and therapeutic targets, IRFs present promising opportunities for disease intervention. Further research is needed to elucidate the precise mechanisms governing IRF regulation, potentially pioneering innovative therapeutic strategies, particularly in cancer treatment, where the equilibrium of IRF activities is of paramount importance.
Collapse
Affiliation(s)
- Lian Wang
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yanghui Zhu
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Nan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yali Xian
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yu Tang
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Ye
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fekrazad Reza
- Radiation Sciences Research Center, Laser Research Center in Medical Sciences, AJA University of Medical Sciences, Tehran, Iran
- International Network for Photo Medicine and Photo Dynamic Therapy (INPMPDT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Gu He
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiang Wen
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Xian Jiang
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| |
Collapse
|
|
5
|
Zeng C, Zhu X, Li H, Huang Z, Chen M. The Role of Interferon Regulatory Factors in Liver Diseases. Int J Mol Sci 2024; 25:6874. [PMID: 38999981 PMCID: PMC11241258 DOI: 10.3390/ijms25136874] [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: 05/07/2024] [Revised: 06/12/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
The interferon regulatory factors (IRFs) family comprises 11 members that are involved in various biological processes such as antiviral defense, cell proliferation regulation, differentiation, and apoptosis. Recent studies have highlighted the roles of IRF1-9 in a range of liver diseases, including hepatic ischemia-reperfusion injury (IRI), alcohol-induced liver injury, Con A-induced liver injury, nonalcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC). IRF1 is involved in the progression of hepatic IRI through signaling pathways such as PIAS1/NFATc1/HDAC1/IRF1/p38 MAPK and IRF1/JNK. The regulation of downstream IL-12, IL-15, p21, p38, HMGB1, JNK, Beclin1, β-catenin, caspase 3, caspase 8, IFN-γ, IFN-β and other genes are involved in the progression of hepatic IRI, and in the development of HCC through the regulation of PD-L1, IL-6, IL-8, CXCL1, CXCL10, and CXCR3. In addition, IRF3-PPP2R1B and IRF4-FSTL1-DIP2A/CD14 pathways are involved in the development of NAFLD. Other members of the IRF family also play moderately important functions in different liver diseases. Therefore, given the significance of IRFs in liver diseases and the lack of a comprehensive compilation of their molecular mechanisms in different liver diseases, this review is dedicated to exploring the molecular mechanisms of IRFs in various liver diseases.
Collapse
Affiliation(s)
| | | | | | | | - Mingkai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan 430060, China; (C.Z.); (X.Z.); (H.L.); (Z.H.)
| |
Collapse
|
|
6
|
Chen J, He F, Peng H, Guo J. The underlying mechanism and targeted therapy strategy of miRNAs cross-regulating EMT process through multiple signaling pathways in hepatocellular carcinoma. Front Mol Biosci 2024; 11:1378386. [PMID: 38584703 PMCID: PMC10995332 DOI: 10.3389/fmolb.2024.1378386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 03/04/2024] [Indexed: 04/09/2024] Open
Abstract
The consistent notion holds that hepatocellular carcinoma (HCC) initiation, progression, and clinical treatment failure treatment failure are affected by the accumulation of various genetic and epigenetic alterations. MicroRNAs (miRNAs) play an irreplaceable role in a variety of physiological and pathological states. meanwhile, epithelial-mesenchymal transition (EMT) is a crucial biological process that controls the development of HCC. miRNAs regulate the intermediation state of EMTor mesenchymal-epithelial transition (MTE)thereby regulating HCC progression. Notably, miRNAs regulate key HCC-related molecular pathways, including the Wnt/β-catenin pathway, PTEN/PI3K/AKT pathway, TGF-β pathway, and RAS/MAPK pathway. Therefore, we comprehensively reviewed how miRNAs produce EMT effects by multiple signaling pathways and their potential significance in the pathogenesis and treatment response of HCC. emphasizing their molecular pathways and progression in HCC initiation. Additionally, we also pay attention to regulatory mechanisms that are partially independent of signaling pathways. Finally, we summarize and propose miRNA-targeted therapy and diagnosis and defense strategies forHCC. The identification of the mechanism leading to the activation of EMT programs during HCC disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Consequently, we summarize the latest progress in this direction, with a promising path for further insight into this fast-moving field.
Collapse
Affiliation(s)
- Juan Chen
- Department of Pathology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Fuguo He
- Department of Pathology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Peng
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Jinjun Guo
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
7
|
Romeo M, Dallio M, Scognamiglio F, Ventriglia L, Cipullo M, Coppola A, Tammaro C, Scafuro G, Iodice P, Federico A. Role of Non-Coding RNAs in Hepatocellular Carcinoma Progression: From Classic to Novel Clinicopathogenetic Implications. Cancers (Basel) 2023; 15:5178. [PMID: 37958352 PMCID: PMC10647270 DOI: 10.3390/cancers15215178] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a predominant malignancy with increasing incidences and mortalities worldwide. In Western countries, the progressive affirmation of Non-alcoholic Fatty Liver Disease (NAFLD) as the main chronic liver disorder in which HCC occurrence is appreciable even in non-cirrhotic stages, constitutes a real health emergency. In light of this, a further comprehension of molecular pathways supporting HCC onset and progression represents a current research challenge to achieve more tailored prognostic models and appropriate therapeutic approaches. RNA non-coding transcripts (ncRNAs) are involved in the regulation of several cancer-related processes, including HCC. When dysregulated, these molecules, conventionally classified as "small ncRNAs" (sncRNAs) and "long ncRNAs" (lncRNAs) have been reported to markedly influence HCC-related progression mechanisms. In this review, we describe the main dysregulated ncRNAs and the relative molecular pathways involved in HCC progression, analyzing their implications in certain etiologically related contexts, and their applicability in clinical practice as novel diagnostic, prognostic, and therapeutic tools. Finally, given the growing evidence supporting the immune system response, the oxidative stress-regulated mechanisms, and the gut microbiota composition as relevant emerging elements mutually influencing liver-cancerogenesis processes, we investigate the relationship of ncRNAs with this triad, shedding light on novel pathogenetic frontiers of HCC progression.
Collapse
Affiliation(s)
- Mario Romeo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marcello Dallio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Flavia Scognamiglio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Lorenzo Ventriglia
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marina Cipullo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Annachiara Coppola
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Chiara Tammaro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Giuseppe Scafuro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Patrizia Iodice
- Division of Medical Oncology, AORN Azienda dei Colli, Monaldi Hospital, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| |
Collapse
|
|
8
|
Ashrafizadeh M, Mohan CD, Rangappa S, Zarrabi A, Hushmandi K, Kumar AP, Sethi G, Rangappa KS. Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response. Med Res Rev 2023; 43:1263-1321. [PMID: 36951271 DOI: 10.1002/med.21950] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 10/09/2022] [Accepted: 02/28/2023] [Indexed: 03/24/2023]
Abstract
Gastrointestinal (GI) tumors (cancers of the esophagus, gastric, liver, pancreas, colon, and rectum) contribute to a large number of deaths worldwide. STAT3 is an oncogenic transcription factor that promotes the transcription of genes associated with proliferation, antiapoptosis, survival, and metastasis. STAT3 is overactivated in many human malignancies including GI tumors which accelerates tumor progression, metastasis, and drug resistance. Research in recent years demonstrated that noncoding RNAs (ncRNAs) play a major role in the regulation of many signaling pathways including the STAT3 pathway. The major types of endogenous ncRNAs that are being extensively studied in oncology are microRNAs, long noncoding RNAs, and circular RNAs. These ncRNAs can either be tumor-promoters or tumor-suppressors and each one of them imparts their activity via different mechanisms. The STAT3 pathway is also tightly modulated by ncRNAs. In this article, we have elaborated on the tumor-promoting role of STAT3 signaling in GI tumors. Subsequently, we have comprehensively discussed the oncogenic as well as tumor suppressor functions and mechanism of action of ncRNAs that are known to modulate STAT3 signaling in GI cancers.
Collapse
Affiliation(s)
- Milad Ashrafizadeh
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, China
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chakrabhavi D Mohan
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, India
| | - Shobith Rangappa
- Adichunchanagiri Institute for Molecular Medicine, Adichunchanagiri University, Nagamangala Taluk, India
| | - Ali Zarrabi
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, Sariyer, Turkey
| | - Kiavash Hushmandi
- Division of Epidemiology, Faculty of Veterinary Medicine, Department of Food Hygiene and Quality Control, University of Tehran, Tehran, Iran
| | - Alan Prem Kumar
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Gautam Sethi
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | |
Collapse
|
|
9
|
Hashemi M, Sabouni E, Rahmanian P, Entezari M, Mojtabavi M, Raei B, Zandieh MA, Behroozaghdam M, Mirzaei S, Hushmandi K, Nabavi N, Salimimoghadam S, Ren J, Rashidi M, Raesi R, Taheriazam A, Alexiou A, Papadakis M, Tan SC. Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance. Cell Mol Biol Lett 2023; 28:33. [PMID: 37085753 PMCID: PMC10122325 DOI: 10.1186/s11658-023-00438-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/15/2023] [Indexed: 04/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is considered one of the greatest challenges to human life and is the most common form of liver cancer. Treatment of HCC depends on chemotherapy, radiotherapy, surgery, and immunotherapy, all of which have their own drawbacks, and patients may develop resistance to these therapies due to the aggressive behavior of HCC cells. New and effective therapies for HCC can be developed by targeting molecular signaling pathways. The expression of signal transducer and activator of transcription 3 (STAT3) in human cancer cells changes, and during cancer progression, the expression tends to increase. After induction of STAT3 signaling by growth factors and cytokines, STAT3 is phosphorylated and translocated to the nucleus to regulate cancer progression. The concept of the current review revolves around the expression and phosphorylation status of STAT3 in HCC, and studies show that the expression of STAT3 is high during the progression of HCC. This review addresses the function of STAT3 as an oncogenic factor in HCC, as STAT3 is able to prevent apoptosis and thus promote the progression of HCC. Moreover, STAT3 regulates both survival- and death-inducing autophagy in HCC and promotes cancer metastasis by inducing the epithelial-mesenchymal transition (EMT). In addition, upregulation of STAT3 is associated with the occurrence of chemoresistance and radioresistance in HCC. Specifically, non-protein-coding transcripts regulate STAT3 signaling in HCC, and their inhibition by antitumor agents may affect tumor progression. In this review, all these topics are discussed in detail to provide further insight into the role of STAT3 in tumorigenesis, treatment resistance, and pharmacological regulation of HCC.
Collapse
Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Eisa Sabouni
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Parham Rahmanian
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Behnaz Raei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Arad Zandieh
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mitra Behroozaghdam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Jun Ren
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, 200032, China
| | - 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.
| | - Rasoul Raesi
- Department of Health Services Management, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical-Surgical Nursing, Mashhad University of Medical Sciences, Mashhad, 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.
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia
- AFNP Med Austria, Vienna, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| |
Collapse
|
|
10
|
Ishaq Y, Ikram A, Alzahrani B, Khurshid S. The Role of miRNAs, circRNAs and Their Interactions in Development and Progression of Hepatocellular Carcinoma: An Insilico Approach. Genes (Basel) 2022; 14:genes14010013. [PMID: 36672755 PMCID: PMC9858589 DOI: 10.3390/genes14010013] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/06/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of malignant tumor. miRNAs are noncoding RNAs and their differential expression patterns are observed in HCC-induced by alcoholism, HBV and HCV infections. By acting as a competing endogenous RNA (ceRNA), circRNA regulates the miRNA function, indirectly controlling the gene expression and leading to HCC progression. In the present study, data mining was performed to screen out all miRNAs and circRNA involved in alcohol, HBV or HCV-induced HCC with statistically significant (≤0.05%) expression levels reported in various studies. Further, the interaction of miRNAs and circRNA was also investigated to explore their role in HCC due to various causative agents. Together, these study data provide a deeper understanding of the circRNA-miRNA regulatory mechanisms in HCC. These screened circRNA, miRNA and their interactions can be used as prognostic biomarkers or therapeutic targets for the treatment of HCC.
Collapse
Affiliation(s)
- Yasmeen Ishaq
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
| | - Aqsa Ikram
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
- Correspondence:
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, Jouf University, Sakaka 42421, Saudi Arabia
| | - Sana Khurshid
- Department of Molecular Biology, Virtual University of Pakistan, 1-Davis Road, Lahore 54000, Pakistan
| |
Collapse
|
|
11
|
Sadrkhanloo M, Entezari M, Orouei S, Ghollasi M, Fathi N, Rezaei S, Hejazi ES, Kakavand A, Saebfar H, Hashemi M, Goharrizi MASB, Salimimoghadam S, Rashidi M, Taheriazam A, Samarghandian S. STAT3-EMT axis in tumors: Modulation of cancer metastasis, stemness and therapy response. Pharmacol Res 2022; 182:106311. [PMID: 35716914 DOI: 10.1016/j.phrs.2022.106311] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 02/07/2023]
Abstract
Epithelial-to-mesenchymal transition (EMT) mechanism is responsible for metastasis of tumor cells and their spread to various organs and tissues of body, providing undesirable prognosis. In addition to migration, EMT increases stemness and mediates therapy resistance. Hence, pathways involved in EMT regulation should be highlighted. STAT3 is an oncogenic pathway that can elevate growth rate and migratory ability of cancer cells and induce drug resistance. The inhibition of STAT3 signaling impairs cancer progression and promotes chemotherapy-mediated cell death. Present review focuses on STAT3 and EMT interaction in modulating cancer migration. First of all, STAT3 is an upstream mediator of EMT and is able to induce EMT-mediated metastasis in brain tumors, thoracic cancers and gastrointestinal cancers. Therefore, STAT3 inhibition significantly suppresses cancer metastasis and improves prognosis of patients. EMT regulators such as ZEB1/2 proteins, TGF-β, Twist, Snail and Slug are affected by STAT3 signaling to stimulate cancer migration and invasion. Different molecular pathways such as miRNAs, lncRNAs and circRNAs modulate STAT3/EMT axis. Furthermore, we discuss how STAT3 and EMT interaction affects therapy response of cancer cells. Finally, we demonstrate targeting STAT3/EMT axis by anti-tumor agents and clinical application of this axis for improving patient prognosis.
Collapse
Affiliation(s)
- Mehrdokht Sadrkhanloo
- Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sima Orouei
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Marzieh Ghollasi
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Nikoo Fathi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shamin Rezaei
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elahe Sadat Hejazi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirabbas Kakavand
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hamidreza Saebfar
- European University Association, League of European Research Universities, University of Milan, Italy
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, 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.
| | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran.
| |
Collapse
|
|
12
|
The Role of MicroRNA in the Regulation of Tumor Epithelial–Mesenchymal Transition. Cells 2022; 11:cells11131981. [PMID: 35805066 PMCID: PMC9265548 DOI: 10.3390/cells11131981] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 02/01/2023] Open
Abstract
Consistently, the high metastasis of cancer cells is the bottleneck in the process of tumor treatment. In this process of metastasis, a pivotal role is executed by epithelial–mesenchymal transition (EMT). The epithelial-to-mesenchymal transformation was first proposed to occur during embryonic development. Later, its important role in explaining embryonic developmental processes was widely reported. Recently, EMT and its intermediate state were also identified as crucial drivers in tumor progression with the gradual deepening of research. To gain insights into the potential mechanism, increasing attention has been focused on the EMT-related transcription factors. Correspondingly, miRNAs target transcription factors to control the EMT process of tumor cells in different types of cancers, while there are still many exciting and challenging questions about the phenomenon of microRNA regulation of cancer EMT. We describe the relevant mechanisms of miRNAs regulating EMT, and trace the regulatory roles and functions of major EMT-related transcription factors, including Snail, Twist, zinc finger E-box-binding homeobox (ZEB), and other families. In addition, on the basis of the complex regulatory network, we hope that the exploration of the regulatory relationship of non-transcription factors will provide a better understanding of EMT and cancer metastasis. The identification of the mechanism leading to the activation of EMT programs during diverse disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Here, we summarize the recent progress in this direction, with a promising path for further insight into this fast-moving field.
Collapse
|
|
13
|
Overexpression of microRNA-345 Affects the Invasive Capacity of Pancreatic Ductal Adenocarcinoma Cell Lines by Suppressing MUC1 and TJP2 Expression. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12115351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
The majority of pancreatic carcinomas are pancreatic ductal adenocarcinomas (PDAC), and the presence of non-invasive pancreatic intraepithelial neoplasia or intraductal papillary mucinous neoplasm, as an associated lesion, is considered important. These microscopic hyperplastic or grossly papillomatous lesions exhibit varying degrees of morphological atypia and may develop into invasive carcinomas. In this study, we investigated whether mucin-1 (MUC1) is involved in the progression of pancreatic carcinoma and examined the mechanisms by which microRNAs regulate MUC1 expression in vitro. In PDAC cell lines, suppression of MUC1 expression reduced cell proliferation and invasion; PDAC cell lines transfected with an miR-345 precursor suppressed the expression of MUC1, and reduced cell proliferation and invasion. Tight junction protein 2 (TJP2), a putative target of miR-345, is regulated by MUC1. The suppression of TJP2 expression reduced cell proliferation by inducing apoptosis. These results suggest that MUC1 and TJP2, the putative target molecules of miR-345, are critical in maintaining the invasive potential of pancreatic carcinoma cells, and regulating their expression may prevent the progression of non-invasive pancreatic intraductal lesions to invasive carcinomas. This study provides new insights for the development of novel molecular targeted therapies for pancreatic carcinomas.
Collapse
|
|
14
|
Khare S, Khare T, Ramanathan R, Ibdah JA. Hepatocellular Carcinoma: The Role of MicroRNAs. Biomolecules 2022; 12:biom12050645. [PMID: 35625573 PMCID: PMC9138333 DOI: 10.3390/biom12050645] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. HCC is diagnosed in its advanced stage when limited treatment options are available. Substantial morphologic, genetic and epigenetic heterogeneity has been reported in HCC, which poses a challenge for the development of a targeted therapy. In this review, we discuss the role and involvement of several microRNAs (miRs) in the heterogeneity and metastasis of hepatocellular carcinoma with a special emphasis on their possible role as a diagnostic and prognostic tool in the risk prediction, early detection, and treatment of hepatocellular carcinoma.
Collapse
Affiliation(s)
- Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
| | - Raghu Ramanathan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Jamal A. Ibdah
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
- Correspondence: ; Tel.: 1-573-882-7349; Fax: 1-573-884-4595
| |
Collapse
|
|
15
|
El-Mahdy HA, Sallam AAM, Ismail A, Elkhawaga SY, Elrebehy MA, Doghish AS. miRNAs inspirations in hepatocellular carcinoma: Detrimental and favorable aspects of key performers. Pathol Res Pract 2022; 233:153886. [PMID: 35405621 DOI: 10.1016/j.prp.2022.153886] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/23/2022] [Accepted: 04/01/2022] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. HCC initiation, progression, and therapy failure are all influenced by various variables, including microRNAs (miRNAs). miRNAs are short non-coding RNA sequences that modulate target mRNA expression by deteriorating or repressing translation. miRNAs play an imperative role in HCC pathogenesis by triggering the induction of cancer stem cells (CSCs) and their proliferation, while also delaying apoptosis, sustaining the cell cycle, and inspiring angiogenesis, invasion, and metastasis. Additionally, miRNAs modulate crucial HCC-related molecular pathways such as the p53 pathway, the Wnt/β-catenin pathway, VEGFR2, and PTEN/PI3K/AKT pathway. Consequently, the goal of this review was to give an up-to-date overview of oncogenic and tumor suppressor (TS) miRNAs, as well as their potential significance in HCC pathogenesis and treatment responses, highlighting their underpinning molecular pathways in HCC initiation and progression. Similarly, the biological importance and clinical application of miRNAs in HCC are summarized.
Collapse
Affiliation(s)
- Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
| |
Collapse
|
|
16
|
Bhatt S, Singh P, Sharma A, Rai A, Dohare R, Sankhwar S, Sharma A, Syed MA. Deciphering Key Genes and miRNAs Associated With Hepatocellular Carcinoma via Network-Based Approach. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2022; 19:843-853. [PMID: 32795971 DOI: 10.1109/tcbb.2020.3016781] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Hepatocellular carcinoma (HCC)is a common type of liver cancer and has a high mortality world-widely. The diagnosis, prognoses, and therapeutics are very poor due to the unclear molecular mechanism of progression of the disease. To unveil the molecular mechanism of progression of HCC, we extract a large sample of mRNA expression levels from the GEO database where a total of 167 samples were used for study, and out of them, 115 samples were from HCC tumor tissue. This study aims to investigate the module of differentially expressed genes (DEGs)which are co-expressed only in HCC sample data but not in normal tissue samples. Thereafter, we identified the highly significant module of significant co-expressed genes and formed a PPI network for these genes. There were only six genes (namely, MSH3, DMC1, ALPP, IL10, ZNF223, and HSD17B7)obtained after analysis of the PPI network. Out of six only MSH3, DMC1, HSD17B7, and IL10 were found enriched in GO Term & Pathway enrichment analysis and these candidate genes were mainly involved in cellular process, metabolic and catalytic activity, which promote the development & progression of HCC. Lastly, the composite 3-node FFL reveals the driver miRNAs and TFs associated with our key genes.
Collapse
|
|
17
|
Li Y, Lv Y, Wang J, Zhu X, Chen J, Zhang W, Wang C, Jiang L. LncRNA NORAD Mediates the Proliferation and Apoptosis of Diffuse Large-B-Cell Lymphoma via Regulation of miR-345-3p/TRAF6 Axis. Arch Med Res 2022; 53:271-279. [DOI: 10.1016/j.arcmed.2022.01.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/19/2021] [Accepted: 01/25/2022] [Indexed: 12/27/2022]
|
|
18
|
Zhang K, Xu PL, Li YJ, Dong S, Gao HF, Chen LY, Chen H, Chen Z. Comprehensive analysis of expression profile and prognostic significance of interferon regulatory factors in pancreatic cancer. BMC Genom Data 2022; 23:5. [PMID: 35012444 PMCID: PMC8751298 DOI: 10.1186/s12863-021-01019-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 12/13/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is a highly lethal disease and an increasing cause of cancer-associated mortality worldwide. Interferon regulatory factors (IRFs) play vital roles in immune response and tumor cellular biological processes. However, the specific functions of IRFs in PC and tumor immune response are far from systematically clarified. This study aimed to explorer the expression profile, prognostic significance, and biological function of IRFs in PC. RESULTS We observed that the levels of IRF2, 6, 7, 8, and 9 were elevated in tumor compared to normal tissues in PC. IRF7 expression was significantly associated with patients' pathology stage in PC. PC patients with high IRF2, low IRF3, and high IRF6 levels had significantly poorer overall survival. High mRNA expression, amplification and, deep deletion were the three most common types of genetic alterations of IRFs in PC. Low expression of IRF2, 4, 5, and 8 was resistant to most of the drugs or small molecules from Genomics of Drug Sensitivity in Cancer. Moreover, IRFs were positively correlated with the abundance of tumor infiltrating immune cells in PC, including B cells, CD8+ T cells, CD4+ T cells, macrophages, Neutrophil, and Dendritic cells. Functional analysis indicated that IRFs were involved in T cell receptor signaling pathway, immune response, and Toll-like receptor signaling pathway. CONCLUSIONS Our results indicated that certain IRFs could serve as potential therapeutic targets and prognostic biomarkers for PC patients. Further basic and clinical studies are needed to validate our findings and generalize the clinical application of IRFs in PC.
Collapse
Affiliation(s)
- Ke Zhang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Pan-Ling Xu
- Chinese Integrative Medicine Oncology Department, First Affiliated Hospital of Anhui Medical University, Hefei, 230000 Anhui China
| | - Yu-Jie Li
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Shu Dong
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Hui-Feng Gao
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Lian-Yu Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Hao Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Zhen Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| |
Collapse
|
|
19
|
Xu W, Hu B, Cheng Y, Guo Y, Yao W, Qian H. Echinacea purpurea suppresses the cell survival and metastasis of hepatocellular carcinoma through regulating the PI3K/Akt pathway. Int J Biochem Cell Biol 2022; 142:106115. [PMID: 34743003 DOI: 10.1016/j.biocel.2021.106115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/22/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022]
Abstract
Echinacea purpurea (L.) Moench (Ep) is widely used as a kind of dietary supplements, and possesses various pharmacological activities, including immunomodulatory, anti-inflammatory, antitumor effects. However, the inhibitory effects of Ep on the growth and metastasis of hepatocellular carcinoma (HCC) is unclear. Here, the preventive effect and potential mechanism of Ep on HCC was elucidated by systems pharmacology and molecular docking. The results showed that Ep could significantly ameliorate HCC-induced tumor growth and migration in vivo and in vitro. System pharmacology results indicated that 180 genes associated with HCC were regarded as the potential therapeutic targets of Ep, mainly involved in metabolic pathways, cancer pathways, proteoglycans in cancer and PI3K/Akt signaling pathway, which might be a crucial pathway in HCC EMT. A herb-component-target-pathway network was constructed to reveal the interactions between Ep and HCC. Finally, predicted PI3K/Akt pathway was further validated by molecular docking and western blot experiment. This study showed that Ep ameliorates HCC-induced tumor cell survival and migration in mice via the regulation of the PI3K/Akt pathway. Thus, Ep might be a potential new strategy to prevent the growth and metastasis of HCC.
Collapse
Affiliation(s)
- Wenqian Xu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, Wuxi 214122, China
| | - Bin Hu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, Wuxi 214122, China
| | - Yuliang Cheng
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, Wuxi 214122, China
| | - Yahui Guo
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, Wuxi 214122, China
| | - Weirong Yao
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - He Qian
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, Wuxi 214122, China.
| |
Collapse
|
|
20
|
Guo L, Fang T, Jiang Y, Liu D. IRF7 is a Prognostic Biomarker and Associated with Immune Infiltration in Stomach Adenocarcinoma. Int J Gen Med 2021; 14:9887-9902. [PMID: 34938108 PMCID: PMC8687632 DOI: 10.2147/ijgm.s342607] [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: 10/17/2021] [Accepted: 11/30/2021] [Indexed: 12/21/2022] Open
Abstract
Background Stomach adenocarcinoma (STAD) is one of the most prevalent malignances, ranking fifth in incidence and third in mortality among all malignances. Interferon regulatory factors (IRFs) play a vital role in immune response and tumor cellular biological process. The roles of IRFs in STAD are far from being systematically clarified. Methods A series of bioinformatics tools, including GEPIA, UALCAN, TIMER, Kaplan–Meier plotter and LinkedOmics, were applied to explore the expression and clinical significance of IRFs in STAD. Results IRF3/7 expression were upregulated in STAD in sub-group analyses based on race, gender, age, H. Pylori infection status, histological subtypes, tumor grade, individual cancer stages, and nodal metastasis status. High IRF3/7 expression were associated with poor overall survival (OS), post-progression survival (PFPS) and first progression (FP) in STAD. IRF3 and IRF7 were altered in 5% and 6% of all TCGA STAD patients. Further analysis revealed that IRF7 was significantly associated with the abundance of immune cells (B cells, Neutrophils and Dendritic cells) and the expression of most immune biomarkers. Enrichment analysis indicated that IRF7 was mainly involved in adaptive immune response, NOD-like receptor signaling pathway, Necroptosis, and Toll-like receptor signaling pathway. We also identified several IRF7-associated kinase and miRNA targets in STAD. The result of verified experiment revealed that ITF7 expression was increased in STAD tissues compared with normal tissues and prognosis analysis revealed that STAD patients with high IRF7 expression had a poor overall survival. Conclusion IRF7 is upregulated in STAD and associated with poor OS, PPS and FP. Moreover, IRF7 is significantly associated with the abundance of immune cells and the expression of most immune biomarkers, suggesting that IRF7 is as a prognostic biomarker and associated with immune infiltration in STAD.
Collapse
Affiliation(s)
- Lili Guo
- Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, 110001, People's Republic of China
| | - Te Fang
- Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, 110001, People's Republic of China
| | - Yanhua Jiang
- Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, 110001, People's Republic of China
| | - Dingsheng Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, People's Republic of China
| |
Collapse
|
|
21
|
Emerging Role of miR-345 and Its Effective Delivery as a Potential Therapeutic Candidate in Pancreatic Cancer and Other Cancers. Pharmaceutics 2021; 13:pharmaceutics13121987. [PMID: 34959269 PMCID: PMC8707074 DOI: 10.3390/pharmaceutics13121987] [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: 10/18/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis. Dysregulated miRNAs are associated with molecular pathways involved in tumor development, metastasis, and chemoresistance in PDAC, as well as other cancers. Targeted treatment strategies that alter miRNA levels in cancers have promising potential as therapeutic interventions. miRNA-345 (miR-345) plays a critical role in tumor suppression and is differentially expressed in various cancers, including pancreatic cancer (PC). The underlying mechanism(s) and delivery strategies of miR-345 have been investigated by us previously. Here, we summarize the potential therapeutic roles of miR-345 in different cancers, with emphasis on PDAC, for miRNA drug discovery, development, status, and implications. Further, we focus on miRNA nanodelivery system(s), based on different materials and nanoformulations, specifically for the delivery of miR-345.
Collapse
|
|
22
|
Xu X, Wu Y, Yi K, Hu Y, Ding W, Xing C. IRF1 regulates the progression of colorectal cancer via interferon‑induced proteins. Int J Mol Med 2021; 47:104. [PMID: 33907823 PMCID: PMC8054637 DOI: 10.3892/ijmm.2021.4937] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 03/17/2021] [Indexed: 12/21/2022] Open
Abstract
Radiation is one of the main methods for the treatment of colorectal cancer (CRC) before or after surgery. However, radiotherapy tolerance of patients with CRC is often a major concern. Interferon regulatory factor 1 (IRF1) is a member of the IRF family and is involved in the development of multiple diseases, including tumors. The present study investigated the role of IRF1 in the development and radiation sensitivity of CRC. Immunohistochemistry was performed to examine the expression levels of IRF1 in tissue samples from patients with CRC, as well as in nude mice. MTT, 5‑ethynyl‑20‑deoxyuridine, colony formation, cell cycle alteration and apoptosis assays were performed in CRC cell lines. Western blotting and immunofluorescence were used to detect the expression levels of a series of proteins. RNA sequencing was applied to identify genes whose expression was upregulated by IRF1 overexpression. Xenograft nude mouse models and hematoxylin and eosin staining were used to validate the present findings in vivo. It was revealed that the expression levels of IRF1 were significantly lower in CRC tissues than in adjacent tissues. IRF1 upregulation inhibited cell proliferation and colony formation, caused G1 cell arrest, promoted cell apoptosis, and enhanced the sensitivity of CRC cells to X‑ray irradiation. The role of IRF1 in promoting the radiosensitivity of CRC was further demonstrated in nude mice with CRC xenografts. In addition, RNA sequencing revealed that overexpression of IRF1 in CRC cells significantly increased the expression levels of interferon‑induced protein family members interferon α inducible protein 6, interferon induced transmembrane protein 1 and interferon induced protein 35 (fold change >2.0). In summary, the present study demonstrated that the upregulation of IRF1 inhibited the progression and promoted the radiosensitivity of CRC, likely by regulating interferon‑induced proteins.
Collapse
Affiliation(s)
- Xiaohui Xu
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
- Department of General Surgery, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215400, P.R. China
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215400, P.R. China
- Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
| | - Yong Wu
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Ke Yi
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Yan Hu
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Weiqun Ding
- Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
| | - Chungen Xing
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| |
Collapse
|
|
23
|
Epigenetic Regulation of Hepatocellular Carcinoma Progression through the mTOR Signaling Pathway. Can J Gastroenterol Hepatol 2021; 2021:5596712. [PMID: 34123955 PMCID: PMC8169250 DOI: 10.1155/2021/5596712] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 05/11/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is an aggressive tumor with a high mortality rate because of the limited systemic and locoregional treatment modalities. The development and progression of HCC depend on epigenetic changes that result in the activation or inhibition of some signaling pathways. The mTOR signaling pathway is essential for many pathophysiological processes and is considered a major regulator of cancer. Increasing evidence has shown that epigenetics plays a key role in HCC biology by regulating the mTOR signaling pathway. Therefore, epigenetic regulation through the mTOR signaling pathway to diagnose and treat HCC will become a very promising strategy.
Collapse
|
|
24
|
Tao H, Li J, Liu J, Yuan T, Zhang E, Liang H, Huang Z. Construction of a ceRNA Network and a Prognostic lncRNA Signature associated with Vascular Invasion in Hepatocellular Carcinoma based on Weighted Gene Co-Expression Network Analysis. J Cancer 2021; 12:3754-3768. [PMID: 34093785 PMCID: PMC8176257 DOI: 10.7150/jca.57260] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/21/2021] [Indexed: 12/28/2022] Open
Abstract
Background: Understanding risk factors for vascular invasion (VI) is crucial for assessing the risk of recurrence and overall prognosis of hepatocellular carcinoma (HCC). This study aimed to construct a prognostic long non-coding RNA (lncRNA) signature and a ceRNA Network associated with vascular invasion in HCC. Methods: Differentially expressed genes (DEGs) of HCC patients associated with VI were identified by analyzing data from TCGA. Weighted gene co-expression network analysis (WGCNA) was used to identify associations between gene expression modules and clinical features. A VI-related prognostic lncRNA signature was then established using univariate, LASSO and multivariate Cox proportional hazards regression analyses. Based on the hub modules identified by the WGCNA, we constructed a VI-related lncRNA-miRNA-mRNA ceRNA network and screened hub lncRNAs for further research. Finally, we conducted in vitro and in vivo experiments to determine the biological roles of the identified hub gene BBOX1-AS1. Results: The key module related to VI and OS was identified using WGCNA, after which a prognostic model consisting of eight lncRNAs was established, and verified using time-dependent receiver operating characteristic (ROC) curve analysis. BBOX1-AS1 was confirmed to be highly expressed in HCC tissues, and its expression was significantly correlated with a poor prognosis. Silencing BBOX1-AS1 in vitro significantly suppressed the proliferation, migration and invasion of HCC cells. In vivo experiments demonstrated that knocking down of BBOX1-AS1 could result in significant decrease of tumor volume and tumor weight. Conclusions: The VI-related lncRNA signature established in this study can be used to predict the clinical outcomes of HCC patients. In addition, we constructed a VI-related lncRNA-miRNA-mRNA ceRNA network and demonstrated that BBOX1-AS1 might be a novel biomarker associated with VI in HCC.
Collapse
Affiliation(s)
- Haisu Tao
- Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Jiang Li
- Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Junjie Liu
- Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Tong Yuan
- Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Erlei Zhang
- Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Zhiyong Huang
- Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| |
Collapse
|
|
25
|
Yang G, Wang G, Xiong Y, Sun J, Li W, Tang T, Li J. CDC20 promotes the progression of hepatocellular carcinoma by regulating epithelial‑mesenchymal transition. Mol Med Rep 2021; 24:483. [PMID: 33907851 PMCID: PMC8127032 DOI: 10.3892/mmr.2021.12122] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 03/29/2021] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of primary liver cancer, which is associated with high mortality. HCC is one of the most common malignant tumors worldwide. Cell division cycle 20 (CDC20) has been reported to be associated with the development of various malignant tumors and epithelial-mesenchymal transition (EMT) has been reported to be involved in the malignant metastasis of HCC. Therefore, the present study hypothesized that CDC20 may participate in the malignant biological behavior of HCC via EMT. The present study analyzed the expression levels of CDC20 in HCC and the association between CDC20 and poor prognosis. Furthermore, the effects of CDC20 on the proliferation, invasion and migration of HCC cells were examined using proliferation, migration and invasion assays. Finally, alterations in EMT were analyzed. The results revealed that CDC20 was highly expressed in HCC and HCC cell lines (P<0.05), and its high expression level was significantly associated with poor prognosis in patients with HCC (P<0.05). CDC20 silencing inhibited the proliferation, migration and invasion of HCC cells. Furthermore, CDC20 silencing increased the expression levels of E-cadherin, and decreased the expression levels of N-cadherin, vimentin and Ki-67. In conclusion, the present study reported that CDC20 may be a novel therapeutic target in HCC and CDC20 could promote the progression of HCC by regulating EMT.
Collapse
Affiliation(s)
- Gang Yang
- Department of Hepatocellular Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Guan Wang
- Physical Examination Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Yongfu Xiong
- Department of Hepatocellular Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Ji Sun
- Department of Hepatocellular Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Weinan Li
- Department of Hepatocellular Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Tao Tang
- Department of Hepatocellular Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| | - Jingdong Li
- Department of Hepatocellular Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
| |
Collapse
|
|
26
|
Liu XY, Wang JQ, Ashby CR, Zeng L, Fan YF, Chen ZS. Gold nanoparticles: synthesis, physiochemical properties and therapeutic applications in cancer. Drug Discov Today 2021; 26:1284-1292. [PMID: 33549529 DOI: 10.1016/j.drudis.2021.01.030] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 08/12/2020] [Accepted: 01/29/2021] [Indexed: 02/07/2023]
Abstract
Gold nanoparticles (AuNPs) have been shown to be useful as carriers of various anticancer drugs as well as diagnosis platforms. In this review, we discuss the synthesis and physiochemical properties of AuNPs. We also highlight the photothermal and photodynamic properties of AuNPs and relevant applications in therapeutic studies. Furthermore, we review the applications of AuNPs in cancer treatment as and their underlying anticancer mechanisms in multiple types of cancer.
Collapse
Affiliation(s)
- Xin-Yu Liu
- School of Clinical Medicine, Weifang Medical University, Weifang 261053, Shandong, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA
| | - Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA
| | - Leli Zeng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA; Precision Medicine Center, Research Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong 518107, China
| | - Ying-Fang Fan
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA; Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA.
| |
Collapse
|
|
27
|
Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
Collapse
|
|
28
|
Luo K, Zhang L, Liao Y, Zhou H, Yang H, Luo M, Qing C. Effects and mechanisms of Eps8 on the biological behaviour of malignant tumours (Review). Oncol Rep 2021; 45:824-834. [PMID: 33432368 PMCID: PMC7859916 DOI: 10.3892/or.2021.7927] [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: 08/29/2020] [Accepted: 12/09/2020] [Indexed: 12/31/2022] Open
Abstract
Epidermal growth factor receptor pathway substrate 8 (Eps8) was initially identified as the substrate for the kinase activity of EGFR, improving the responsiveness of EGF, which is involved in cell mitosis, differentiation and other physiological functions. Numerous studies over the last decade have demonstrated that Eps8 is overexpressed in most ubiquitous malignant tumours and subsequently binds with its receptor to activate multiple signalling pathways. Eps8 not only participates in the regulation of malignant phenotypes, such as tumour proliferation, invasion, metastasis and drug resistance, but is also related to the clinicopathological characteristics and prognosis of patients. Therefore, Eps8 is a potential tumour diagnosis and prognostic biomarker and even a therapeutic target. This review aimed to describe the structural characteristics, role and related molecular mechanism of Eps8 in malignant tumours. In addition, the prospect of Eps8 as a target for cancer therapy is examined.
Collapse
Affiliation(s)
- Kaili Luo
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Lei Zhang
- Department of Gynecology, Yunnan Tumor Hospital and The Third Affiliated Hospital of Kunming Medical University; Kunming, Yunnan 650118, P.R. China
| | - Yuan Liao
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Hongyu Zhou
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Hongying Yang
- Department of Gynecology, Yunnan Tumor Hospital and The Third Affiliated Hospital of Kunming Medical University; Kunming, Yunnan 650118, P.R. China
| | - Min Luo
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Chen Qing
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| |
Collapse
|
|
29
|
Ashrafizadeh M, Gholami MH, Mirzaei S, Zabolian A, Haddadi A, Farahani MV, Kashani SH, Hushmandi K, Najafi M, Zarrabi A, Ahn KS, Khan H. Dual relationship between long non-coding RNAs and STAT3 signaling in different cancers: New insight to proliferation and metastasis. Life Sci 2021; 270:119006. [PMID: 33421521 DOI: 10.1016/j.lfs.2020.119006] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/28/2020] [Accepted: 12/29/2020] [Indexed: 12/14/2022]
Abstract
Uncontrolled growth and metastasis of cancer cells is an increasing challenge for overcoming cancer, and improving survival of patients. Complicated signaling networks account for proliferation and invasion of cancer cells that need to be elucidated for providing effective cancer therapy, and minimizing their malignancy. Long non-coding RNAs (lncRNAs) are RNA molecules with a length of more than 200 nucleotides. They participate in cellular events, and their dysregulation in a common phenomenon in different cancers. Noteworthy, lncRNAs can regulate different molecular pathways, and signal transducer and activator of transcription 3 (STAT3) is one of them. STAT3 is a tumor-promoting factors in cancers due to its role in cancer proliferation (cell cycle progression and apoptosis inhibition) and metastasis (EMT induction). LncRNAs can function as upstream mediators of STAT3 pathway, reducing/enhancing its expression. This dual relationship is of importance in affecting proliferation and metastasis of cancer cells. The response of cancer cells to therapy such as chemotherapy and radiotherapy is regulated by lncRNA/STAT3 axis. Tumor-promoting lncRNAs including NEAT1, SNHG3 and H19 induces STAT3 expression, while tumor-suppressing lncRNAs such as MEG3, PTCSC3 and NKILA down-regulate STAT3 expression. Noteworthy, upstream mediators of STAT3 such as microRNAs can be regulated by lncRNAs. These complicated signaling networks are mechanistically described in the current review.
Collapse
Affiliation(s)
- Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla 34956, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey
| | | | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirabbas Haddadi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | | | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran; Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey.
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan.
| |
Collapse
|
|
30
|
Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma-A Review. Int J Mol Sci 2020; 21:ijms21218362. [PMID: 33171811 PMCID: PMC7664704 DOI: 10.3390/ijms21218362] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/05/2020] [Accepted: 11/05/2020] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is the fourth leading cause of cancer deaths globally, of which hepatocellular carcinoma (HCC) is the major subtype. Viral hepatitis B and C infections, alcohol abuse, and metabolic disorders are multiple risk factors for liver cirrhosis and HCC development. Although great therapeutic advances have been made in recent decades, the prognosis for HCC patients remains poor due to late diagnosis, chemotherapy failure, and frequent recurrence. MicroRNAs (miRNAs) are endogenous, non-coding RNAs that regulate various molecular biological phenomena by suppressing the translation of target messenger RNAs (mRNAs). miRNAs, which often become dysregulated in malignancy, control cell proliferation, migration, invasion, and development in HCC by promoting or suppressing tumors. Exploring the detailed mechanisms underlying miRNA-mediated HCC development and progression can likely improve the outcomes of patients with HCC. This review summarizes the molecular and functional roles of miRNAs in the pathogenesis of HCC. Further, it elucidates the utility of miRNAs as novel biomarkers and therapeutic targets.
Collapse
|
|
31
|
Liu J, Li SM. MiR-484 suppressed proliferation, migration, invasion and induced apoptosis of gastric cancer via targeting CCL-18. Int J Exp Pathol 2020; 101:203-214. [PMID: 32985776 DOI: 10.1111/iep.12366] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 05/22/2020] [Accepted: 06/28/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is a common and high-incidence malignant gastro-intestinal cancer that seriously threatens human life. Evidence suggests that microRNAs (miRNAs) play an essential role in regulating the occurrence and development of gastric cancer, but the possible mechanisms and effects remain to be further explored. In the present study, a new tumour suppresser function of miR-484 was identified in gastric cancer. The expression of miR-484 was obviously decreased, and the expression of CCL-18 was obviously increased in gastric cancer tissues and cell lines. In addition, upregulation of miR-484 suppressed cell proliferation, migration and invasion, and induced cell cycle arrest in G1 phase and cell apoptosis in gastric cancer cells. Besides, miR-484 mimics could block the PI3K/AKT signalling pathway. Moreover, CCL-18 was confirmed as a direct target of miR-484 by binding its 3'-UTR, and over-expression of CCL-18 could restore the effects of miR-484 on the growth and metastasis of gastric cancer. Finally, in vivo experiments showed that over-expression of miR-484 inhibited the subcutaneous tumorigenicity of gastric cancer cells, and the inhibition was blocked after over-expression of CCL-18. To conclude, miR-484 expression was downregulated in gastric cancer tissues and cells and played an anti-cancer role in the occurrence and development of gastric cancer, which may be achieved by inhibiting the expression of transcription factor CCL-18 and blocking the PI3K/AKT pathway.
Collapse
Affiliation(s)
- Jin Liu
- Department of Oncology, Suqian First Hospital, Suqian, China
| | - Shi Meng Li
- Department of Oncology, Suqian First Hospital, Suqian, China
| |
Collapse
|
|
32
|
Guo Q, Zhu X, Wei R, Zhao L, Zhang Z, Yin X, Zhang Y, Chu C, Wang B, Li X. miR-130b-3p regulates M1 macrophage polarization via targeting IRF1. J Cell Physiol 2020; 236:2008-2022. [PMID: 32853398 DOI: 10.1002/jcp.29987] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 07/07/2020] [Accepted: 07/21/2020] [Indexed: 12/12/2022]
Abstract
Polarized macrophages can be broadly classified into classically activated macrophages (M1) and alternatively activated macrophages (M2) in response to the microenvironment signals. Interferon regulatory factor 1 (IRF1) has been demonstrated to play a critical role in macrophage polarization. However, the mechanisms underlying the regulation of IRF1 expression in macrophage polarization still remain unclear. In this study, IRF1 expression was significantly increased in interferon-γ (IFN-γ) and lipopolysaccharide (LPS)-treated RAW264.7 cells. Moreover, miR-130b-3p was decreased and negatively associated with Irf1 in M1 macrophages. miR-130b-3p repressed M1 polarization by inhibiting IRF1 and subsequently reducing the levels of the targets of IRF1, C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 10 (CXCL10), inducible NO synthase (iNOS), and tumor necrosis factor (TNF). Consistent with these data, overexpressed miR-130b-3p in LPS-treated mice suppressed M1 macrophage polarization in lung macrophages and peritoneal macrophages by inhibiting Irf1 expression and alleviated the inflammation in mouse lung tissues. Furthermore, the predicted binding site between the Irf1 messenger RNA 3'-untranslated region (3'-UTR) and miR-130b-3p was confirmed by the dual-luciferase reporter assay. In conclusion, our research gave the first evidence that miR-130b-3p affected the polarization of M1 macrophages by directly inhibiting Irf1. The miR-130b-3p/IRF1 pathway may be a potential target for regulating macrophage polarization.
Collapse
Affiliation(s)
- Qiang Guo
- Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xiaoxiao Zhu
- Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Ran Wei
- Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Lin Zhao
- Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Zhen Zhang
- Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xunqiang Yin
- Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.,School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yunhong Zhang
- Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.,School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Chu Chu
- Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.,School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Bin Wang
- Department of Peripheral Vascular Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Xia Li
- Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| |
Collapse
|
|
33
|
Lin S, Zhuang J, Zhu L, Jiang Z. Matrine inhibits cell growth, migration, invasion and promotes autophagy in hepatocellular carcinoma by regulation of circ_0027345/miR-345-5p/HOXD3 axis. Cancer Cell Int 2020; 20:246. [PMID: 32549793 PMCID: PMC7296946 DOI: 10.1186/s12935-020-01293-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 05/26/2020] [Indexed: 12/14/2022] Open
Abstract
Background Matrine has been reported to exert anti-tumor effects in multiple types of cancers containing hepatocellular carcinoma (HCC). However, the anti-tumor molecular mechanisms of matrine in HCC is still not fully revealed. Methods Cell viability, apoptosis, cycle, migration and invasion were determined by Cell counting kit-8 (CCK-8), Flow cytometry and Transwell assays, respectively. Levels of all protein were analyzed by western blot analysis. The levels of circular RNA_0027345 (circ_0027345), microRNA-345-5p (miR-345-5p) and homeobox-containingD3 (HOXD3) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The interaction between circ_0027345 and circ_0027345 was identified using dual-luciferase reporter assay. The mouse xenograft model was constructed to explore the effect of matrine on tumor growth in vivo. Results Matrine suppressed cell growth, migration and invasion, while promoted apoptosis and autophagy in HCC cells. Matrine down-regulated the levels of circ_0027345 and HOXD3, and up-regulated miR-345-5p expression. Besides, circ_0027345 overexpression could reverse the inhibitory effect of matrine on cell progression. As the target gene of circ_0027345, miR-345-5p elevation counteracted the promotion effect of circ_0027345 overexpression on development of HCC cells. Moreover, miR-345-5p knockdown could facilitate cell growth, migration, invasion and repress cell apoptosis and autophagy by targeting HOXD3. Meanwhile, matrine restrained tumor growth of HCC by regulating circ_0027345/miR-345-5p/HOXD3 axis in vivo. Conclusion Matrine inhibited cell development and tumorigenesis in HCC by increasing miR-345-5p and decreasing circ_0027345 and HOXD3.
Collapse
Affiliation(s)
- Shaobing Lin
- Department of Pharmacy, Fujian Provincial Hospital, Fuzhou, China
| | - Jie Zhuang
- Department of Pharmacy, Fujian Provincial Hospital, Fuzhou, China
| | - Liping Zhu
- Department of Pharmacy, Fujian Provincial Hospital, Fuzhou, China
| | - Zongsheng Jiang
- Edinburgh University Joint Institute of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang China
| |
Collapse
|
|
34
|
Banerjee AK, Bhattacharya R, Mal C. HMG2D: A tool to identify miRNAs/drugs/genes associated with diseases like cancers. Meta Gene 2020. [DOI: 10.1016/j.mgene.2020.100699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
|
|
35
|
A dual role of Irf1 in maintaining epithelial identity but also enabling EMT and metastasis formation of breast cancer cells. Oncogene 2020; 39:4728-4740. [PMID: 32404986 DOI: 10.1038/s41388-020-1326-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 05/02/2020] [Accepted: 05/05/2020] [Indexed: 01/06/2023]
Abstract
An epithelial to mesenchymal transition (EMT) is an embryonic dedifferentiation program which is aberrantly activated in cancer cells to acquire cellular plasticity. This plasticity increases the ability of breast cancer cells to invade into surrounding tissue, to seed metastasis at distant sites and to resist to chemotherapy. In this study, we have observed a higher expression of interferon-related factors in basal-like and claudin-low subtypes of breast cancer in patients, known to be associated with EMT. Notably, Irf1 exerts essential functions during the EMT process, yet it is also required for the maintenance of an epithelial differentiation status of mammary gland epithelial cells: RNAi-mediated ablation of Irf1 in mammary epithelial cells results in the expression of mesenchymal factors and Smad transcriptional activity. Conversely, ablation of Irf1 during TGFβ-induced EMT prevents a mesenchymal transition and stabilizes the expression of E-cadherin. In the basal-like murine breast cancer cell line 4T1, RNAi-mediated ablation of Irf1 reduces colony formation and cell migration in vitro and shedding of circulating tumor cells and metastasis formation in vivo. This context-dependent dual role of Irf1 in the regulation of epithelial-mesenchymal plasticity provides important new insights into the functional contribution and therapeutic potential of interferon-regulated factors in breast cancer.
Collapse
|
|
36
|
Danbaran GR, Aslani S, Sharafkandi N, Hemmatzadeh M, Hosseinzadeh R, Azizi G, Jadidi-Niaragh F, Babaie F, Mohammadi H. How microRNAs affect the PD-L1 and its synthetic pathway in cancer. Int Immunopharmacol 2020; 84:106594. [PMID: 32416456 DOI: 10.1016/j.intimp.2020.106594] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/27/2020] [Accepted: 05/08/2020] [Indexed: 12/17/2022]
Abstract
Programmed cell death-ligand 1 (PD-L1) is a glycoprotein that is expressed on the cell surface of both hematopoietic and nonhematopoietic cells. PD-L1 play a role in the immune tolerance and protect self-tissues from immune system attack. Dysfunction of this molecule has been highlighted in the pathogenesis of tumors, autoimmunity, and infectious disorders. MicroRNAs (miRNAs) are endogenous molecules that are classified as small non-coding RNA with approximately 20-22 nucleotides (nt) length. The function of miRNAs is based on complementary interactions with target mRNA via matching completely or incompletely. The result of this function is decay of the target mRNA or preventing mRNA translation. In the past decades, several miRNAs have been discovered which play an important role in the regulation of PD-L1 in various malignancies. In this review, we discuss the effect of miRNAs on PD-L1 expression and consider the effect of miRNAs on the synthetic pathway of PD-L1, especially during cancers.
Collapse
Affiliation(s)
| | - Saeed Aslani
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nadia Sharafkandi
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Maryam Hemmatzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Hosseinzadeh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Babaie
- Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
| |
Collapse
|
|
37
|
Zhang J, Wang C, Yan S, Yang Y, Zhang X, Guo W. miR-345 inhibits migration and stem-like cell phenotype in gastric cancer via inactivation of Rac1 by targeting EPS8. Acta Biochim Biophys Sin (Shanghai) 2020; 52:259-267. [PMID: 32147678 DOI: 10.1093/abbs/gmz166] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 11/18/2019] [Accepted: 12/27/2019] [Indexed: 01/02/2023] Open
Abstract
Tumor metastasis is the main cause of treatment failure and death in patients with late stage of gastric cancer (GC). Studies showed that microRNAs (miRNAs) are important regulators in the process of tumor metastasis. In this study, we used miRNA array analysis to search for metastasis-associated miRNAs in primary and matched metastasis tissues of patients with GC and found that miR-345-5p (miR-345) was significantly higher in primary sites. Decreased expression of miR-345 was observed in GC tissues and cell lines, which was correlated with aggressive stage and grade. Patients with a higher level of miR-345 had a better prognosis. miR-345 could inhibit the migration and spheroid formation abilities in GC cell lines in transwell assay and spheroid formation assay. RNA sequencing and bioinformatics analysis revealed that miR-345 downregulated the epidermal growth factor receptor pathway substrate 8 (EPS8) and its downstream Rac1 signaling. Mechanistically, we confirmed that miR-345 could target EPS8 by directly binding to its 3' untranslated region by luciferase reporter assay. Further rescue assay showed that the ability of miR-345 in inhibiting the migration, stem-like cell phenotype, and epithelial-mesenchymal transition (EMT) in GC was partly dependent on targeting EPS8. In conclusion, miR-345 plays an inhibitory role in GC metastasis through inhibiting cell migration, EMT, and cancer stem cell phenotype via inactivation of Rac1 signaling by targeting EPS8, which provides the potential therapeutic and predictive value of miR-345 in GC.
Collapse
Affiliation(s)
- Jieyun Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Chenchen Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Shican Yan
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yanan Yang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiaowei Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| |
Collapse
|
|
38
|
Abstract
Abdominal tumors (AT) in children account for approximately 17% of all pediatric solid tumor cases, and frequently exhibit embryonal histological features that differentiate them from adult cancers. Current molecular approaches have greatly improved the understanding of the distinctive pathology of each tumor type and enabled the characterization of novel tumor biomarkers. As seen in abdominal adult tumors, microRNAs (miRNAs) have been increasingly implicated in either the initiation or progression of childhood cancer. Moreover, besides predicting patient prognosis, they represent valuable diagnostic tools that may also assist the surveillance of tumor behavior and treatment response, as well as the identification of the primary metastatic sites. Thus, the present study was undertaken to compile up-to-date information regarding the role of dysregulated miRNAs in the most common histological variants of AT, including neuroblastoma, nephroblastoma, hepatoblastoma, hepatocarcinoma, and adrenal tumors. Additionally, the clinical implications of dysregulated miRNAs as potential diagnostic tools or indicators of prognosis were evaluated.
Collapse
|
|
39
|
Chen W, Tang D, Ou M, Dai Y. Mining Prognostic Biomarkers of Hepatocellular Carcinoma Based on Immune-Associated Genes. DNA Cell Biol 2020; 39:499-512. [PMID: 32069130 DOI: 10.1089/dna.2019.5099] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
This research aims to investigate the immune-associated gene signature from databases to improve the prognostic value in hepatocellular carcinoma (HCC) by multidimensional methods using various bioinformatic methods. Fifty-one immune-associated genes were mined out, which were associated with clinical characters through univariate and multivariate Cox regression analyses, and 51 immune-associated genes could be well-divided HCC samples into high-risk and low-risk clusters. Next, we performed least absolute shrinkage and selection operator (LASSO) Cox regression method to reveal 18 immune-associated genes' signature and calculate risk score of each gene for receiver operating characteristic (ROC) analysis. Comparing with low-risk cluster, high-risk cluster had higher risk score with unfavorable prognosis. Then, multivariate Cox regression analysis showed that risk score of 18 immune-associated genes' signature was associated with tumor invasion and tumor-node-metastasis (TNM) stage. ROC analysis indicated combined TNM stage, and risk score performed more sensitive and specific than single TNM stage or risk score in survival prediction. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the pathways enriched in tumorigenesis were related to risk score, and those pathways could separate HCC samples into high and low clusters. In addition, the survival prediction of 18 immune-associated genes' signature was well validated in independent test data set, external data set, and Real-time Quantitative PCR (RT-qPCR) experiment. The 18 immune-associated genes' signature was constructed, which could be used in effective prediction of HCC prognosis.
Collapse
Affiliation(s)
- Wenbiao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Clinical Medical Research Center, The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Donge Tang
- Clinical Medical Research Center, The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, China
| | - Minglin Ou
- Scientific Research Center, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Yong Dai
- Clinical Medical Research Center, The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, China
| |
Collapse
|
|
40
|
Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial-Mesenchymal Transition. Cells 2020; 9:cells9010217. [PMID: 31952344 PMCID: PMC7017057 DOI: 10.3390/cells9010217] [Citation(s) in RCA: 306] [Impact Index Per Article: 61.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/06/2020] [Accepted: 01/13/2020] [Indexed: 12/23/2022] Open
Abstract
The JAK/STAT3 signaling pathway plays an essential role in various types of cancers. Activation of this pathway leads to increased tumorigenic and metastatic ability, the transition of cancer stem cells (CSCs), and chemoresistance in cancer via enhancing the epithelial–mesenchymal transition (EMT). EMT acts as a critical regulator in the progression of cancer and is involved in regulating invasion, spread, and survival. Furthermore, accumulating evidence indicates the failure of conventional therapies due to the acquisition of CSC properties. In this review, we summarize the effects of JAK/STAT3 activation on EMT and the generation of CSCs. Moreover, we discuss cutting-edge data on the link between EMT and CSCs in the tumor microenvironment that involves a previously unknown function of miRNAs, and also discuss new regulators of the JAK/STAT3 signaling pathway.
Collapse
|
|
41
|
Huang JX, Wu YC, Cheng YY, Wang CL, Yu CJ. IRF1 Negatively Regulates Oncogenic KPNA2 Expression Under Growth Stimulation and Hypoxia in Lung Cancer Cells. Onco Targets Ther 2020; 12:11475-11486. [PMID: 31920336 PMCID: PMC6939401 DOI: 10.2147/ott.s221832] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 12/11/2019] [Indexed: 12/11/2022] Open
Abstract
Purpose Karyopherin alpha 2 (KPNA2) has been reported as an oncogenic protein in numerous human cancers and is currently considered a potential therapeutic target. However, the transcriptional regulation and physiological conditions underlying KPNA2 expression remain unclear. The aim of the present study was to investigate the role and regulation of interferon regulatory factor-1 (IRF1) in modulating KPNA2 expression in lung adenocarcinoma (ADC). Materials and methods Bioinformatics tools and chromatin immunoprecipitation were used to analyze the transcription factor (TF) binding sites in the KPNA2 promoter region. We searched for a potential role of IRF1 in non-small-cell lung cancer (NSCLC) using Oncomine and Kaplan-Meier Plotter datasets. qRT-PCR was applied to examine the role of IRF1 and signaling involved in regulating KPNA2 transcription. Western blotting was used to determine the effects of extracellular stimulation and intracellular signaling on the modulation of KPNA2-related TF expression. Results IRF1 was identified as a novel TF that suppresses KPNA2 gene expression. We observed that IRF1 expression was lower in cancerous tissues than in normal lung tissues and that its low expression was correlated with poor prognosis in NSCLC. Notably, both ataxia telangiectasia mutated (ATM) and mechanistic target of rapamycin (mTOR) inhibitors reduced KPNA2 expression, which was accompanied by increased expression of IRF1 but decreased expression of E2F1, a TF that promotes KPNA2 expression in lung ADC cells. IRF1 knockdown restored the reduced levels of KPNA2 in ATM inhibitor-treated cells. We further demonstrated that epidermal growth factor (EGF)-activated mTOR and hypoxia-induced ATM suppressed IRF1 expression but promoted E2F1 expression, which in turn upregulated KPNA2 expression in lung ADC cells. Conclusion IRF1 acts as a potential tumor suppressor in NSCLC. EGF and hypoxia promote KPNA2 expression by simultaneously suppressing IRF1 expression and enhancing E2F1 expression in lung ADC cells. Our study provides new insights into targeted therapy for lung cancer.
Collapse
Affiliation(s)
- Jie-Xin Huang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Cheng Wu
- Department of Thoracic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ya-Yun Cheng
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chih-Liang Wang
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chia-Jung Yu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| |
Collapse
|
|
42
|
Zhang Y, Huang B, Chen Z, Yang S. Knockdown of LINC00473 Enhances Radiosensitivity in Hepatocellular Carcinoma via Regulating the miR-345-5p/FOXP1 Axis. Onco Targets Ther 2020; 13:173-183. [PMID: 32021265 PMCID: PMC6957929 DOI: 10.2147/ott.s240113] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 12/24/2019] [Indexed: 12/24/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Radioresistance is a significant obstacle in HCC therapy. Long non-coding RNA 473 (LINC00473) has been found to impair the effect of radiotherapy. This study aimed to explore the function and molecular basis of LINC00473 in the radiosensitivity of HCC cells. Methods The levels of LINC00473, miR-345-5p and Forkhead Box P1 (FOXP1) were determined by quantitative real-time polymerase chain reaction. Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Survival fraction was calculated by colony survival assay after exposure to different doses of radiation. Cell apoptosis was evaluated by flow cytometry. The interaction among LINC00473, miR-345-5p and FOXP1 was confirmed by dual-luciferase reporter assay. The protein level of FOXP1 was detected by Western blot assay. Results LINC00473 and FOXP1 were up-regulated, while miR-345-5p was down-regulated in HCC tissues and cells. Radiation elevated LINC00473 expression in a dose- and time-dependent manner. Depletion of LINC00473 inhibited proliferation and heightened radiosensitivity and apoptosis in HCC cells. In addition, LINC00473 was a sponge of miR-345-5p. Also, miR-345-5p overexpression sensitized HCC cells to radiation. Moreover, miR-345-5p directly targeted FOXP1. MiR-345-5p inhibition or FOXP1 up-regulation reversed the enhanced radiosensitivity caused by LINC00473 knockdown. Conclusion LINC00473 contributed to radioresistance in HCC via modulating the miR-345-5p/FOXP1 axis, which might provide a promising diagnostic marker for HCC radiotherapy.
Collapse
Affiliation(s)
- Yuhong Zhang
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, People's Republic of China
| | - Bo Huang
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, People's Republic of China
| | - Zhi Chen
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, People's Republic of China
| | - Shiming Yang
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, People's Republic of China
| |
Collapse
|
|
43
|
Zhao M, Wang K, Shang J, Liang Z, Zheng W, Gu J. MiR-345-5p inhibits tumorigenesis of papillary thyroid carcinoma by targeting SETD7. Arch Med Sci 2020; 16:888-897. [PMID: 32542092 PMCID: PMC7286325 DOI: 10.5114/aoms.2019.83823] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 01/08/2019] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION This study aimed to explore the effects of miR-345-5p on papillary thyroid carcinoma (PTC) and uncover the possible mechanisms. MATERIAL AND METHODS MiR-345-5p and SETD7 mRNA levels were analyzed by quantitative real-time PCR and SETD7 protein level was measured by Western blot. The viability, colony formation ability and apoptosis of PTC cells were measured with CCK-8, soft agar colony formation and flow cytometry assay, respectively. Luciferase reporter assay was used to identify miR-345-5p's target. RESULTS Compared to neighboring normal tissues, there was lower miR-345-5p expression and higher SETD7 expression in PTC tissues. Moreover, Spearman's correlation analysis indicated that there was a negative correlation between miR-345-5p and SETD7 expression in PTC tissues. MiR-345-5p mimics inhibited the viability and colony formation of TPC1 and B-CPAP cells and promoted apoptosis, whereas anti-miR-345-5p promoted PTC cell proliferation and inhibited apoptosis. SETD7 was confirmed to be a direct target of miR-345-5p through target scan analysis and luciferase reporter assay. Additionally, overexpression of SETD7 promoted the viability and colony formation of TPC1 and B-CPAP cells and inhibited apoptosis, whereas downregulation of SETD7 by shRNAs had opposite effects on PTC cells. Furthermore, overexpression of SETD7 attenuated the miR-345-5p induced anti-tumor effects on PTC cells. CONCLUSIONS MiR-345-5p exhibited suppressive effects on PTC via targeting SETD7.
Collapse
Affiliation(s)
| | - Kejing Wang
- Corresponding author: Kejing Wang, Department of Head and Neck Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China, Phone: +86 571 88122233, Fax: +86 571 88122233, E-mail:
| | | | | | | | | |
Collapse
|
|
44
|
Weidle UH, Schmid D, Birzele F, Brinkmann U. MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance. Cancer Genomics Proteomics 2020; 17:1-21. [PMID: 31882547 PMCID: PMC6937123 DOI: 10.21873/cgp.20163] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is responsible for the second-leading cancer-related death toll worldwide. Although sorafenib and levantinib as frontline therapy and regorafenib, cabazantinib and ramicurimab have now been approved for second-line therapy, the therapeutic benefit is in the range of only a few months with respect to prolongation of survival. Aggressiveness of HCC is mediated by metastasis. Intrahepatic metastases and distant metastasis to the lungs, lymph nodes, bones, omentum, adrenal gland and brain have been observed. Therefore, the identification of metastasis-related new targets and treatment modalities is of paramount importance. In this review, we focus on metastasis-related microRNAs (miRs) as therapeutic targets for HCC. We describe miRs which mediate or repress HCC metastasis in mouse xenograft models. We discuss 18 metastasis-promoting miRs and 35 metastasis-inhibiting miRs according to the criteria as outlined. Six of the metastasis-promoting miRs (miR-29a, -219-5p, -331-3p, 425-5p, -487a and -1247-3p) are associated with unfavourable clinical prognosis. Another set of six down-regulated miRs (miR-101, -129-3p, -137, -149, -503, and -630) correlate with a worse clinical prognosis. We discuss the corresponding metastasis-related targets as well as their potential as therapeutic modalities for treatment of HCC-related metastasis. A subset of up-regulated miRs -29a, -219-5p and -425-5p and down-regulated miRs -129-3p and -630 were evaluated in orthotopic metastasis-related models which are suitable to mimic HCC-related metastasis. Those miRNAs may represent prioritized targets emerging from our survey.
Collapse
Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Daniela Schmid
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| |
Collapse
|
|
45
|
MicroRNAs in Animal Models of HCC. Cancers (Basel) 2019; 11:cancers11121906. [PMID: 31805631 PMCID: PMC6966618 DOI: 10.3390/cancers11121906] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/27/2019] [Accepted: 11/28/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.
Collapse
|
|
46
|
Zhou X, Yang J, Zhang Z, Zhang L, Lie L, Zhu B, Xu L, Gao Y, Du X, Huang Y, Wang R, Liu H, Li Y, Hu S, Zhou C, Wen Q, Pan Q, Ma L. Interferon regulatory factor 1 eliminates mycobacteria by suppressing p70 S6 kinase via mechanistic target of rapamycin signaling. J Infect 2019; 79:262-276. [DOI: 10.1016/j.jinf.2019.06.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 04/23/2019] [Accepted: 06/12/2019] [Indexed: 01/21/2023]
|
|
47
|
Jiang Y, Han QJ, Zhang J. Hepatocellular carcinoma: Mechanisms of progression and immunotherapy. World J Gastroenterol 2019; 25:3151-3167. [PMID: 31333308 PMCID: PMC6626719 DOI: 10.3748/wjg.v25.i25.3151] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 04/28/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is one of the most common malignancies, and various pathogenic factors can lead to its occurrence and development. Among all primary liver cancers, hepatocellular carcinoma (HCC) is the most common. With extensive studies, an increasing number of molecular mechanisms that promote HCC are being discovered. Surgical resection is still the most effective treatment for patients with early HCC. However, early detection and treatment are difficult for most HCC patients, and the postoperative recurrence rate is high, resulting in poor clinical prognosis of HCC. Although immunotherapy takes longer than conventional chemotherapy to produce therapeutic effects, it persists for longer. In recent years, the emergence of many new immunotherapies, such as immune checkpoint blockade and chimeric antigen receptor T cell therapies, has given new hope for the treatment of HCC.
Collapse
MESH Headings
- Adjuvants, Immunologic/administration & dosage
- Antineoplastic Agents, Immunological/therapeutic use
- Cancer Vaccines/therapeutic use
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Clinical Trials as Topic
- Disease Progression
- Humans
- Immunotherapy, Adoptive/methods
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/prevention & control
- Receptors, Chimeric Antigen/immunology
- Treatment Outcome
Collapse
Affiliation(s)
- Yu Jiang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
| | - Qiu-Ju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, China
| |
Collapse
|
|
48
|
Wang XH, Wu HY, Gao J, Wang XH, Gao TH, Zhang SF. IGF1R facilitates epithelial-mesenchymal transition and cancer stem cell properties in neuroblastoma via the STAT3/AKT axis. Cancer Manag Res 2019; 11:5459-5472. [PMID: 31354352 PMCID: PMC6580139 DOI: 10.2147/cmar.s196862] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 05/16/2019] [Indexed: 12/12/2022] Open
Abstract
Background Neuroblastoma (NB) displays the most heterogeneity in clinical manifestation. The insulin-like growth factor 1 receptor (IGF1R) has long been recognized for its role in tumourigenesis and growth. The IGF/IGF1R pathway is important in maintaining cell survival. It is reported that IGF1R participates in the occurrence of NB, but the mechanism is still unclear. Methods Human NB cell lines IMR-32 and SH-SY5Y were recruited in this study. IGF1R was knocked down by transfection with short hairpin RNA. Signal transducer and activator of transcription 3 (STAT3) expression was inhibited by Cryptotanshinone treatment. Cell proliferation, migration, and invasion were determined by MTT assay, wound healing assay, and cell invasion assay, respectively. The cancer stem cell properties were characterized by tumour sphere formation assay and colony formation assay. The mRNA and protein expression levels of related proteins were detected by RT-PCR and Western blot, respectively. Results The knockdown of IGF1R inhibits NB cell tumourigenesis and the epithelial-mesenchymal transition (EMT) of NB cells. Additionally, IGF1R was found to stimulate cancer stem cell-like properties in NPC cells. The knockdown of IGF1R significantly reduced the phosphorylation of AKT, and STAT3, indicating that the activation of the AKT and STAT3 pathways was inhibited by IGF1R knockdown. Furthermore, IGF1R was demonstrated to stimulate cancer stem cell-like properties in NB cells via the regulation of the STAT3/AKT axis. Conclusion IGF1R promotes cancer stem cell properties to facilitate EMT in neuroblastoma via the STAT3/AKT axis.
Collapse
Affiliation(s)
- Xiao-Hui Wang
- Department of Pediatric Surgery, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, People's Republic of China
| | - Hai-Ying Wu
- Department of Obstetrics, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, People's Republic of China
| | - Jian Gao
- Department of Pediatric Surgery, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, People's Republic of China
| | - Xu-Hui Wang
- Department of Pediatric Surgery, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, People's Republic of China
| | - Tian-Hui Gao
- Department of Medical Oncology, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, People's Republic of China
| | - Shu-Feng Zhang
- Department of Pediatric Surgery, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Zhengzhou 450003, People's Republic of China
| |
Collapse
|
|
49
|
Cai Y, Lin Y, Xiong X, Lu J, Zhou R, Jin Y, You Z, Ye H, Li F, Cheng N. Knockdown expression of MECR, a novel gene of mitochondrial FAS II inhibits growth and colony-formation, promotes apoptosis of hepatocelluar carcinoma cells. Biosci Trends 2019; 13:234-244. [PMID: 31178528 DOI: 10.5582/bst.2019.01109] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Mitochondrial trans-2-enoyl-CoA reductase (MECR) is a protein-coding gene, and the protein encoded by this gene is an oxidoreductase that catalyzes the last step in mitochondrial fatty acid synthesis (mtFASII). Numerous studies have shown disorder of lipid metabolism is closely related with malignance, especially in liver cancer. Through pre-experiment, we found that the expression of MECR gene was highly expressed in hepatocelluar carcinoma (HCC) cell lines in vitro. This suggests that the MECR gene may play a role of oncogene in HCC. Therefore, we conducted a preliminary experimental study on the role of MECR gene in HCC cells in vitro. Objective to explore whether the MECR gene can affect the malignant biological behavior of HCC. We selected HCC cell line BEL-7404 as experimental cell, which involves the highest expression of MECR in the pre-experiment. We constructed MECR knockdwon lentivirus vector, and then infected HCC cell lines to down-regulate MECR expression, and establish negative control group (NC). Through various experiments of cytology, our study showed that knockdown of MECR inhibited cell proliferation and colony formation, promoted apoptosis, and inhibited metastasis in HCC cell lines BEL-7404. MECR might serve as a novel gene therapeutic target for the treatment of HCC. Further study is needed to elucidate the signaling pathway through which MECR functions in HCC.
Collapse
Affiliation(s)
- Yulong Cai
- Department of Biliary Surgery, West China Hospital, Sichuan University
| | - Yixin Lin
- Department of Biliary Surgery, West China Hospital, Sichuan University
| | - Xianze Xiong
- Department of Biliary Surgery, West China Hospital, Sichuan University
| | - Jiong Lu
- Department of Biliary Surgery, West China Hospital, Sichuan University
| | - Rongxing Zhou
- Department of Biliary Surgery, West China Hospital, Sichuan University
| | - Yanwen Jin
- Department of Biliary Surgery, West China Hospital, Sichuan University
| | - Zhen You
- Department of Biliary Surgery, West China Hospital, Sichuan University
| | - Hui Ye
- Department of Biliary Surgery, West China Hospital, Sichuan University
| | - Fuyu Li
- Department of Biliary Surgery, West China Hospital, Sichuan University
| | - Nansheng Cheng
- Department of Biliary Surgery, West China Hospital, Sichuan University
| |
Collapse
|
|
50
|
DUXAP10 inhibition attenuates the proliferation and metastasis of hepatocellular carcinoma cells by regulation of the Wnt/β-catenin and PI3K/Akt signaling pathways. Biosci Rep 2019; 39:BSR20181457. [PMID: 30996112 PMCID: PMC6542759 DOI: 10.1042/bsr20181457] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 03/21/2019] [Accepted: 04/09/2019] [Indexed: 12/14/2022] Open
Abstract
The long non-coding RNA DUXAP10 has been involved in the development, progression, and metastasis in several human cancers, but its biological function and underlying mechanism in hepatocellular carcinoma (HCC) still undetermined. The present study was proposed to explore the effect of DUXAP10 on the growth and metastasis of HCC cells and the potential mechanisms involved. The results showed that DUXAP10 is dramatically elevated in HCC tumor tissues and cell lines. Knockdown of DUXAP10 by DUXAP10 si-RNA significantly inhibited the cell viability, proliferation and induce the apoptosis of HCC cell line. Meanwhile, inhibition of DUXAP10 attenuates the cell migration, invasion, and epithelial-mesenchymal transition (EMT) process. No significant change of JNK MAPK pathway was detected in DUXAP10 siRNA transfected HCC cell lines. The β-catenin and pAkt levels were decreased in the Hep G2+DUXAP10 siRNA and SMMC7721+DUXAP10 siRNA groups, while the activation of Wnt/β-catenin or PI3K/Akt suppressed the inhibition of DUXAP10 siRNA on cell proliferation and migration. Collectively, DUXAP10 plays a critical role in regulating HCC development, potentially by regulating EMT and cell proliferation through the PI3K/Akt and Wnt/β-catenin signaling. Inhibition of DUXAP10 in HCC HepG2 cells could attenuate the EMT and cell proliferation and invasion. Therefore, DUXAP10 might be a promising therapy target to inhibit the growth of HCC.
Collapse
|