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Barjasteh AH, Jaseb Mazhar AleKassar R, Al-Asady AM, Latifi H, Avan A, Khazaei M, Ryzhikov M, Hassanian SM. Therapeutic Potentials of MiRNA for Colorectal Cancer Liver Metastasis Treatment: A Narrative Review. IRANIAN JOURNAL OF MEDICAL SCIENCES 2025; 50:202-219. [PMID: 40255223 PMCID: PMC12008659 DOI: 10.30476/ijms.2024.102910.3622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 11/01/2024] [Accepted: 11/26/2024] [Indexed: 04/22/2025]
Abstract
Colorectal cancer (CRC) ranks among the most prevalent cancers worldwide and is the fourth leading cause of cancer-related deaths. Metastasis poses a significant obstacle in CRC treatment, as distant metastasis, particularly to the liver, remains the primary cause of mortality. Colorectal liver metastasis (CRLM) occurs frequently due to the liver's direct vascular connection to the colorectal region via the portal vein. Standard treatment approaches for CRLM are limited; only a few patients qualify for surgical intervention, resulting in a persistently low survival rate. Additionally, resistance to chemotherapy is common, emphasizing the need for more effective targeted therapies. Emerging evidence highlights the pivotal role of microRNAs (miRNAs) in modulating critical pathways associated with CRLM, including tumor invasion, epithelial-mesenchymal transition, and angiogenesis. MiRNAs exhibit dual functions as tumor suppressors and oncogenes by targeting multiple genes, thus playing a complex role in both the initiation and progression of metastasis. The regulatory mechanisms of miRNAs could help to identify novel biomarkers for early diagnosis and prognosis of CRLM, as well as promising therapeutic targets to overcome chemoresistance. Despite numerous studies on miRNA involvement in CRC metastasis, dedicated reviews focusing on miRNAs and CRLM remain scarce. This review aims to approach targeted therapies by examining the current understanding of miRNA involvement in CRLM and exploring their potential as diagnostic, prognostic, and therapeutic agents. Through an integrative approach, we aim to provide insights that could transform CRLM management and improve patient outcomes.
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Affiliation(s)
- Amir Hossein Barjasteh
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rawa Jaseb Mazhar AleKassar
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abdulridha Mohammed Al-Asady
- Department of Medical Sciences, Faculty of Nursing, Warith Al-Anbiyaa University, Iraq
- Department of Medical Sciences, Faculty of Dentistry, University of Kerbala, Iraq
- Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanieh Latifi
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4059, Australia
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Taheri Z, Zaki-Dizaji M. Epigenetically Regulating Non-coding RNAs in Colorectal Cancer: Promises and Potentials. Middle East J Dig Dis 2025; 17:40-53. [PMID: 40322568 PMCID: PMC12048831 DOI: 10.34172/mejdd.2025.404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Accepted: 12/09/2024] [Indexed: 05/08/2025] Open
Abstract
Colorectal cancer (CRC) is a common malignancy with high mortality. Despite advancements in understanding its molecular causes and improved drug therapies, patient survival rates remain low. The main reasons for the high mortality rate are cancer metastasis and the emergence of drug-resistant cancer cell populations. While genetic changes are recognized as the main driver of CRC occurrence and progression, recent studies suggest that epigenetic regulation is a crucial marker in cancer, influencing the interplay between genetics and the environment. Research has shown the significant regulatory roles of non-coding RNAs (ncRNAs) in CRC development. This review explores epigenetically regulated ncRNAs and their functions, aiming to understand key regulatory mechanisms that impact CRC development. Additionally, it discusses the potential use of these ncRNAs in CRC diagnosis, prognosis, and targeted treatments.
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Affiliation(s)
- Zahra Taheri
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Majid Zaki-Dizaji
- Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Vahidi S, Agah S, Mirzajani E, Asghari Gharakhyli E, Norollahi SE, Rahbar Taramsari M, Babaei K, Samadani AA. microRNAs, oxidative stress, and genotoxicity as the main inducers in the pathobiology of cancer development. Horm Mol Biol Clin Investig 2024; 45:55-73. [PMID: 38507551 DOI: 10.1515/hmbci-2023-0012] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 03/06/2024] [Indexed: 03/22/2024]
Abstract
Cancer is one of the most serious leading causes of death in the world. Many eclectic factors are involved in cancer progression including genetic and epigenetic alongside environmental ones. In this account, the performance and fluctuations of microRNAs are significant in cancer diagnosis and treatment, particularly as diagnostic biomarkers in oncology. So, microRNAs manage and control the gene expression after transcription by mRNA degradation, or also they can inhibit their translation. Conspicuously, these molecular structures take part in controlling the cellular, physiological and pathological functions, which many of them can accomplish as tumor inhibitors or oncogenes. Relatively, Oxidative stress is defined as the inequality between the creation of reactive oxygen species (ROS) and the body's ability to detoxify the reactive mediators or repair the resulting injury. ROS and microRNAs have been recognized as main cancer promoters and possible treatment targets. Importantly, genotoxicity has been established as the primary reason for many diseases as well as several malignancies. The procedures have no obvious link with mutagenicity and influence the organization, accuracy of the information, or fragmentation of DNA. Conclusively, mutations in these patterns can lead to carcinogenesis. In this review article, we report the impressive and practical roles of microRNAs, oxidative stress, and genotoxicity in the pathobiology of cancer development in conjunction with their importance as reliable cancer biomarkers and their association with circulating miRNA, exosomes and exosomal miRNAs, RNA remodeling, DNA methylation, and other molecular elements in oncology.
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Affiliation(s)
- Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shahram Agah
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ebrahim Mirzajani
- Department of Biochemistry and Biophysics, School of Medicine, 37554 Guilan University of Medical Sciences , Rasht, Iran
| | | | - Seyedeh Elham Norollahi
- Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Morteza Rahbar Taramsari
- Department of Forensic Medicine, School of Medicine, 37554 Guilan University of Medical Sciences , Rasht, Iran
| | - Kosar Babaei
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran
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Kar S, Mukherjee R, Guha S, Talukdar D, Das G, Murmu N. Modulating the acetylation of α-tubulin by LncRNAs and microRNAs helps in the progression of cancer. Cell Biochem Funct 2024; 42:e3953. [PMID: 38414166 DOI: 10.1002/cbf.3953] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/20/2024] [Accepted: 02/06/2024] [Indexed: 02/29/2024]
Abstract
Malignant tumor cells go through morphological and gene expression alterations, including rearrangement of cytoskeleton proteins that promote invasion and metastasis. Microtubules form a major cytoskeleton component that plays a significant role in regulating multiple cellular activities and function depending on the presence of posttranslational modification (PTM). Acetylation is a type of PTM that generally occurs in the lysine 40 region of α-tubulin and is known to be critically associated with cancer metastasis. Current evidence demonstrates that noncoding RNAs, such as long noncoding RNA (lncRNA) and microRNA (or miRNA), which are correlated with gene regulation modulate the expression of acetylated tubulin in the development and metastasis of cancer. This review provides an overview about the role of lncRNA and miRNA in regulation of tubulin acetylation in various types of cancer.
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Affiliation(s)
- Sneha Kar
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India
| | - Rimi Mukherjee
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India
| | - Subhabrata Guha
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India
| | - Debojit Talukdar
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India
| | - Gaurav Das
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India
| | - Nabendu Murmu
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India
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Xue X, Liu Z, Liang Y, Kwon YY, Liu R, Martin D, Hui S. Glutathione peroxidase 4 suppresses manganese-dependent oxidative stress to reduce colorectal tumorigenesis. RESEARCH SQUARE 2024:rs.3.rs-3837925. [PMID: 38260380 PMCID: PMC10802749 DOI: 10.21203/rs.3.rs-3837925/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
The role of glutathione peroxidase 4 (GPX4) in ferroptosis and various cancers is well-established; however, its specific contribution to colorectal cancer has been unclear. Surprisingly, in a genetic mouse model of colon tumors, the deletion of GPX4 specifically in colon epithelial cells increased tumor burden but decreased oxidized glutathione. Notably, this specific GPX4 deletion did not enhance susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice with varied iron diets but showed vulnerability in mice with a vitamin E-deficient diet. Additionally, a high manganese diet heightened susceptibility, while a low manganese diet reduced DSS-induced colitis in colon epithelial-specific GPX4-deficient mice. Strikingly, the low manganese diet also significantly reduced colorectal cancer formation in both colon epithelial-specific GPX4-deficient and wildtype mice. Mechanistically, antioxidant proteins, especially manganese-dependent superoxide dismutase (MnSOD or SOD2), correlated with disease severity. Treatment with tempol, a superoxide dismutase mimetic radical scavenger, suppressed GPX4 deficiency-induced colorectal tumors. In conclusion, the study elucidates the critical role of GPX4 in inhibiting colorectal cancer progression by regulating oxidative stress in a manganese-dependent manner. The findings underscore the intricate interactions between GPX4, dietary factors, and their collective influence on colorectal cancer development, providing potential insights for personalized therapeutic strategies.
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Sado AI, Batool W, Ahmed A, Zafar S, Patel SK, Mohan A, Zia U, Aminpoor H, Kumar V, Tejwaney U. Role of microRNA in colorectal carcinoma (CRC): a narrative review. Ann Med Surg (Lond) 2024; 86:308-318. [PMID: 38222721 PMCID: PMC10783342 DOI: 10.1097/ms9.0000000000001494] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 11/01/2023] [Indexed: 01/16/2024] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that play a critical role in regulating gene expression by binding to target messenger RNAs (mRNAs). They were first discovered around 8 years after the identification of the first miRNA in 1993, and since then, there has been a significant increase in miRNA-related research and discoveries. MiRNAs have been implicated in various biological processes, including cancer, particularly in colorectal cancer (CRC). In CRC, miRNAs act as either oncogenes or tumor suppressors, influencing essential cellular functions such as cell proliferation, apoptosis, angiogenesis, and metastasis. The dysregulation of miRNAs in CRC can arise from different factors, leading to abnormal expression levels of their target mRNAs and subsequently affecting protein production. Consequently, miRNAs may directly target oncogenes or tumor suppressor genes, thereby contributing to cancer initiation and progression. Notably, tumors often exhibit reduced expression of mature miRNAs. In CRC research, miRNAs offer potential as diagnostic biomarkers and therapeutic targets. Specific miRNA profiles could serve as non-invasive tools for early CRC detection and risk assessment. Additionally, miRNA-based therapies present a promising approach for targeted cancer treatment by modulating miRNA expression. However, challenges related to delivery systems and long-term safety must be addressed to fully harness their therapeutic potential.
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Affiliation(s)
| | | | | | | | | | | | - Umar Zia
- Khyber Medical University, Peshawar, Pakistan
| | | | - Vikash Kumar
- The Brooklyn Hospital Center, Brooklyn, New York
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Huang L, Liang D, Zhang Y, Chen X, Chen J, Wen C, Liu H, Yang X, Yang X, Lin S. METTL3 promotes colorectal cancer metastasis by promoting the maturation of pri-microRNA-196b. J Cancer Res Clin Oncol 2023; 149:5095-5108. [PMID: 36348020 PMCID: PMC10349789 DOI: 10.1007/s00432-022-04429-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 10/16/2022] [Indexed: 11/09/2022]
Abstract
PURPOSE Methyltransferase-like 3 (METTL3), a key member of the m6A methyltransferase complex, is upregulated in multiple human malignancies and plays a role in regulating tumor migration. This study aimed to reveal the underlying mechanism by which METTL3 in regulates the metastasis of colorectal cancer (CRC). METHODS We compared METTL3 expression levels in CRC tumor tissues and adjacent nontumor tissues by immunohistochemistry (IHC). The functional roles of METTL3 in CRC were assessed by real-time cell migration assays, wound-healing assays and Transwell assays. miRNA sequencing (miRNA-seq), RNA-binding protein immunoprecipitation (RIP) assays and N6-methyladenosine immunoprecipitation (MeRIP) assays were performed to confirm the molecular mechanism underlying the involvement of METTL3 in CRC cell metastasis. RESULTS We found that METTL3 was overexpressed in CRC tissues. METTL3 knockdown significantly inhibited CRC cell migration and invasion, while METTL3 overexpression had the opposite effects. Furthermore, we demonstrated that METTL3 regulates miR-196b expression via an N6-methyladenosine (m6A)-pri-miR-196b-dependent mechanism and thereby promotes CRC metastasis. CONCLUSION This study shows the important role of METTL3 in CRC metastasis and provides novel insight into m6A modification in CRC metastasis.
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Affiliation(s)
- Lanlan Huang
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Danlu Liang
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yu Zhang
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaoting Chen
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Junxiong Chen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chuangyu Wen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Huanliang Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaorong Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiangling Yang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Shaoqiang Lin
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
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Pérez-Carrillo L, Giménez-Escamilla I, García-Manzanares M, Triviño JC, Feijóo-Bandín S, Aragón-Herrera A, Lago F, Martínez-Dolz L, Portolés M, Tarazón E, Roselló-Lletí E. Altered MicroRNA Maturation in Ischemic Hearts: Implication of Hypoxia on XPO5 and DICER1 Dysregulation and RedoximiR State. Antioxidants (Basel) 2023; 12:1337. [PMID: 37507877 PMCID: PMC10376795 DOI: 10.3390/antiox12071337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/19/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023] Open
Abstract
Ischemic cardiomyopathy (ICM) is associated with abnormal microRNA expression levels that involve an altered gene expression profile. However, little is known about the underlying causes of microRNA disruption in ICM and whether microRNA maturation is compromised. Therefore, we focused on microRNA maturation defects analysis and the implication of the microRNA biogenesis pathway and redox-sensitive microRNAs (redoximiRs). Transcriptomic changes were investigated via ncRNA-seq (ICM, n = 22; controls, n = 8) and mRNA-seq (ICM, n = 13; control, n = 10). The effect of hypoxia on the biogenesis of microRNAs was evaluated in the AC16 cell line. ICM patients showed a reduction in microRNA maturation compared to control (4.30 ± 0.94 au vs. 5.34 ± 1.07 au, p ˂ 0.05), accompanied by a deregulation of the microRNA biogenesis pathway: a decrease in pre-microRNA export (XPO5, FC = -1.38, p ˂ 0.05) and cytoplasmic processing (DICER, FC = -1.32, p ˂ 0.01). Both processes were regulated by hypoxia in AC16 cells (XPO5, FC = -1.65; DICER1, FC = -1.55; p ˂ 0.01; Exportin-5, FC = -1.81; Dicer, FC = -1.15; p ˂ 0.05). Patients displayed deregulation of several redoximiRs, highlighting miR-122-5p (FC = -2.41, p ˂ 0.001), which maintained a good correlation with the ejection fraction (r = 0.681, p ˂ 0.01). We evidenced a decrease in microRNA maturation mainly linked to a decrease in XPO5-mediated pre-microRNA export and DICER1-mediated processing, together with a general effect of hypoxia through deregulation of biogenesis pathway and the redoximiRs.
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Affiliation(s)
- Lorena Pérez-Carrillo
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Isaac Giménez-Escamilla
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - María García-Manzanares
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Medicine and Animal Surgery, Veterinary School, CEU Cardenal Herrera University, C/Lluís Vives, 1, 46115 Alfara del Patriarca, Spain
| | | | - Sandra Feijóo-Bandín
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Tr.ª da Choupana, 15706 Santiago de Compostela, Spain
| | - Alana Aragón-Herrera
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Tr.ª da Choupana, 15706 Santiago de Compostela, Spain
| | - Francisca Lago
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Tr.ª da Choupana, 15706 Santiago de Compostela, Spain
| | - Luis Martínez-Dolz
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
- Heart Failure and Transplantation Unit, Cardiology Department, University and Polytechnic La Fe Hospital, Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Manuel Portolés
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Estefanía Tarazón
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Esther Roselló-Lletí
- Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avd. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Avd. Monforte de Lemos 3-5, 28029 Madrid, Spain
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Yang MH, Ha IJ, Ahn J, Kim CK, Lee M, Ahn KS. Potential function of loliolide as a novel blocker of epithelial-mesenchymal transition in colorectal and breast cancer cells. Cell Signal 2023; 105:110610. [PMID: 36707041 DOI: 10.1016/j.cellsig.2023.110610] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/20/2023] [Accepted: 01/21/2023] [Indexed: 01/27/2023]
Abstract
Loliolide (LL), a naturally occurring monoterpenoid lactone isolated from Vicia tenuifolia Roth, can exhibit numerous pharmacological effects such as those related to anti-Parkinson, anti-oxidant, anti-cholinesterase, and anti-depressant. Epithelial-mesenchymal transition (EMT) plays a pivotal role in regulating tumor metastasis. CXCR4 and CXCR7 are G-protein-coupled receptors (GPRs), which can be stimulated by CXCL12. CXCL12/CXCR4/CXCXR7 axis can cause activation of multiple pathways including MAPKs, JAK/STAT pathway, and manganese superoxide dismutase (MnSOD) signaling. These events can initiate EMT process and induce cell invasion and migration. Here, we investigated whether LL can modulate the CXCR4 and CXCR7 and EMT process in colon cancer and breast cancer cells. We found that LL suppressed levels of CXCR4 and CXCR7, and exerted an inhibitory effect on these chemokines even after stimulation by CXCL12. LL suppressed expression of MnSOD and mesenchymal markers, whereas induced epithelial markers. In addition, LL significantly attenuated cellular invasion, migration, and metastasis. We noted that LL inhibited CXCR4/7 and EMT process even after stimulation of CXCL12 and MnSOD overexpression. Therefore, in this study, we provide evidences that targeting CXCR4/7 and MnSOD could inhibit the invasion, migration, and metastasis of cancer cells as well as negatively regulate the EMT process. Overall, our study suggested that LL might act as a potent suppressor of EMT process against colon and breast cancer cells.
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Affiliation(s)
- Min Hee Yang
- KHU-KIST Department of Converging Science and Technology and Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - In Jin Ha
- Korean Medicine Clinical Trial Center (K-CTC), Korean Medicine Hospital, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jeongjun Ahn
- College of Pharmacy, Sunchon National University, 255 Jungangno, Suncheon-si, Jeonnam 57922, Republic of Korea.
| | - Chang-Kwon Kim
- College of Pharmacy, Sunchon National University, 255 Jungangno, Suncheon-si, Jeonnam 57922, Republic of Korea.
| | - Mina Lee
- College of Pharmacy, Sunchon National University, 255 Jungangno, Suncheon-si, Jeonnam 57922, Republic of Korea.
| | - Kwang Seok Ahn
- KHU-KIST Department of Converging Science and Technology and Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
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10
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Kim NY, Ha IJ, Um JY, Kumar AP, Sethi G, Ahn KS. Loganic acid regulates the transition between epithelial and mesenchymal-like phenotypes by alleviating MnSOD expression in hepatocellular carcinoma cells. Life Sci 2023; 317:121458. [PMID: 36731649 DOI: 10.1016/j.lfs.2023.121458] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/19/2022] [Accepted: 01/25/2023] [Indexed: 01/31/2023]
Abstract
AIMS Cancer metastasis is the major cause of cancer-related deaths. There are few prior studies reported on molecules targeting C-X-C chemokine receptor (CXCR) family and manganese superoxide dismutase (MnSOD). CXCRs are known to involve in angiogenesis, metastasis, cell survival and MnSOD is reported to be related in Epithelial-mesenchymal transition (EMT). MAIN METHODS Cell viability and cell proliferation were measured by MTT and BrdU assay. Protein expression level of CXCR4/7, MMP-2/9, MnSOD, and EMT markers were evaluated by Western blot analysis. mRNA levels of Snail and Occludin were analyzed by Real-time RT-qPCR. Expression of EMT markers in cells was observed by immunocytochemistry. Cell invasion and migrations were evaluated by wound healing assay and boyden chamber assay. KEY FINDINGS We noticed that LGA abolished proliferation, invasive ability, and cellular migration. LGA down-regulated the protein levels of mesenchymal markers such as Twist, Snail, Fibronectin, and Vimentin in CXCL12-treated HCC cells. It also suppressed the gelatinolytic activity of MMP-9/2. The amplification of MnSOD increased EMT-like phenotypes but with LGA treatment, these phenotypes were markedly attenuated. The overexpression of MnSOD increased the ROS levels significantly but ROS levels were decreased upon exposure to LGA and deletion of MnSOD suppressed the levels of various mesenchymal proteins. SIGNIFICANCE LGA could function as a novel anti-metastatic agent by suppressing metastasis and EMT process via attenuation of MnSOD expression in hepatocellular carcinoma cells.
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Affiliation(s)
- Na Young Kim
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - In Jin Ha
- Korean Medicine Clinical Trial Center (K-CTC), Korean Medicine Hospital, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jae-Young Um
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
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11
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Jung YY, Um JY, Sethi G, Ahn KS. Potential Application of Leelamine as a Novel Regulator of Chemokine-Induced Epithelial-to-Mesenchymal Transition in Breast Cancer Cells. Int J Mol Sci 2022; 23:ijms23179848. [PMID: 36077241 PMCID: PMC9456465 DOI: 10.3390/ijms23179848] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/16/2022] [Accepted: 08/21/2022] [Indexed: 11/15/2022] Open
Abstract
CXCR7 and CXCR4 are G protein-coupled receptors (GPCRs) that can be stimulated by CXCL12 in various human cancers. CXCR7/4–CXCL12 binding can initiate activation of multiple pathways including JAK/STAT and manganese superoxide dismutase (MnSOD) signaling, and initiate epithelial–mesenchymal transition (EMT) process. It is established that cancer cell invasion and migration are caused because of these events. In particular, the EMT process is an important process that can determine the prognosis for cancer. Since the antitumor effect of leelamine (LEE) has been reported in various previous studies, here, we have evaluated the influence of LEE on the CXCR7/4 signaling axis and EMT processes. We first found that LEE suppressed expression of CXCR7 and CXCR4 both at the protein and mRNA levels, and showed inhibitory effects on these chemokines even after stimulation by CXCL12 ligand. In addition, LEE also reduced the level of MnSOD and inhibited the EMT process to attenuate the invasion and migration of breast cancer cells. In addition, phosphorylation of the JAK/STAT pathway, which acts down-stream of these chemokines, was also abrogated by LEE. It was also confirmed that LEE can induce an imbalance of GSH/GSSG and increases ROS, thereby resulting in antitumor activity. Thus, we establish that targeting CXCR7/4 in breast cancer cells can not only inhibit the invasion and migration of cancer cells but also can affect JAK/STAT, EMT process, and production of ROS. Overall, the findings suggest that LEE can function as a novel agent affecting the breast cancer.
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Affiliation(s)
- Young Yun Jung
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
| | - Jae-Young Um
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
- Correspondence: (G.S.); (K.S.A.); Tel.: +65-6516-3267 (G.S.); +82-2-961-2316 (K.S.A.)
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
- Correspondence: (G.S.); (K.S.A.); Tel.: +65-6516-3267 (G.S.); +82-2-961-2316 (K.S.A.)
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12
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MicroRNA Methylome Signature and Their Functional Roles in Colorectal Cancer Diagnosis, Prognosis, and Chemoresistance. Int J Mol Sci 2022; 23:ijms23137281. [PMID: 35806286 PMCID: PMC9266458 DOI: 10.3390/ijms23137281] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/27/2022] [Accepted: 06/27/2022] [Indexed: 02/01/2023] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite significant advances in the diagnostic services and patient care, several gaps remain to be addressed, from early detection, to identifying prognostic variables, effective treatment for the metastatic disease, and the implementation of tailored treatment strategies. MicroRNAs, the short non-coding RNA species, are deregulated in CRC and play a significant role in the occurrence and progression. Nevertheless, microRNA research has historically been based on expression levels to determine its biological significance. The exact mechanism underpinning microRNA deregulation in cancer has yet to be elucidated, but several studies have demonstrated that epigenetic mechanisms play important roles in the regulation of microRNA expression, particularly DNA methylation. However, the methylation profiles of microRNAs remain unknown in CRC patients. Methylation is the next major paradigm shift in cancer detection since large-scale epigenetic alterations are potentially better in identifying and classifying cancers at an earlier stage than somatic mutations. This review aims to provide insight into the current state of understanding of microRNA methylation in CRC. The new knowledge from this study can be utilized for personalized health diagnostics, disease prediction, and monitoring of treatment.
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13
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Jung YY, Mohan CD, Eng H, Narula AS, Namjoshi OA, Blough BE, Rangappa KS, Sethi G, Kumar AP, Ahn KS. 2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells. Biomolecules 2022; 12:891. [PMID: 35883447 PMCID: PMC9312507 DOI: 10.3390/biom12070891] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/08/2022] [Accepted: 06/21/2022] [Indexed: 02/01/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a crucial process in which the polarized epithelial cells acquire the properties of mesenchymal cells and gain invasive properties. We have previously demonstrated that manganese superoxide dismutase (MnSOD) can regulate the EMT phenotype by modulating the intracellular reactive oxygen species. In this report, we have demonstrated the EMT-suppressive effects of 2,3,5,6-Tetramethylpyrazine (TMP, an alkaloid isolated from Chuanxiong) in colon cancer cells. TMP suppressed the expression of MnSOD, fibronectin, vimentin, MMP-9, and N-cadherin with a parallel elevation of occludin and E-cadherin in unstimulated and TGFβ-stimulated cells. Functionally, TMP treatment reduced the proliferation, migration, and invasion of colon cancer cells. TMP treatment also modulated constitutive activated as well as TGFβ-stimulated PI3K/Akt/mTOR, Wnt/GSK3/β-catenin, and MAPK signaling pathways. TMP also inhibited the EMT program in the colon cancer cells-transfected with pcDNA3-MnSOD through modulation of MnSOD, EMT-related proteins, and oncogenic pathways. Overall, these data indicated that TMP may inhibit the EMT program through MnSOD-mediated abrogation of multiple signaling events in colon cancer cells.
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Affiliation(s)
- Young Yun Jung
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea;
| | | | - Huiyan Eng
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | | | - Ojas A. Namjoshi
- Engine Biosciences, 733 Industrial Rd., San Carlos, CA 94070, USA;
| | - Bruce E. Blough
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, NC 27616, USA;
| | | | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea;
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14
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Raji S, Sahranavard M, Mottaghi M, Sahebkar A. MiR-212 value in prognosis and diagnosis of cancer and its association with patient characteristics: a systematic review and meta-analysis. Cancer Cell Int 2022; 22:163. [PMID: 35473623 PMCID: PMC9044851 DOI: 10.1186/s12935-022-02584-0] [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: 03/30/2022] [Accepted: 04/11/2022] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Delayed cancer diagnosis and inefficient cancer prognosis determination are problems faced in cancer diagnosis and treatment. MicroRNAs (miRs), especially miR-212, have shown a promise in cancer diagnosis and prognosis. Herein, we performed a systematic review and meta-analysis to assess the prognostic and diagnostic value of miR-212 level in cancer and evaluated its association with patient characteristics. METHODS A fully electronic literature search using related keywords was performed in PubMed, Scopus, Web of Science, Embase, and ScienceDirect databases by June 6, 2021, with no time or language restriction. Meta-analysis was performed to pool survival prognosis data using hazard ratio (HR), association using odds ratio (OR), and diagnostic data using sensitivity, specificity, and diagnostic odds ratio (DOR). Sub-group analysis and meta-regression were performed as appropriate. RESULTS Results of 28 studies on 1880 patients showed a poor cancer prognosis with high levels of miR-212 in pancreatic ductal adenocarcinoma (PDAC, HR = 2.451 [1.447-4.149]), and a poor cancer prognosis with low levels of miR-212 in other cancers (HR = 2.514 [2.162-2.923]). Higher alpha-fetoprotein (AFP) level and Edmondson-Steiner grade were factors associated with miR-212 low level incidence. Diagnostic odds ratio 10.688 (3.644-31.348) and SROC AUC of 0.84 confirmed high diagnostic performance of miR-212. CONCLUSION Our systematic review and meta-analysis results confirm miR-212 high value in cancer prognosis and diagnosis. High level of miR-212 showed poor prognosis in PDAC and low level of miR-212 showed poor prognosis in other cancers. in conclusion, miR-212 could be a novel potential biomarker in cancer diagnosis and prognosis.
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Affiliation(s)
- Sara Raji
- Persian Cohort Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Sahranavard
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahdi Mottaghi
- Kidney Transplantation Complications Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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15
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Vaghari-Tabari M, Targhazeh N, Moein S, Qujeq D, Alemi F, Majidina M, Younesi S, Asemi Z, Yousefi B. From inflammatory bowel disease to colorectal cancer: what's the role of miRNAs? Cancer Cell Int 2022; 22:146. [PMID: 35410210 PMCID: PMC8996392 DOI: 10.1186/s12935-022-02557-3] [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: 08/24/2021] [Accepted: 03/21/2022] [Indexed: 12/27/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn's disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20-22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Forough Alemi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidina
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Simin Younesi
- Schoole of Health and Biomedical Sciences, RMIT University, Melborne, VIC, Australia
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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16
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Zhou H, Liu Z, Wang Y, Wen X, Amador EH, Yuan L, Ran X, Xiong L, Ran Y, Chen W, Wen Y. Colorectal liver metastasis: molecular mechanism and interventional therapy. Signal Transduct Target Ther 2022; 7:70. [PMID: 35246503 PMCID: PMC8897452 DOI: 10.1038/s41392-022-00922-2] [Citation(s) in RCA: 151] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/25/2022] [Accepted: 02/09/2022] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently occurring malignancy tumors with a high morbidity additionally, CRC patients may develop liver metastasis, which is the major cause of death. Despite significant advances in diagnostic and therapeutic techniques, the survival rate of colorectal liver metastasis (CRLM) patients remains very low. CRLM, as a complex cascade reaction process involving multiple factors and procedures, has complex and diverse molecular mechanisms. In this review, we summarize the mechanisms/pathophysiology, diagnosis, treatment of CRLM. We also focus on an overview of the recent advances in understanding the molecular basis of CRLM with a special emphasis on tumor microenvironment and promise of newer targeted therapies for CRLM, further improving the prognosis of CRLM patients.
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Affiliation(s)
- Hui Zhou
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Zhongtao Liu
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Yongxiang Wang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xiaoyong Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Eric H Amador
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA
| | - Liqin Yuan
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xin Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Xiong
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
| | - Yuping Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Wei Chen
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA.
- Medical Technology Research Centre, Chelmsford Campus, Anglia Ruskin University, Chelmsford, CM1 1SQ, UK.
| | - Yu Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
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17
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Spectrum of microRNAs and their target genes in cancer: intervention in diagnosis and therapy. Mol Biol Rep 2022; 49:6827-6846. [PMID: 35031927 DOI: 10.1007/s11033-021-07040-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 11/30/2021] [Indexed: 12/11/2022]
Abstract
Till date, several groups have studied the mechanism of microRNA (miRNA) biogenesis, processing, stability, silencing, and their dysregulation in cancer. The miRNA coding genes recurrently go through abnormal amplification, deletion, transcription, and epigenetic regulation in cancer. Some miRNAs function as tumor promoters while few others are tumor suppressors based on the transcriptional regulation of target genes. A review of miRNAs and their target genes in a wide range of cancers is attempted in this article, which may help in the development of new diagnostic tools and intervention therapies. The contribution of miRNAs for drug sensitivity or resistance in cancer therapy and opportunities of miRNAs in cancer prognosis or diagnosis and therapy is also presented in detail.
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18
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Perumal N, Kanchan RK, Doss D, Bastola N, Atri P, Chirravuri-Venkata R, Thapa I, Vengoji R, Maurya SK, Klinkebiel D, Talmon GA, Nasser MW, Batra SK, Mahapatra S. MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting nuclear factor I/B (NFIB). Acta Neuropathol Commun 2021; 9:195. [PMID: 34922631 PMCID: PMC8684142 DOI: 10.1186/s40478-021-01299-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 12/01/2021] [Indexed: 12/30/2022] Open
Abstract
Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors and associated with poor survival. NFIB silencing reduced cancer cell proliferation, migration, and invasion. Concurrently, reduced medullosphere formation and stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and identify a novel oncogenic target implicated in metastasis and tumor recurrence.
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Affiliation(s)
- Naveenkumar Perumal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ranjana K Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - David Doss
- Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, 68124, USA
| | - Noah Bastola
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | | | - Ishwor Thapa
- School of Interdisciplinary Informatics, University of Nebraska at Omaha, Omaha, NE, 68182, USA
| | - Raghupathy Vengoji
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Shailendra K Maurya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - David Klinkebiel
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Geoffrey A Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mohd W Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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19
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Ciesielska S, Slezak-Prochazka I, Bil P, Rzeszowska-Wolny J. Micro RNAs in Regulation of Cellular Redox Homeostasis. Int J Mol Sci 2021; 22:6022. [PMID: 34199590 PMCID: PMC8199685 DOI: 10.3390/ijms22116022] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/27/2021] [Accepted: 05/30/2021] [Indexed: 02/08/2023] Open
Abstract
In living cells Reactive Oxygen Species (ROS) participate in intra- and inter-cellular signaling and all cells contain specific systems that guard redox homeostasis. These systems contain both enzymes which may produce ROS such as NADPH-dependent and other oxidases or nitric oxide synthases, and ROS-neutralizing enzymes such as catalase, peroxiredoxins, thioredoxins, thioredoxin reductases, glutathione reductases, and many others. Most of the genes coding for these enzymes contain sequences targeted by micro RNAs (miRNAs), which are components of RNA-induced silencing complexes and play important roles in inhibiting translation of their targeted messenger RNAs (mRNAs). In this review we describe miRNAs that directly target and can influence enzymes responsible for scavenging of ROS and their possible role in cellular redox homeostasis. Regulation of antioxidant enzymes aims to adjust cells to survive in unstable oxidative environments; however, sometimes seemingly paradoxical phenomena appear where oxidative stress induces an increase in the levels of miRNAs which target genes which are supposed to neutralize ROS and therefore would be expected to decrease antioxidant levels. Here we show examples of such cellular behaviors and discuss the possible roles of miRNAs in redox regulatory circuits and further cell responses to stress.
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Affiliation(s)
- Sylwia Ciesielska
- Department of Systems Biology and Engineering, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland; (P.B.); (J.R.-W.)
- Biotechnology Centre, Silesian University of Technology, 44-100 Gliwice, Poland;
| | | | - Patryk Bil
- Department of Systems Biology and Engineering, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland; (P.B.); (J.R.-W.)
- Biotechnology Centre, Silesian University of Technology, 44-100 Gliwice, Poland;
| | - Joanna Rzeszowska-Wolny
- Department of Systems Biology and Engineering, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland; (P.B.); (J.R.-W.)
- Biotechnology Centre, Silesian University of Technology, 44-100 Gliwice, Poland;
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20
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Weidle UH, Brinkmann U, Auslaender S. microRNAs and Corresponding Targets Involved in Metastasis of Colorectal Cancer in Preclinical In Vivo Models. Cancer Genomics Proteomics 2021; 17:453-468. [PMID: 32859626 DOI: 10.21873/cgp.20204] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/17/2020] [Indexed: 12/27/2022] Open
Abstract
The high death toll of colorectal cancer patients is due to metastatic disease which is difficult to treat. The liver is the preferred site of metastasis, followed by the lungs and peritoneum. In order to identify new targets and new modalities of intervention we surveyed the literature for microRNAs (miRs) which modulate metastasis of colorectal cancer in preclinical in vivo models. We identified 12 up-regulated and 19 down-regulated miRs corresponding to the latter criterium. The vast majority (n=16) of identified miRs are involved in modulation of epithelial-mesenchymal transition (EMT). Other categories of metastasis-related miRs exhibit tumor- and metastasis-suppressing functions, modulation of signaling pathways, transmembrane receptors and a class of miRs, which interfere with targets which do not fit into these categories. Finally, we discuss the principles of miR inhibition and reconstitution of function, prospective clinical evaluation of with miR-related agents in the context of clinical evaluation in metastasis relevant settings.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Simon Auslaender
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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21
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Dos Santos IL, Penna KGBD, Dos Santos Carneiro MA, Libera LSD, Ramos JEP, Saddi VA. Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review. Mol Biol Rep 2021; 48:1853-1867. [PMID: 33598796 DOI: 10.1007/s11033-020-06075-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 12/10/2020] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) is a multifactorial disease commonly diagnosed worldwide, with high mortality rates. Several studies demonstrate important associations between differential expression of micro-RNAs (miRs) and the prognosis of CRC. The present study aimed to identify differentially expressed tissue miRs associated with prognostic factors in CRC patients, through a systematic review of the Literature. Using the PubMed database, Cochrane Library and Web of Science, studies published in English evaluating miRs differentially expressed in tumor tissue and significantly associated with the prognostic aspects of CRC were selected. All the included studies used RT-PCR (Taqman or SYBR Green) for miR expression analysis and the period of publication was from 2009 to 2018. A total of 115 articles accomplished the inclusion criteria and were included in the review. The studies investigated the expression of 100 different miRs associated with prognostic aspects in colorectal cancer patients. The most frequent oncogenic miRs investigated were miR-21, miR-181a, miR-182, miR-183, miR-210 and miR-224 and the hyperexpression of these miRs was associated with distant metastasis, lymph node metastasis and worse survival in patients with CRC. The most frequent tumor suppressor miRs were miR-126, miR-199b and miR-22 and the hypoexpression of these miRs was associated with distant metastasis, worse prognosis and a higher risk of disease relapse (worse disease-free survival). Specific tissue miRs are shown to be promising prognostic biomarkers in patients with CRC, given their strong association with the prognostic aspects of these tumors, however, new studies are necessary to establish the sensibility and specificity of the individual miRs in order to use them in clinical practice.
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Affiliation(s)
- Igor Lopes Dos Santos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil.
| | - Karlla Greick Batista Dias Penna
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | | | | | - Jéssica Enocencio Porto Ramos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | - Vera Aparecida Saddi
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
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22
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Gerovska D, Larrinaga G, Solano-Iturri JD, Márquez J, García Gallastegi P, Khatib AM, Poschmann G, Stühler K, Armesto M, Lawrie CH, Badiola I, Araúzo-Bravo MJ. An Integrative Omics Approach Reveals Involvement of BRCA1 in Hepatic Metastatic Progression of Colorectal Cancer. Cancers (Basel) 2020; 12:E2380. [PMID: 32842712 PMCID: PMC7565528 DOI: 10.3390/cancers12092380] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 12/26/2022] Open
Abstract
(1) Background & Aims: The roles of different cells in the tumor microenvironment (TME) are critical to the metastatic process. The phenotypic transformation of the liver cells is one of the most important stages of the hepatic metastasis progression of colorectal cancer (CRC). Our aim was to identify the major molecules (i.e., genes, miRNAs and proteins) involved in this process. (2) Methods: We isolated and performed whole-genome analysis of gene, miRNA, and protein expression in three types of liver cells (Ito cells, Kupffer cells, and liver sinusoidal endothelial cells) from the TME of a murine model of CRC liver metastasis. We selected the statistically significant differentially expressed molecules using the Student's t-test with Benjamini-Hochberg correction and performed functional statistically-significant enrichment analysis of differentially expressed molecules with hypergeometric distribution using the curated collection of molecular signatures, MSigDB. To build a gene-miRNA-protein network centered in Brca1, we developed a software package (miRDiana) that collects miRNA targets from the union of the TargetScan, MicroCosm, mirTarBase, and miRWalk databases. This was used to search for miRNAs targeting Brca1. We validated the most relevant miRNAs with real-time quantitative PCR. To investigate BRCA1 protein expression, we built tissue microarrays (TMAs) from hepatic metastases of 34 CRC patients. (3) Results: Using integrated omics analyses, we observed that the Brca1 gene is among the twenty transcripts simultaneously up-regulated in all three types of TME liver cells during metastasis. Further analysis revealed that Brca1 is the last BRCA1-associated genome surveillance complex (BASC) gene activated in the TME. We confirmed this finding in human reanalyzing transcriptomics datasets from 184 patients from non-tumor colorectal tissue, primary colorectal tumor and colorectal liver metastasis of the GEO database. We found that the most probable sequence of cell activation during metastasis is Endothelial→Ito→Kupffer. Immunohistochemical analysis of human liver metastases showed the BRCA1 protein was co-localized in Ito, Kupffer, and endothelial cells in 81.8% of early or synchronous metastases. However, in the greater part of the metachronous liver metastases, this protein was not expressed in any of these TME cells. (4) Conclusions: These results suggest a possible role of the co-expression of BRCA1 in Ito, Kupffer, and sinusoidal endothelial cells in the early occurrence of CRC liver metastases, and point to BRCA1 as a potential TME biomarker.
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Affiliation(s)
- Daniela Gerovska
- Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, Calle Doctor Beguiristain s/n, 20014 San Sebastián, Spain;
- Computational Biomedicine Data Analysis Platform, Biodonostia Health Research Institute, Calle Doctor Beguiristain s/n, 20014 San Sebastián, Spain
| | - Gorka Larrinaga
- Department of Nursing I, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Bizkaia, Spain;
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Bizkaia, Spain
- BioCruces Health Research Institute, 48903 Barakaldo, Bizkaia, Spain;
| | - Jon Danel Solano-Iturri
- BioCruces Health Research Institute, 48903 Barakaldo, Bizkaia, Spain;
- Department of Anatomic Pathology, Cruces University Hospital, University of the Basque Country (UPV/EHU), 48903 Barakaldo, Bizkaia, Spain
| | - Joana Márquez
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of Basque Country (UPV/EHU), 48940 Leioa, Spain; (J.M.); (P.G.G.)
| | - Patricia García Gallastegi
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of Basque Country (UPV/EHU), 48940 Leioa, Spain; (J.M.); (P.G.G.)
| | - Abdel-Majid Khatib
- University of Bordeaux, Allée Geoffroy St Hilaire, 33615 Pessac, France; INSERM, LAMC, UMR 1029, Allée Geoffroy St Hilaire, 33615 Pessac, France;
| | - Gereon Poschmann
- Institute of Molecular Medicine, Proteome Research, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (G.P.); (K.S.)
| | - Kai Stühler
- Institute of Molecular Medicine, Proteome Research, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (G.P.); (K.S.)
- Molecular Proteomics Laboratory, Biologisch-Medizinisches Forschungszentrum, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - María Armesto
- Molecular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastián, Spain; (M.A.); (C.H.L.)
| | - Charles H. Lawrie
- Molecular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastián, Spain; (M.A.); (C.H.L.)
- Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
- IKERBASQUE, Basque Foundation for Science, Calle María Díaz Harokoa 3, 48013 Bilbao, Spain
| | - Iker Badiola
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of Basque Country (UPV/EHU), 48940 Leioa, Spain; (J.M.); (P.G.G.)
| | - Marcos J. Araúzo-Bravo
- Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, Calle Doctor Beguiristain s/n, 20014 San Sebastián, Spain;
- Computational Biomedicine Data Analysis Platform, Biodonostia Health Research Institute, Calle Doctor Beguiristain s/n, 20014 San Sebastián, Spain
- IKERBASQUE, Basque Foundation for Science, Calle María Díaz Harokoa 3, 48013 Bilbao, Spain
- CIBER of Frailty and Healthy Aging (CIBERfes), 28029 Madrid, Spain
- Computational Biology and Bioinformatics Group, Max Planck Institute for Molecular Biomedicine, Röntgenstr. 20, 48149 Münster, Germany
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23
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Anti-Metastatic Activity of an Anti-EGFR Monoclonal Antibody against Metastatic Colorectal Cancer with KRAS p.G13D Mutation. Int J Mol Sci 2020; 21:ijms21176037. [PMID: 32839411 PMCID: PMC7504481 DOI: 10.3390/ijms21176037] [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: 06/01/2020] [Revised: 08/12/2020] [Accepted: 08/20/2020] [Indexed: 12/11/2022] Open
Abstract
The now clinically-used anti-epidermal growth factor receptor (EGFR) monoclonal antibodies have demonstrated significant efficacy only in patients with metastatic colorectal cancer (mCRC), with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS). However, no effective treatments for patients with mCRC with KRAS mutated tumors have been approved yet. Therefore, a new strategy for targeting mCRC with KRAS mutated tumors is desired. In the present study, we examined the anti-tumor activities of a novel anti-EGFR monoclonal antibody, EMab-17 (mouse IgG2a, kappa), in colorectal cancer (CRC) cells with the KRAS p.G13D mutation. This antibody recognized endogenous EGRF in CRC cells with or without KRAS mutations, and showed a high sensitivity for CRC cells in flow cytometry, indicating that EMab-17 possesses a high binding affinity to the endogenous EGFR. In vitro experiments showed that EMab-17 exhibited antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity activities against CRC cells. In vivo analysis revealed that EMab-17 inhibited the metastases of HCT-15 and HCT-116 cells in the livers of nude mouse metastatic models, unlike the anti-EGFR monoclonal antibody EMab-51 of subtype mouse IgG1. In conclusion, EMab-17 may be useful in an antibody-based therapy against mCRC with the KRAS p.G13D mutation.
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24
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Mehrgou A, Ebadollahi S, Seidi K, Ayoubi-Joshaghani MH, Ahmadieh Yazdi A, Zare P, Jaymand M, Jahanban-Esfahlan R. Roles of miRNAs in Colorectal Cancer: Therapeutic Implications and Clinical Opportunities. Adv Pharm Bull 2020; 11:233-247. [PMID: 33880345 PMCID: PMC8046386 DOI: 10.34172/apb.2021.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/03/2020] [Accepted: 07/26/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most disseminated diseases across the globe engaging the digestive system. Various therapeutic methods from traditional to the state-of-the-art ones have been applied in CRC patients, however, the attempts have been unfortunate to lead to a definite cure. MiRNAs are a smart group of non-coding RNAs having the capabilities of regulating and controlling coding genes. By utilizing this stock-in-trade biomolecules, not only disease’s symptoms can be eliminated, there may also be a good chance for the complete cure of the disease in the near future. Herein, we provide a comprehensive review delineating the therapeutic relationship between miRNAs and CRC. To this, various clinical aspects of miRNAs which act as a tumor suppressor and/or an oncogene, their underlying cellular processes and clinical outcomes, and, in particular, their effects and expression level changes in patients treated with chemo- and radiotherapy are discussed. Finally, based on the results deducted from scientific research studies, therapeutic opportunities based on targeting/utilizing miRNAs in the preclinical as well as clinical settings are highlighted.
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Affiliation(s)
- Amir Mehrgou
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shima Ebadollahi
- Department of Biochemistry and Biophysics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Khaled Seidi
- Biotechnology Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran
| | - Mohammad Hosein Ayoubi-Joshaghani
- Drug Applied Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran.,Student Research Committees, Tabriz University of Medical Sciences, 9841 Tabriz, Iran
| | | | - Peyman Zare
- Dioscuri Center of Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.,Faculty of Medicine, Cardinal Stefan Wyszyński University in Warsaw, 01-938 Warsaw, Poland
| | - Mehdi Jaymand
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Rana Jahanban-Esfahlan
- Stem Cell Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran.,Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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25
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Chu YL, Li H, Ng PLA, Kong ST, Zhang H, Lin Y, Tai WCS, Yu ACS, Yim AKY, Tsang HF, Cho WCS, Wong SCC. The potential of circulating exosomal RNA biomarkers in cancer. Expert Rev Mol Diagn 2020; 20:665-678. [PMID: 32188269 DOI: 10.1080/14737159.2020.1745064] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 03/17/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION There are great potentials of using exosomal RNAs (exoRNA) as biomarkers in cancers. The isolation of exoRNA requires the use of ultracentrifugation to isolate cell-free RNA followed by detection using real-time PCR, microarray, next-generation sequencing, or Nanostring nCounter system. The use of exoRNA enrichment panels has largely increased the detection sensitivity and specificity when compared to traditional diagnostic tests. Moreover, using exoRNA as biomarkers can assist the early detection of chemo and radioresistance cancer, and in turn opens up the possibility of personalized treatment to patients. Finally, exoRNA can be detected at an early stage of cancer recurrence to improve the survival rate. AREAS COVERED In this review, the authors summarized the detection methods of exoRNA as well as its potential as a biomarker in cancer diagnosis and chemo and radioresistance. EXPERT OPINION The application of exoRNAs in clinical diagnosis is still in its infancy. Further researches on extracellular vesicles isolation, detection protocols, exoRNA classes and subclasses, and the regulatory biological pathways have to be performed before exoRNA can be applied translationally.
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Affiliation(s)
- Yin Lam Chu
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | - Harriet Li
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | - Pik Lan Amanda Ng
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | - Siu Ting Kong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | - Hao Zhang
- Institute of Precision Cancer Medicine and Pathology, Jinan University Medical College , Guangzhou, Guangdong, China
| | - Yusheng Lin
- Department of Immunotherapy and Gastrointestinal Oncology, Affiliated Cancer Hospital of Shantou University Medical College , Shantou, Guangdong, China
| | - William Chi Shing Tai
- Department of Applied Biology and Chemical Technology, Faculty of Applied Sciences and Textiles, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region , Kowloon, China
| | | | | | - Hin Fung Tsang
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | | | - Sze Chuen Cesar Wong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
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26
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Carbonell T, Gomes AV. MicroRNAs in the regulation of cellular redox status and its implications in myocardial ischemia-reperfusion injury. Redox Biol 2020; 36:101607. [PMID: 32593128 PMCID: PMC7322687 DOI: 10.1016/j.redox.2020.101607] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/31/2020] [Accepted: 06/12/2020] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) are small RNAs that do not encode for proteins and play key roles in the regulation of gene expression. miRNAs are involved in a comprehensive range of biological processes such as cell cycle control, apoptosis, and several developmental and physiological processes. Oxidative stress can affect the expression levels of multiple miRNAs and, conversely, miRNAs may regulate the expression of redox sensors, alter critical components of the cellular antioxidants, interact with the proteasome, and affect DNA repair systems. The number of publications identifying redox-sensitive miRNAs has increased significantly over the last few years, and some miRNA targets such as Nrf2, SIRT1 and NF-κB have been identified. The complex interplay between miRNAs and ROS is discussed together with their role in myocardial ischemia-reperfusion injury and the potential use of circulating miRNAs as biomarkers of myocardial infarction. Detailed knowledge of redox-sensitive miRNAs is needed to be able to effectively use individual compounds or sets of miRNA-modulating compounds to improve the health-related outcomes associated with different diseases.
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Affiliation(s)
- Teresa Carbonell
- Department of Cell Biology, Physiology and Immunology, University of Barcelona, Avda Diagonal 643, 08028, Barcelona, Spain.
| | - Aldrin V Gomes
- Department of Physiology and Membrane Biology, University of California, Davis, 176 Briggs Hall, One Shields Avenue, Davis, CA, 95616, USA; Department of Physiology, Neurobiology and Behavior, University of California, Davis, 176 Briggs Hall, One Shields Avenue, Davis, CA, 95616, USA
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27
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Crosstalk of MicroRNAs and Oxidative Stress in the Pathogenesis of Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:2415324. [PMID: 32411322 PMCID: PMC7204110 DOI: 10.1155/2020/2415324] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 02/02/2020] [Accepted: 02/08/2020] [Indexed: 02/06/2023]
Abstract
Oxidative stress refers to an imbalance between reactive oxygen species (ROS) generation and body's capability to detoxify the reactive mediators or to fix the relating damage. MicroRNAs are considered to be important mediators that play essential roles in the regulation of diverse aspects of carcinogenesis. Growing studies have demonstrated that the ROS can regulate microRNA biogenesis and expression mainly through modulating biogenesis course, transcription factors, and epigenetic changes. On the other hand, microRNAs may in turn modulate the redox signaling pathways, altering their integrity, stability, and functionality, thus contributing to the pathogenesis of multiple diseases. Both ROS and microRNAs have been identified to be important regulators and potential therapeutic targets in cancers. However, the information about the interplay between oxidative stress and microRNA regulation is still limited. The present review is aimed at summarizing the current understanding of molecular crosstalk between microRNAs and the generation of ROS in the pathogenesis of cancer.
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28
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Chen W, Song J, Bian H, Yang X, Xie X, Zhu Q, Qin C, Qi J. The functions and targets of miR-212 as a potential biomarker of cancer diagnosis and therapy. J Cell Mol Med 2020; 24:2392-2401. [PMID: 31930653 PMCID: PMC7028855 DOI: 10.1111/jcmm.14966] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 12/17/2019] [Accepted: 12/22/2019] [Indexed: 12/14/2022] Open
Abstract
Cancer is a major health problem worldwide. An increasing number of researchers are studying the diagnosis, therapy and mechanisms underlying the development and progression of cancer. The study of noncoding RNA has attracted a lot of attention in recent years. It was found that frequent alterations of miRNA expression not only have various functions in cancer but also that miRNAs can act as clinical markers of diagnosis, stage and progression of cancer. MiR-212 is an important example of miRNAs involved in cancer. According to recent studies, miR-212 may serve as an oncogene or tumour suppressor by influencing different targets or pathways during the oncogenesis and the development and metastasis of cancer. Its deregulation may serve as a marker for the diagnosis or prognosis of cancer. In addition, it was recently reported that miR-212 was related to the sensitivity or resistance of cancer cells to chemotherapy or radiotherapy. Here, we summarize the current understanding of miR-212 functions in cancer by describing the relevant signalling pathways and targets. The role of miR-212 as a biomarker and its therapeutic potential in cancer is also described. The aim of this review was to identify new methods for the diagnosis and treatment of human cancers.
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Affiliation(s)
- Wenjun Chen
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Departments of Gastroenterology, The Affiliated Weihai Second Municipal Hospital of Qingdao University, Qingdao, China
| | - Jing Song
- Departments of Gastroenterology, The Affiliated Weihai Second Municipal Hospital of Qingdao University, Qingdao, China
| | - Hongjun Bian
- Departments of Emergency Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Xia Yang
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Xiaoyu Xie
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Qiang Zhu
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Chengyong Qin
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Jianni Qi
- Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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29
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Kalinina EV, Ivanova-Radkevich VI, Chernov NN. Role of MicroRNAs in the Regulation of Redox-Dependent Processes. BIOCHEMISTRY (MOSCOW) 2019; 84:1233-1246. [DOI: 10.1134/s0006297919110026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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30
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R. Babu K, Tay Y. The Yin-Yang Regulation of Reactive Oxygen Species and MicroRNAs in Cancer. Int J Mol Sci 2019; 20:ijms20215335. [PMID: 31717786 PMCID: PMC6862169 DOI: 10.3390/ijms20215335] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 10/23/2019] [Accepted: 10/24/2019] [Indexed: 01/17/2023] Open
Abstract
Reactive oxygen species (ROS) are highly reactive oxygen-containing chemical species formed as a by-product of normal aerobic respiration and also from a number of other cellular enzymatic reactions. ROS function as key mediators of cellular signaling pathways involved in proliferation, survival, apoptosis, and immune response. However, elevated and sustained ROS production promotes tumor initiation by inducing DNA damage or mutation and activates oncogenic signaling pathways to promote cancer progression. Recent studies have shown that ROS can facilitate carcinogenesis by controlling microRNA (miRNA) expression through regulating miRNA biogenesis, transcription, and epigenetic modifications. Likewise, miRNAs have been shown to control cellular ROS homeostasis by regulating the expression of proteins involved in ROS production and elimination. In this review, we summarized the significance of ROS in cancer initiation, progression, and the regulatory crosstalk between ROS and miRNAs in cancer.
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Affiliation(s)
- Kamesh R. Babu
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore;
| | - Yvonne Tay
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore;
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- Correspondence: ; Tel.: +65-6516-7756
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31
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Wang X, Zhu W, Xu C, Wang F, Zhu X, Sun Y, Guo Y, Fu X, Zhang Y, Zang Y. MicroRNA-370 functions as a tumor suppressor in hepatocellular carcinoma via inhibition of the MAPK/JNK signaling pathway by targeting BEX2. J Hum Genet 2019; 64:1203-1217. [PMID: 31530937 DOI: 10.1038/s10038-019-0653-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 07/08/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. Accumulating studies have revealed that microRNAs (miRNAs) play a critical role in the development and progression of HCC. Through microarray-based gene expression profiling of HCC, miR-370, and BEX2 were identified in HCC. Hence, this study aimed to evaluate their abilities on the cellular processes in HCC. It was determined that BEX2 was highly expressed and miR-370 was poorly expressed in HCC cell lines and tissues. Then, the cell line presenting with the highest BEX2 expression and the lowest miR-370 expression was selected for subsequent gain- and loss-of-function experimentation. The antitumor effect of miR-370 on HCC cell proliferation, invasion, migration, and apoptosis, as well as the MAPK/JNK signaling pathway was examined. Meanwhile, the interaction among miR-370, BEX2, and MAPK/JNK signaling pathway was identified. BEX2 is verified to be a target of miR-370. Moreover, miR-370 exerted antitumor effect on HCC development through suppression of the MAPK/JNK signaling pathway by targeting BEX2. Later, it was further verified by in vivo experiment that overexpression of miR-370 inhibited tumor growth. Above results provide evidence that miR-370 could downregulate BEX2 gene and inhibit activation of MAPK/JNK signaling pathway, thus inhibiting the development of HCC. It provides a worth-trying novel therapeutic target for HCC treatment.
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Affiliation(s)
- Xin Wang
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
| | - Wenyan Zhu
- Operating Room, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
| | - Chuanshen Xu
- Transplantation Care Unit, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
| | - Feng Wang
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
| | - Xiaodan Zhu
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
| | - Yandong Sun
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
| | - Yuan Guo
- Department of Liver Surgery, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
| | - Xiaoyue Fu
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
| | - Yong Zhang
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China
| | - Yunjin Zang
- Department of Liver Transplantation, The Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China.
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32
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Ludwig N, Hecksteden A, Kahraman M, Fehlmann T, Laufer T, Kern F, Meyer T, Meese E, Keller A, Backes C. Spring is in the air: seasonal profiles indicate vernal change of miRNA activity. RNA Biol 2019; 16:1034-1043. [PMID: 31035857 DOI: 10.1080/15476286.2019.1612217] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The envisioned application of miRNAs as diagnostic or prognostic biomarkers calls for an in-depth understanding of their distribution and variability in different physiological states. While effects with respect to ethnic origin, age, or gender are known, the inter-individual variability of miRNAs across the four seasons remained largely hidden. We sequentially profiled the complete repertoire of blood-borne miRNAs for 25 physiologically normal individuals in spring, summer, fall, and winter (altogether 95 samples) and validated the results on 292 individuals (919 samples collected with the Mitra home sampling device) by RT-qPCR. Principal variance component analysis suggests that the largest variability observed in miRNA expression is due to individual variability and the individuals' gender. But the results also highlight a deviation of miRNA activity in samples collected during spring time. Following adjustment for multiple testing, remarkable differences are observed between spring and fall (77 miRNAs). The two most dys-regulated miRNAs were miR-181c-5p and miR-106b-5p (adjusted p-value of 0.007). Other significant miRNAs include miR-140-3p, miR-21-3p, and let-7c-5p. The dys-regulation was validated by RT-qPCR. Systems biology analysis further provides strong evidence for the immunological origin of the signals: dys-regulated miRNAs are enriched in CD56 cells and belong to various signalling and immune-system-related pathways. Our data suggest that besides known confounding factors such as age and sex, also the season in which a test is conducted might have a considerable influence on the expression of blood-borne miRNAs and subsequently might interfere with diagnosis based on such signatures.
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Affiliation(s)
- Nicole Ludwig
- a Department of Human Genetics , Saarland University Hospital , Homburg , Germany.,b Center for Human and Molecular Biology , Saarland University , Homburg , Germany
| | - Anne Hecksteden
- c Department of Sports Medicine , Saarland University , Saarbrücken , Germany
| | - Mustafa Kahraman
- d Chair for Clinical Bioinformatics , Saarland University , Saarbrücken , Germany.,e Hummingbird Diagnostics GmbH , Heidelberg , Germany
| | - Tobias Fehlmann
- d Chair for Clinical Bioinformatics , Saarland University , Saarbrücken , Germany
| | - Thomas Laufer
- d Chair for Clinical Bioinformatics , Saarland University , Saarbrücken , Germany.,e Hummingbird Diagnostics GmbH , Heidelberg , Germany
| | - Fabian Kern
- d Chair for Clinical Bioinformatics , Saarland University , Saarbrücken , Germany
| | - Tim Meyer
- c Department of Sports Medicine , Saarland University , Saarbrücken , Germany
| | - Eckart Meese
- a Department of Human Genetics , Saarland University Hospital , Homburg , Germany
| | - Andreas Keller
- d Chair for Clinical Bioinformatics , Saarland University , Saarbrücken , Germany
| | - Christina Backes
- d Chair for Clinical Bioinformatics , Saarland University , Saarbrücken , Germany
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Chen W, Huang Y, Zhang S, Zheng X, Xie S, Mao J, Cai Y, Lu X, Hu L, Shen J, Dong Y, Chai K. MicroRNA-212 suppresses nonsmall lung cancer invasion and migration by regulating ubiquitin-specific protease-9. J Cell Biochem 2019; 120:6482-6489. [PMID: 30335901 DOI: 10.1002/jcb.27939] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 10/02/2018] [Indexed: 12/17/2022]
Abstract
MicroRNAs (miRNAs) play crucial roles in various biological processes, including migration, proliferation, differentiation, cell cycling, and apoptosis. Epithelial-mesenchymal transition (EMT) has been shown to be related to the capability of migration and invasion in many tumor cells. In this study, we used wound-healing assay and transwell invasion to analysis the capability of migration and invasion in non-small-cell lung carcinoma (NSCLC), respectively. The expression of ubiquitin-specific protease-9-X-linked (USP9X) and miR-212 messenger RNA (mRNA) was determined by quantitative real-time polymerase chain reaction and Western blot analysis was used to determine the E-cadherin and vimentin expression. Our results showed that miR-212 mimic inhibited cell migration and invasion, while miR-212 inhibitor increased cell migration and invasion. There was no significant difference between WP1130 and miR-212 mimic combined with WP1130 groups. Moreover, WP1130 inhibited the capability of the migration and invasion of NSCLC cells. Western blot analysis displayed that miR-212 mimic upregulated E-cadherin expression and downregulated vimentin expression, while miR-212 inhibitor downregulated E-cadherin and upregulated vimentin expression. These data showed that miR-212 regulated NSCLC cell invasion and migration by regulating USP9X expression. Taken together, these findings indicated that miR-212 regulated NSCLC cells migration and invasion through targeting USP9X involved in EMT.
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Affiliation(s)
- Wei Chen
- Cancer Institute of Integrated Taditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Yuye Huang
- Department of pharmacy, The Affiliated Cangnan Hospital of Wenzhou Medical University, The People's Hospital of Cangnan, Wenzhou, China
| | - Shufen Zhang
- Cancer Institute of Integrated Taditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Xiaoxiao Zheng
- Cancer Institute of Integrated Taditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Shangzhi Xie
- Cancer Institute of Integrated Taditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Jiayan Mao
- Cancer Institute of Integrated Taditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Ying Cai
- Cancer Institute of Integrated Taditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Xuemei Lu
- Cancer Institute of Integrated Taditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Liqiang Hu
- Cancer Institute of Integrated Taditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Jian Shen
- Cancer Institute of Integrated Taditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Ying Dong
- Department of Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Kequn Chai
- Cancer Institute of Integrated Taditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
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Chen W, Zhou Y, Zhi X, Ma T, Liu H, Chen BW, Zheng X, Xie S, Zhao B, Feng X, Dang X, Liang T. Delivery of miR-212 by chimeric peptide-condensed supramolecular nanoparticles enhances the sensitivity of pancreatic ductal adenocarcinoma to doxorubicin. Biomaterials 2019; 192:590-600. [PMID: 30553134 DOI: 10.1016/j.biomaterials.2018.11.035] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 11/15/2018] [Accepted: 11/29/2018] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a destructive cancer with poor prognosis. Both novel therapeutic targets and approaches are needed to improve the overall survival of PDAC patients. MicroRNA-212 (miR-212) has been reported as a tumor suppressor in multiple cancers, but its definitive role and exact mechanism in the progression of pancreatic cancer is unclear. In this study, we developed a new chimeric peptide (PL-1) composed of plectin-1-targeted PDAC-specific and arginine-rich RNA-binding motifs which could condense miRNA to self-assemble supramolecular nanoparticles. These nanoparticles could deliver miR-212 into PDAC cells specifically and efficiently which also showed good stability in RNase and serum. Moreover, we demonstrated that PL-1/miR-212 nanoparticles could dramatically enhance the chemotherapeutic effect of doxorubicin for PDAC both in vitro and in vivo. In terms of mechanism, combined miR-212 intervention by PL-1/miR-212 nanoparticles resulted in obvious decrease of USP9X expression (ubiquitin specific peptidase 9, X-linked, USP9X) and eventually enhanced the doxorubicin induced apoptosis and autophagy of PDAC cells. These findings provide a new promising anti-cancer strategy via PL-1/miR-212 nanoparticles and identify miR-212/USP9X as a new potential target for future systemic therapy against human PDAC.
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Affiliation(s)
- Wei Chen
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Zhi
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tao Ma
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hao Liu
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Brayant Wei Chen
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoxiao Zheng
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shangzhi Xie
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bin Zhao
- Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China
| | - Xinhua Feng
- Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China
| | - Xiaowei Dang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.
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Fu Z, Cao X, Yang Y, Song Z, Zhang J, Wang Z. Upregulation of FoxM1 by MnSOD Overexpression Contributes to Cancer Stem-Like Cell Characteristics in the Lung Cancer H460 Cell Line. Technol Cancer Res Treat 2018; 17:1533033818789635. [PMID: 30111255 PMCID: PMC6096686 DOI: 10.1177/1533033818789635] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Manganese superoxide dismutase promotes migration and invasion in lung cancer cells via upregulation of the transcription factor forkhead box M1. Here, we assessed whether upregulation of forkhead box M1 by manganese superoxide dismutase overexpression mediates the acquisition of cancer stem-like cell characteristics in non-small cell lung cancer H460 cells. The second-generation spheroids from H460 cells were used as lung cancer stem-like cells. The levels of manganese superoxide dismutase, forkhead box M1, stemness markers (CD133, CD44, and ALDH1), and transcription factors (Bmi1, Nanog, and Sox2) were analyzed by Western blot. Sphere formation in vitro and carcinogenicity of lung cancer stem-like cells were evaluated by spheroid formation assay and limited dilution xenograft assays. Knockdown or overexpression of manganese superoxide dismutase or/and forkhead box M1 by transduction with short hairpin RNA(shRNA) or complementary DNA were performed for mechanistic studies. We showed that manganese superoxide dismutase and forkhead box M1 amounts as well as the expression levels of stemness markers and transcription factors sphere formation in vitro, and carcinogenicity of lung cancer stem-like cells were higher than in monolayer cells. Lung cancer stem-like cells transduced with manganese superoxide dismutase shRNA or FoxM1 shRNA exhibited decreased sphere formation and lower amounts of stemness markers and transcription factors. Overexpression of manganese superoxide dismutase or FoxM1 in H460 cells resulted in elevated sphere formation rates and protein levels of stemness markers and transcription factors. Meanwhile, manganese superoxide dismutase knockdown or overexpression accordingly altered forkhead box M1 levels. However, forkhead box M1 knockdown or overexpression had no effect on manganese superoxide dismutase levels but inhibited or promoted lung cancer stem-like cell functions. Interestingly, forkhead box M1 overexpression alleviated the inhibitory effects of manganese superoxide dismutase knockdown in lung cancer stem-like cells. In a panel of non-small cell lung cancer cells, including H441, H1299, and H358 cells, compared to the respective monolayer counterparts, the expression levels of manganese superoxide dismutase and forkhead box M1 were elevated in the corresponding spheroids. These findings revealed the role of forkhead box M1 upregulation by manganese superoxide dismutase overexpression in maintaining lung cancer stem-like cell properties. Therefore, inhibition of forkhead box M1 upregulation by manganese superoxide dismutase overexpression may represent an effective therapeutic strategy for non-small cell lung cancer.
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Affiliation(s)
- Zhimin Fu
- 1 Department of Cardiothoracic Surgery, the First People's Hospital of Chenzhou, Chenzhou, Hunan, People's Republic of China.,2 Department of Thoracic Surgery, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangzhou Shi, People's Republic of China
| | - Xiaocheng Cao
- 3 Laboratory of Medicine, Medical College, Hunan Normal University, Changsha, Hunan, People's Republic of China
| | - Yi Yang
- 4 Department of Gynecology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangzhou, People's Republic of China
| | - Zhenwei Song
- 3 Laboratory of Medicine, Medical College, Hunan Normal University, Changsha, Hunan, People's Republic of China
| | - Jiansong Zhang
- 3 Laboratory of Medicine, Medical College, Hunan Normal University, Changsha, Hunan, People's Republic of China
| | - Zheng Wang
- 2 Department of Thoracic Surgery, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangzhou Shi, People's Republic of China
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Liu Y, Bao Z, Tian W, Huang G. miR-885-5p suppresses osteosarcoma proliferation, migration and invasion through regulation of β-catenin. Oncol Lett 2018; 17:1996-2004. [PMID: 30675266 DOI: 10.3892/ol.2018.9768] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 09/24/2018] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRs) have been reported to serve key roles in cancer. To investigate the function of miR-885-5p in osteosarcoma, the expression levels of miR-885-5p were analyzed in 85 osteosarcoma tissue samples and adjacent non-cancerous tissue samples, using reverse transcription-quantitative polymerase chain reaction analysis. It was demonstrated that miR-885-5p was downregulated in osteosarcoma tissues and cell lines. Notably, the expression level of miR-885-5p was closely associated with tumor size, Tumor-Node-Metastasis stage and lymph node metastasis. Additionally, low expression levels of miR-885-5p also predicted a poor prognosis of osteosarcoma. To further decipher the roles of miR-885-5p in osteosarcoma, it was determined that β-catenin, a key component of the Wnt signaling pathway, was a target of miR-885-5p. Furthermore, several functional experiments, including a colony formation assay, CCK-8 assay, wound healing assay and Transwell invasion assay, revealed that miR-885-5p suppressed cell proliferation, migration and invasion through inhibition of β-catenin. The results of the present study provide a novel insight into the molecular roles of miR-885-5p in osteosarcoma.
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Affiliation(s)
- Yan Liu
- Department of Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China.,Department of Orthopedics, Jingjiang Hospital of Chinese Medicine, Jingjiang, Jiangsu 214500, P.R. China
| | - Zili Bao
- Department of Orthopedics, Jingjiang Hospital of Chinese Medicine, Jingjiang, Jiangsu 214500, P.R. China
| | - Wanqing Tian
- Department of Orthopedics, Jingjiang Hospital of Chinese Medicine, Jingjiang, Jiangsu 214500, P.R. China
| | - Guicheng Huang
- Department of Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
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Shao CZ, Xia KP. Sevoflurane anesthesia represses neurogenesis of hippocampus neural stem cells via regulating microRNA-183-mediated NR4A2 in newborn rats. J Cell Physiol 2018; 234:3864-3873. [PMID: 30191980 DOI: 10.1002/jcp.27158] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 07/10/2018] [Indexed: 12/23/2022]
Abstract
Sevoflurane has been commonly utilized in nonobstetric surgeries in pregnant women, and its impacts on fetal brain are still not completely known. Ectopic NR4A2 expression has been reported to be related with familial Parkinson disease, and through dual luciferase we found that NR4A2 is a target gene of microRNA-183 (miR-183). We proposed a hypothesis that miR-183 may participate in the process by targeting NR4A2 in neurons after sevoflurane anesthesia. To verify the effect of sevoflurane on hippocampal neural stem cells (NSCs) proliferation and differentiation, we conducted EdU assay and immunofluorescence staining. Next, for better understanding of the impact of miR-183, we altered the miR-183 expression using mimic and inhibitor. Meanwhile, the targeting relationship between miR-183 and NR4A2 was validated by a bioinformatics website and dual-luciferase reporter gene assay. Finally, expressions of miR-184, NR4A2, SRY (sex-determining region Y)-box 2 (Sox2), and brain-derived neurotrophic factor (BDNF) were determined and evaluated by reverse transcription quantitative polymerase chain reaction and western blot analysis. First, sevoflurane was determined a crucial factor in biological behaviors of hippocampal NSCs. Moreover, upregulated miR-183 expression by mimic inhibited the proliferation and differentiation of NSCs. Sevoflurane negatively regulated NR4A2 and Sox2 expressions but positively regulated miR-183 and BDNF expressions. Our findings revealed the underlying novel mechanism by which sevoflurane inhibits hippocampal NSC proliferation and differentiation through interaction with miR-183 and NR4A2. The study provides reliable reference for safe application of sevoflurane anesthesia in neonates.
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Affiliation(s)
- Chang-Zhong Shao
- Department of Anesthesiology, Linyi People's Hospital Affiliated to Shandong University, Linyi, China
| | - Kun-Peng Xia
- Department of Anesthesiology, Linyi People's Hospital Affiliated to Shandong University, Linyi, China
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38
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Cheng L, Geng L, Dai B, Zheng T, Fu J, Qiao L, Cai W, Wang Y, Yang J. Repression of let-7a cluster prevents adhesion of colorectal cancer cells by enforcing a mesenchymal phenotype in presence of liver inflammation. Cell Death Dis 2018; 9:489. [PMID: 29695839 PMCID: PMC5916926 DOI: 10.1038/s41419-018-0477-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 02/06/2018] [Accepted: 02/14/2018] [Indexed: 01/10/2023]
Abstract
The liver is the most common site of metastasis in patients with colorectal cancer, and colorectal cancer liver metastasis (CRLM) is associated with poor rates of survival. However, CRLM occurs infrequently in livers exhibiting signs of hepatitis or cirrhosis, suggesting a role for inflammation in attenuating CRLM. The molecular mechanisms driving this phenomenon remain unclear. The aim of this study was to confirm the mechanism by which liver inflammation inhibits CRLM. We used BALB/c animal models of inflammatory liver diseases to confirm that liver inflammation inhibits CRLM, and then elucidated the molecular mechanisms governing that process. Out data showed that liver inflammation induces IFN-γ expression, which then downregulates expression of the let-7a cluster through IRF-1 in colorectal cancer cells. Finally, we showed that modulation of let-7a expression regulated the epithelial–mesenchymal transition in colorectal cancer cell lines, and inhibited their capacity to metastasize in vivo. Cumulatively, we clarified the critical role played by the IFN-γ/IRF-1/let-7a cluster/EMT pathway in regulating the spread of circulating colorectal cancer cells to the liver, and highlighted the critical role that the hepatitis microenvironment plays in modulating that process.
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Affiliation(s)
- Lipeng Cheng
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Li Geng
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Binghua Dai
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Tao Zheng
- Department of General Surgery, People's Liberation Army Nanjing General Hospital, Nanjing, 210002, China
| | - Jun Fu
- Department of Hepatobiliary Pancreatic and Spleen Surgery, Xuzhou Central Hospital, Xuzhou, 221000, China
| | - Liang Qiao
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Wenchang Cai
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Yue Wang
- Research Center of Developmental Biology, Second Military Medical University, Shanghai, 200433, China.
| | - Jiamei Yang
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.
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Kinoshita C, Aoyama K, Nakaki T. Neuroprotection afforded by circadian regulation of intracellular glutathione levels: A key role for miRNAs. Free Radic Biol Med 2018; 119:17-33. [PMID: 29198727 DOI: 10.1016/j.freeradbiomed.2017.11.023] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 11/21/2017] [Accepted: 11/27/2017] [Indexed: 01/17/2023]
Abstract
Circadian rhythms are approximately 24-h oscillations of physiological and behavioral processes that allow us to adapt to daily environmental cycles. Like many other biological functions, cellular redox status and antioxidative defense systems display circadian rhythmicity. In the central nervous system (CNS), glutathione (GSH) is a critical antioxidant because the CNS is extremely vulnerable to oxidative stress; oxidative stress, in turn, causes several fatal diseases, including neurodegenerative diseases. It has long been known that GSH level shows circadian rhythm, although the mechanism underlying GSH rhythm production has not been well-studied. Several lines of recent evidence indicate that the expression of antioxidant genes involved in GSH homeostasis as well as circadian clock genes are regulated by post-transcriptional regulator microRNA (miRNA), indicating that miRNA plays a key role in generating GSH rhythm. Interestingly, several reports have shown that alterations of miRNA expression as well as circadian rhythm have been known to link with various diseases related to oxidative stress. A growing body of evidence implicates a strong correlation between antioxidative defense, circadian rhythm and miRNA function, therefore, their dysfunctions could cause numerous diseases. It is hoped that continued elucidation of the antioxidative defense systems controlled by novel miRNA regulation under circadian control will advance the development of therapeutics for the diseases caused by oxidative stress.
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Affiliation(s)
- Chisato Kinoshita
- Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Koji Aoyama
- Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Toshio Nakaki
- Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
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40
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Gao S, Zhao ZY, Wu R, Zhang Y, Zhang ZY. Prognostic value of microRNAs in colorectal cancer: a meta-analysis. Cancer Manag Res 2018; 10:907-929. [PMID: 29750053 PMCID: PMC5935085 DOI: 10.2147/cmar.s157493] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Numerous studies have shown that miRNA levels are closely related to the survival time of patients with colon, rectal, or colorectal cancer (CRC). However, the outcomes of different investigations have been inconsistent. Accordingly, a meta-analysis was conducted to study associations among the three types of cancers. Materials and methods Studies published in English that estimated the expression levels of miRNAs with survival curves in CRC were identified until May 20, 2017 by online searches in PubMed, Embase, Web of Science, and the Cochrane Library by two independent authors. Pooled HRs with 95% CIs were used to estimate the correlation between miRNA expression and overall survival. Results A total of 63 relevant articles regarding 13 different miRNAs, with 10,254 patients were ultimately included. CRC patients with high expression of blood miR141 (HR 2.52, 95% CI 1.68-3.77), tissue miR21 (HR 1.31, 95% CI 1.12-1.53), miR181a (HR 1.52, 95% CI 1.26-1.83), or miR224 (HR 2.12, 95% CI 1.04-4.34), or low expression of tissue miR126 (HR 1.55, 95% CI 1.24-1.93) had significantly poor overall survival (P<0.05). Conclusion In general, blood miR141 and tissue miR21, miR181a, miR224, and miR126 had significant prognostic value. Among these, blood miR141 and tissue miR224 were strong biomarkers of prognosis for CRC.
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Affiliation(s)
- Song Gao
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Zhi-Ying Zhao
- School of Computer Science and Engineering, Northeastern University, Shenyang
| | - Rong Wu
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
| | - Yue Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhen-Yong Zhang
- Second Department of Clinical Oncology, Shengjing Hospital of China Medical University
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Yan TT, Ren LL, Shen CQ, Wang ZH, Yu YN, Liang Q, Tang JY, Chen YX, Sun DF, Zgodzinski W, Majewski M, Radwan P, Kryczek I, Zhong M, Chen J, Liu Q, Zou W, Chen HY, Hong J, Fang JY. miR-508 Defines the Stem-like/Mesenchymal Subtype in Colorectal Cancer. Cancer Res 2018; 78:1751-1765. [PMID: 29374066 DOI: 10.1158/0008-5472.can-17-2101] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 11/13/2017] [Accepted: 01/23/2018] [Indexed: 11/16/2022]
Abstract
Colorectal cancer includes an invasive stem-like/mesenchymal subtype, but its genetic drivers, functional, and clinical relevance are uncharacterized. Here we report the definition of an altered miRNA signature defining this subtype that includes a major genomic loss of miR-508. Mechanistic investigations showed that this miRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, and BMI1. Loss of miR-508 in colorectal cancer was associated with upregulation of the novel hypoxia-induced long noncoding RNA AK000053. Ectopic expression of miR-508 in colorectal cancer cells blunted epithelial-to-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo In clinical colorectal cancer specimens, expression of miR-508 negatively correlated with stemness and EMT-associated gene expression and positively correlated with patient survival. Overall, our results showed that miR-508 is a key functional determinant of the stem-like/mesenchymal colorectal cancer subtype and a candidate therapeutic target for its treatment.Significance: These results define a key functional determinant of a stem-like/mesenchymal subtype of colorectal cancers and a candidate therapeutic target for its treatment. Cancer Res; 78(7); 1751-65. ©2018 AACR.
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Affiliation(s)
- Ting-Ting Yan
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Lin-Lin Ren
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Shandong, China
| | - Chao-Qin Shen
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Zhen-Hua Wang
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ya-Nan Yu
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Shandong, China
| | - Qian Liang
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jia-Yin Tang
- Department of Surgery, Renji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Ying-Xuan Chen
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Dan-Feng Sun
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Witold Zgodzinski
- The Second Department of General Surgery, University School of Medicine in Lublin, Lublin, Poland
| | - Marek Majewski
- The Second Department of General Surgery, University School of Medicine in Lublin, Lublin, Poland
| | - Piotr Radwan
- Department of Gastroenterology, Medical University of Lublin, Lublin, Poland
| | - Ilona Kryczek
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Ming Zhong
- Department of Surgery, Renji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Jinxian Chen
- Department of Surgery, Renji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Qiang Liu
- Department of Pathology, Renji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Weiping Zou
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Shandong, China.
| | - Hao-Yan Chen
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
| | - Jie Hong
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
| | - Jing-Yuan Fang
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
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42
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He X, Fan S. hsa-miR-212 modulates the radiosensitivity of glioma cells by targeting BRCA1. Oncol Rep 2018; 39:977-984. [PMID: 29286157 PMCID: PMC5802039 DOI: 10.3892/or.2017.6156] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 12/12/2017] [Indexed: 01/06/2023] Open
Abstract
Radioresistance remains a major challenge in the treatment of glioma, and the response of patients to radio-therapy varies considerably. MicroRNAs (miRNAs) are involved in various biological processes. The purpose of the present study was to investigate miRNAs involved in the response to radiation in glioma cell lines. Total RNA was isolated from human glioma U251 cells 30 min after γ-ray exposure and hybridized to an miRNA chip array. miRNA expression profiles were analyzed by quantitative real-time PCR. pcDNA3/EGFP-miR-212 mimic transfection was used to verify the function of miR-212 in colony formation tests, and the effect of miR-212 overexpression on U251 cells was examined by western blot analysis of apoptosis-related proteins (Bcl-2, Bax, caspase-3 and cytochrome c). The target genes of miR-212 were predicted using bioinformatic tools including miRNA databases, and breast cancer susceptibility gene 1 (BRCA1) was selected for further confirmation by EGFP fluorescence reporter and loss- and gain-of-function assays. Of the 16 candidate miRNAs showing altered expression, five were assessed by real-time PCR; miR-212 was identified as contributing to the radioresistance of glioma cells and was shown to attenuate radiation-induced apoptosis. miR-212 negatively regulated BRCA1 expression by interacting with its 3'-untranslated region, suggesting a correlation between BRCA1 expression and radiosensitivity in glioma cells. U-118MG and SHG-44 cell lines were used to confirm these observations. The response of glioma cells to radiation involves the miR-212-mediated modulation of BRCA1 gene expression, suggesting that the miR-212/BRCA1 axis may play a potential role in the radiotherapy of gliomas.
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Affiliation(s)
- Xin He
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, P.R. China
| | - Saijun Fan
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, P.R. China
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43
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Lan J, Huang Z, Han J, Shao J, Huang C. Redox regulation of microRNAs in cancer. Cancer Lett 2018; 418:250-259. [PMID: 29330105 DOI: 10.1016/j.canlet.2018.01.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 12/22/2017] [Accepted: 01/05/2018] [Indexed: 02/05/2023]
Abstract
Dysregulation of microRNAs (miRNAs) has long been implicated in tumorigenesis, whereas the underlying mechanisms remain largely unknown. Oxidative stress is a hallmark of cancer that involved in multiple pathophysiological processes, including the aberrant regulation of miRNAs. Compelling evidences have implied complicated interplay between reactive oxygen species (ROS) and miRNAs. Indeed, ROS induces carcinogenesis through either reducing or increasing the miRNA level, leading to the activation of oncogenes or silence of tumor suppressors, respectively. In turn, miRNAs target ROS productive genes or antioxidant responsive elements to affect cellular redox balance, which contributes to establishing a microenvironment favoring cancer cell growth and metastasis. Both miRNAs and ROS have been identified as potential biomarkers and therapeutic targets in human malignancies, and comprehensive understanding of the molecular events herein will facilitate the development of novel cancer therapeutic strategies.
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Affiliation(s)
- Jiang Lan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Junhong Han
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China
| | - Jichun Shao
- Department of Urology, Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Chengdu, Sichuan, China.
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.
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44
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Xie C, Chen B, Wu B, Guo J, Cao Y. LncRNA TUG1 promotes cell proliferation and suppresses apoptosis in osteosarcoma by regulating miR-212-3p/FOXA1 axis. Biomed Pharmacother 2018; 97:1645-1653. [DOI: 10.1016/j.biopha.2017.12.004] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 12/01/2017] [Accepted: 12/01/2017] [Indexed: 01/16/2023] Open
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45
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Vu T, Datta PK. Regulation of EMT in Colorectal Cancer: A Culprit in Metastasis. Cancers (Basel) 2017; 9:cancers9120171. [PMID: 29258163 PMCID: PMC5742819 DOI: 10.3390/cancers9120171] [Citation(s) in RCA: 375] [Impact Index Per Article: 46.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 12/05/2017] [Accepted: 12/05/2017] [Indexed: 12/12/2022] Open
Abstract
Epithelial to mesenchymal transition (EMT) is a process during which cells lose their epithelial characteristics, for instance cell polarity and cell-cell contact, and gain mesenchymal properties, such as increased motility. In colorectal cancer (CRC), EMT is associated with an invasive or metastatic phenotype. In this review, we discuss recent studies exploring novel regulation mechanisms of EMT in CRC, including the identification of new CRC EMT regulators. Upregulation of inducers can promote EMT, leading to increased invasiveness and metastasis in CRC. These inducers can downregulate E-cadherin and upregulate N-cadherin and vimentin (VIM) through modulating EMT-related signaling pathways, for instance WNT/β-catenin and TGF-β, and EMT transcription factors, such as zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2. In addition, several microRNAs (miRNAs), including members of the miR-34 and miR-200 families, are found to target mRNAs of EMT-transcription factors, for example ZEB1, ZEB2, or SNAIL. Downregulation of these miRNAs is associated with distant metastasis and advanced stage tumors. Furthermore, the role of EMT in circulating tumor cells (CTCs) is also discussed. Mesenchymal markers on the surface of EMT CTCs were found to be associated with metastasis and could serve as potential biomarkers for metastasis. Altogether, these studies indicate that EMT is orchestrated by a complicated network, involving regulators of different signaling pathways. Further studies are required to understand the mechanisms underlying EMT in CRC.
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Affiliation(s)
- Trung Vu
- Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
| | - Pran K Datta
- Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
- Birmingham Veterans Affairs Medical Center, Birmingham, AL 35233, USA.
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46
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Zhang J, Zhang Y, Li X, Wang H, Li Q, Liao X. MicroRNA-212 inhibits colorectal cancer cell viability and invasion by directly targeting PIK3R3. Mol Med Rep 2017; 16:7864-7872. [DOI: 10.3892/mmr.2017.7552] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 09/05/2017] [Indexed: 11/06/2022] Open
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47
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Redox regulation in tumor cell epithelial-mesenchymal transition: molecular basis and therapeutic strategy. Signal Transduct Target Ther 2017; 2:17036. [PMID: 29263924 PMCID: PMC5661624 DOI: 10.1038/sigtrans.2017.36] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Revised: 04/25/2017] [Accepted: 04/25/2017] [Indexed: 02/05/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT) is recognized as a driving force of cancer cell metastasis and drug resistance, two leading causes of cancer recurrence and cancer-related death. It is, therefore, logical in cancer therapy to target the EMT switch to prevent such cancer metastasis and recurrence. Previous reports have indicated that growth factors (such as epidermal growth factor and fibroblast growth factor) and cytokines (such as the transforming growth factor beta (TGF-β) family) are major stimulators of EMT. However, the mechanisms underlying EMT initiation and progression remain unclear. Recently, emerging evidence has suggested that reactive oxygen species (ROS), important cellular secondary messengers involved in diverse biological events in cancer cells, play essential roles in the EMT process in cancer cells by regulating extracellular matrix (ECM) remodeling, cytoskeleton remodeling, cell–cell junctions, and cell mobility. Thus, targeting EMT by manipulating the intracellular redox status may hold promise for cancer therapy. Herein, we will address recent advances in redox biology involved in the EMT process in cancer cells, which will contribute to the development of novel therapeutic strategies by targeting redox-regulated EMT for cancer treatment.
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48
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Kanniappan P, Ahmed SA, Rajasekaram G, Marimuthu C, Ch'ng ES, Lee LP, Raabe CA, Rozhdestvensky TS, Tang TH. RNomic identification and evaluation of npcTB_6715, a non-protein-coding RNA gene as a potential biomarker for the detection of Mycobacterium tuberculosis. J Cell Mol Med 2017; 21:2276-2283. [PMID: 28756649 PMCID: PMC5618688 DOI: 10.1111/jcmm.13148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 02/01/2017] [Indexed: 01/15/2023] Open
Abstract
Technological advances in RNA biology greatly improved transcriptome profiling during the last two decades. Besides the discovery of many small RNAs (sRNA) that are involved in the physiological and pathophysiological regulation of various cellular circuits, it becomes evident that the corresponding RNA genes might also serve as potential biomarkers to monitor the progression of disease and treatment. sRNA gene candidate npcTB_6715 was previously identified via experimental RNomic (unpublished data), and we report its application as potential biomarker for the detection of Mycobacterium tuberculosis (MTB) in patient samples. For proof of principle, we developed a multiplex PCR assay and report its validation with 500 clinical cultures, positive for Mycobacteria. The analysis revealed 98.9% sensitivity, 96.1% specificity, positive and negative predictive values of 98.6% and 96.8%, respectively. These results underscore the diagnostic value of the sRNA gene as diagnostic marker for the specific detection of MTB in clinical samples. Its successful application and the general ease of PCR‐based detection compared to standard bacterial culture techniques might be the first step towards ‘point‐of‐care’ diagnostics of Mycobacteria. To the best of our knowledge, this is the first time for the design of diagnostic applications based on sRNA genes, in Mycobacteria.
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Affiliation(s)
- Priyatharisni Kanniappan
- Advanced Medical & Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia.,Department of Pathology, Johor Bahru General Hospital, Johor, Malaysia
| | - Siti Aminah Ahmed
- Advanced Medical & Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | | | - Citartan Marimuthu
- Advanced Medical & Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | - Ewe Seng Ch'ng
- Advanced Medical & Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | - Li Pin Lee
- Advanced Medical & Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | - Carsten A Raabe
- Institute of Experimental Pathology (ZMBE), University of Muenster, Münster, Germany.,Institute of Evolutionary and Medical Genomics, Brandenburg Medical School (MHB), Neuruppin, Germany.,Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation (ZMBE), University of Muenster, Münster, Germany
| | | | - Thean Hock Tang
- Advanced Medical & Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
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49
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Yang Y, Du Y, Liu X, Cho WC. Involvement of Non-coding RNAs in the Signaling Pathways of Colorectal Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 937:19-51. [PMID: 27573893 DOI: 10.1007/978-3-319-42059-2_2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the most common diagnosed cancers worldwide. The metastasis and development of resistance to anti-cancer treatment are major challenges in the treatment of CRC. Understanding mechanisms underpinning the pathogenesis is therefore critical in developing novel agents for CRC treatments. A large number of evidence has demonstrated that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs have functional roles in both the physiological and pathological processes by regulating the expression of their target genes. These molecules are engaged in the pathobiology of neoplastic diseases and are targets for the diagnosis, prognosis and therapy of a variety of cancers, including CRC. In this regard, ncRNAs have emerged as one of the hallmarks of CRC pathogenesis and they also play key roles in metastasis, drug resistance and the stemness of CRC stem cell by regulating various signaling networks. Therefore, a better understanding the ncRNAs involved in the signaling pathways of CRC may lead to the development of novel strategy for diagnosis, prognosis and treatment of CRC. In this chapter, we summarize the latest findings on ncRNAs, with a focus on miRNAs and lncRNAs involving in signaling networks and in the regulation of pathogenic signaling pathways in CRC.
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Affiliation(s)
- Yinxue Yang
- The General Hospital, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Yong Du
- The General Hospital, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Xiaoming Liu
- The General Hospital, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China.
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50
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Wang D, Liu J, Huo T, Tian Y, Zhao L. The role of microRNAs in colorectal liver metastasis: Important participants and potential clinical significances. Tumour Biol 2017; 39:1010428317709640. [PMID: 28651498 DOI: 10.1177/1010428317709640] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Colorectal cancer is one of the most common cancers in the world, and liver metastasis is the leading direct cause of cancer-related deaths in colorectal cancer. MicroRNA is involved in tumor metastasis in many aspects; mounting studies have shown that microRNAs play important roles in colorectal liver metastasis. Although lots of reviews about the association between microRNAs and colorectal cancer metastasis have been published, the reviews specifically focusing on microRNAs and colorectal liver metastasis are still lacking in the literature. To address this issue, here, we summarize the underlying mechanisms of microRNAs in colorectal liver metastasis and explore their potential clinical applications in this aspect.
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Affiliation(s)
- Dongxu Wang
- 1 School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
- 2 Shandong Academy of Medical Sciences, Jinan, China
- 3 Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China
| | - Jie Liu
- 1 School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
- 2 Shandong Academy of Medical Sciences, Jinan, China
- 3 Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China
| | - Tingting Huo
- 3 Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China
- 4 The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yaowen Tian
- 1 School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
- 2 Shandong Academy of Medical Sciences, Jinan, China
- 3 Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China
| | - Lei Zhao
- 1 School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
- 2 Shandong Academy of Medical Sciences, Jinan, China
- 3 Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China
- 4 The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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