|
1
|
Li J, Chen M, Zhao W, Lv A, Lin S, Zheng Y, Cai M, Lin N, Xu L, Huang H. The role of miR-129-5p in regulating γ-globin expression and erythropoiesis in β-thalassemia. Hum Mol Genet 2025; 34:291-303. [PMID: 39657657 DOI: 10.1093/hmg/ddae180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 11/04/2024] [Accepted: 11/29/2024] [Indexed: 12/12/2024] Open
Abstract
The regulation of γ-globin expression is crucial due to its beneficial effects on diseases like β-thalassemia and sickle cell disease. B-cell lymphoma/leukemia 11A (BCL11A) is a significant suppressor of γ-globin, and microRNAs (miRNAs) targeting BCL11A have been shown to alleviate this suppression. In our previous high-throughput sequencing, we identified an 11.32-fold increase in miR-129-5p expression in β-thalassemia patients. However, the regulatory mechanisms of miR-129-5p in the context of erythroid differentiation remain to be elucidated. Our study aimed to elucidate the role of miR-129-5p in γ-globin regulation and erythropoiesis. We measured miR-129-5p levels in peripheral blood from β-thalassemia major and intermedia patients. Fluorescence in situ hybridization, dual-luciferase reporter assays, miRNA pull down assays and western blot analyses were conducted to examine the effects of miR-129-5p on γ-globin expression and BCL11A repression. Cell proliferation, apoptosis, and erythroid differentiation were assessed using cell counting kit-8, Wright-Giemsa, and benzidine staining, and flow cytometry assays. The expression levels of miR-129-5p were significantly elevated in β-thalassemia patients and positively correlated with γ-globin synthesis while negatively correlating with liver damage. miR-129- 5p enhanced γ-globin gene expression in K562 and HUDEP-2 cells by effectively repressing BCL11A. Overexpression of miR-129-5p inhibited cell proliferation, induced cell cycle arrest at the G1/G0 phase, promoted apoptosis and stimulated erythroid differentiation and maturation. Conversely, inhibition of miR-129-5p produced opposite cellular effects. miR-129-5p acts as a positive regulator of erythroid differentiation and γ-globin synthesis. It offers a promising miRNA target for activating the γ-globin gene and reducing ineffective erythropoiesis in β-thalassemia patients.
Collapse
Affiliation(s)
- Jingmin Li
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 88 Jiaotong Road, Taijiang District, Fuzhou 350004, China
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, 18 Daoshan Road, Gulou District, Fuzhou 350001, China
| | - Meihuan Chen
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, 18 Daoshan Road, Gulou District, Fuzhou 350001, China
| | - Wantong Zhao
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, 18 Daoshan Road, Gulou District, Fuzhou 350001, China
| | - Aixiang Lv
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 88 Jiaotong Road, Taijiang District, Fuzhou 350004, China
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, 18 Daoshan Road, Gulou District, Fuzhou 350001, China
| | - Siyang Lin
- The School of Medical Technology and Engineering, Fujian Medical University, 1 Xuefu North Road, Minhou District, Fuzhou 350108, China
| | - Yanping Zheng
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 88 Jiaotong Road, Taijiang District, Fuzhou 350004, China
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, 18 Daoshan Road, Gulou District, Fuzhou 350001, China
| | - Meiying Cai
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, 18 Daoshan Road, Gulou District, Fuzhou 350001, China
| | - Na Lin
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, 18 Daoshan Road, Gulou District, Fuzhou 350001, China
| | - Liangpu Xu
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, 18 Daoshan Road, Gulou District, Fuzhou 350001, China
| | - Hailong Huang
- College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 88 Jiaotong Road, Taijiang District, Fuzhou 350004, China
- Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, 18 Daoshan Road, Gulou District, Fuzhou 350001, China
| |
Collapse
|
|
2
|
Yoon TM, Kim SA, Jung EK, Kim YK, Lee KH, Lim SC. MicroRNA-129-3p Suppresses Tumor Progression and Chemoradioresistance in Head and Neck Squamous Cell Carcinoma. Curr Oncol 2025; 32:54. [PMID: 39851970 PMCID: PMC11763343 DOI: 10.3390/curroncol32010054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/08/2025] [Accepted: 01/18/2025] [Indexed: 01/26/2025] Open
Abstract
(1) Background: MicroRNA-129 (miR-129) participates in tumor progression and chemoresistance in various cancer types. In this study, the role of miR-129-3p, the main mature form of miR-129, in tumor progression and chemoradiotherapy resistance in head and neck cancer was evaluated. (2) Methods: RT-PCR, western blotting, cell proliferation assays, cell apoptosis assays, and cell invasion and migration assays were used. (3) Results: In this study, the miR-129-3p overexpression suppressed the proliferation, invasion, and migration of SNU1041, SCC15, and SCC25 human HNSCC cell lines. Additionally, it induced apoptosis and enhanced radiation-/cisplatin-induced apoptosis of SNU1041, SCC15, and SCC25 cells. Therefore, miR-129-3p could suppress tumor progression and enhance chemoradiosensitivity in human HNSCC. Furthermore, miR-129-3p was downregulated in fresh tumor tissues from patients with HNSCC compared with that in the adjacent normal mucosa. In a nude mouse xenograft model with SNU15 cells, the miR-129-3p overexpression significantly decreased tumor growth, as measured by tumor weight and volume. (4) Conclusions: Our study provides evidence that miR-129-3p suppresses tumor progression and chemoradioresistance in HNSCC. This finding may serve as a basis for developing miR-129-3p-based therapeutic strategies.
Collapse
Affiliation(s)
- Tae Mi Yoon
- Departments of Otorhinolaryngology-Head and Neck Surgery, Chonnam National University Medical School, Hwasun Hospital, Hwasun 58128, Jeonnam, Republic of Korea; (T.M.Y.)
| | - Sun-Ae Kim
- Departments of Otorhinolaryngology-Head and Neck Surgery, Chonnam National University Medical School, Hwasun Hospital, Hwasun 58128, Jeonnam, Republic of Korea; (T.M.Y.)
| | - Eun Kyung Jung
- Departments of Otorhinolaryngology-Head and Neck Surgery, Chonnam National University Medical School, Hwasun Hospital, Hwasun 58128, Jeonnam, Republic of Korea; (T.M.Y.)
| | - Young-Kook Kim
- Departments of Biochemistry, Chonnam National University Medical School, Hwasun Hospital, Hwasun 58128, Jeonnam, Republic of Korea
| | - Kyung-Hwa Lee
- Departments of Pathology, Chonnam National University Medical School, Hwasun Hospital, Hwasun 58128, Jeonnam, Republic of Korea
| | - Sang Chul Lim
- Departments of Otorhinolaryngology-Head and Neck Surgery, Chonnam National University Medical School, Hwasun Hospital, Hwasun 58128, Jeonnam, Republic of Korea; (T.M.Y.)
| |
Collapse
|
|
3
|
Zhang H, Tang H, Tu W, Peng F. Regulatory role of non-coding RNAs in 5-Fluorouracil resistance in gastrointestinal cancers. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:4. [PMID: 39935428 PMCID: PMC11810461 DOI: 10.20517/cdr.2024.167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/29/2024] [Accepted: 01/07/2025] [Indexed: 02/13/2025]
Abstract
Gastrointestinal (GI) cancers are becoming a growing cause of morbidity and mortality globally, posing a significant risk to human life and health. The main treatment for this kind of cancer is chemotherapy based on 5-fluorouracil (5-FU). However, the issue of 5-FU resistance is becoming increasingly prominent, which greatly limits its effectiveness in clinical treatment. Recently, numerous studies have disclosed that some non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), exert remarkable physiological functions within cells. In addition, these ncRNAs can also serve as important information communication molecules in the tumor microenvironment and regulate tumor chemotherapy resistance. In particular, they have been shown to play multiple roles in regulating 5-FU resistance in GI cancers. Herein, we summarize the targets, pathways, and mechanisms involved in regulating 5-FU resistance by ncRNAs and briefly discuss the application potential of ncRNAs as biomarkers or therapeutic targets for 5-FU resistance in GI cancers, aiming to offer a reference to tackle issues related to 5-FU resistance.
Collapse
Affiliation(s)
- Heng Zhang
- Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu 610051, Sichuan, China
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu 610051, Sichuan, China
| | - Hailin Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou 510700, Guangdong, China
| | - Wenling Tu
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu 610051, Sichuan, China
| | - Fu Peng
- Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu 610051, Sichuan, China
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan University, Chengdu 610041, Sichuan, China
| |
Collapse
|
|
4
|
Akash S, Shanto SKHI, Islam MR, Bayil I, Afolabi SO, Guendouzi A, Abdellattif MH, Zaki MEA. Discovery of novel MLK4 inhibitors against colorectal cancer through computational approaches. Comput Biol Med 2024; 182:109136. [PMID: 39298888 DOI: 10.1016/j.compbiomed.2024.109136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/20/2024] [Accepted: 09/08/2024] [Indexed: 09/22/2024]
Abstract
Colorectal cancer (CRC) is a significant health issue globally, affecting approximately 10 % of the world's population. The prevalence of CRC highlights the need for effective treatments and prevention strategies. The current therapeutic option, such as chemotherapy, has significant side effects. Thus, this study investigated the anticancer properties of Sanguinarine derivatives, an alkaloid found in traditional herbs via chemoinformatic approaches. Six Sanguinarine derivatives were discovered through virtual screening and molecular docking to determine their binding affinities against the mixed lineage kinase (MLK4) protein which is responsible for CRC. All the compounds were found to be more effective than standard drug used for colorectal cancer treatment, with Sanguinarine derivative 11 showing the highest affinity. The stability of the drug was confirmed through molecular dynamics simulations at 500 ns. This suggests that compound 11 has a higher chance of replacing 5-Fluorouracil, which is currently a widely used chemotherapy drug. Before molecular dynamics simulations, the pharmacokinetic and chemical properties of Sanguinarine derivatives were determined using pkCSM server and DFT method, respectively. The results support that compound 11 is a good drug candidate, as evidenced by Lipinski's Rule of Five. Therefore, compound 11 is recommended for further analysis via in vivo and in vitro studies to confirm its efficacy and safety.
Collapse
Affiliation(s)
- Shopnil Akash
- Department of Pharmacy, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh.
| | - S K Hasibul Islam Shanto
- Department of Pharmacy, Faculty of Health Science, Northern University Bangladesh, Ashkona, Dhaka, 1230, Bangladesh.
| | - Md Rezaul Islam
- Department of Pharmacy, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Imren Bayil
- Department of Bioinformatics and Computational Biology, Gaziantep University, Turkey.
| | | | - Abdelkrim Guendouzi
- Laboratory of Chemistry: Synthesis, Properties and Applications (LCSPA), University of Saïda, Algeria.
| | - Magda H Abdellattif
- Chemistry Department, College of Sciences, University College of Taraba, Taif University, Saudi Arabia.
| | - Magdi E A Zaki
- Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University Riyadh, Saudi Arabia.
| |
Collapse
|
|
5
|
Guo Y, Ashrafizadeh M, Tambuwala MM, Ren J, Orive G, Yu G. P-glycoprotein (P-gp)-driven cancer drug resistance: biological profile, non-coding RNAs, drugs and nanomodulators. Drug Discov Today 2024; 29:104161. [PMID: 39245345 DOI: 10.1016/j.drudis.2024.104161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 08/07/2024] [Accepted: 09/04/2024] [Indexed: 09/10/2024]
Abstract
Drug resistance has compromised the efficacy of chemotherapy. The dysregulation of drug transporters including P-glycoprotein (P-gp) can mediate drug resistance through drug efflux. In this review, we highlight the role of P-gp in cancer drug resistance and the related molecular pathways, including phosphoinositide 3-kinase (PI3K)-Akt, phosphatase and tensin homolog (PTEN) and nuclear factor-κB (NF-κB), along with non-coding RNAs (ncRNAs). Extracellular vesicles secreted by the cells can transport ncRNAs and other proteins to change P-gp activity in cancer drug resistance. P-gp requires ATP to function, and the induction of mitochondrial dysfunction or inhibition of glutamine metabolism can impair P-gp function, thus increasing chemosensitivity. Phytochemicals, small molecules and nanoparticles have been introduced as P-gp inhibitors to increase drug sensitivity in human cancers.
Collapse
Affiliation(s)
- Yang Guo
- Department of Respiratory and Critical Care Medicine, Shenyang Tenth People's Hospital (Shenyang Chest Hospital), No. 11 Beihai Street, Dadong District, Shenyang 110044, Liaoning, China
| | - Milad Ashrafizadeh
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
| | - Murtaza M Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, UK
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - Gorka Orive
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain; University Institute for Regenerative Medicine and Oral Implantology-UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria-Gasteiz, Spain; Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore 169856, Singapore.
| | - Guiping Yu
- Department of Cardiothoracic Surgery, The Affiliated Jiangyin Hospital of Nantong University, No. 163 Shoushan Road, Jiangyin, China.
| |
Collapse
|
|
6
|
Frings S, Schmidt-Schippers R, Lee WK. Epigenetic alterations in bioaccumulators of cadmium: Lessons from mammalian kidneys and plants. ENVIRONMENT INTERNATIONAL 2024; 191:109000. [PMID: 39278047 DOI: 10.1016/j.envint.2024.109000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 08/07/2024] [Accepted: 09/05/2024] [Indexed: 09/17/2024]
Abstract
Faced with unpredictable changes in global weather patterns, release and redistribution of metals through land erosion and water movements add to the increasing use of metals in industrial activities causing high levels of environmental pollution and concern to the health of all living organisms. Cadmium is released into the environment by smelting and mining, entering the food chain via contaminated soils, water, and phosphate fertilizers. Bioaccumulation of cadmium in plants represents the first major step into the human food chain and contributes to toxicity of several organs, especially the kidneys, where biomagnification of cadmium occurs over decades of exposure. Even in small amounts, cadmium brings about alterations at the molecular and cellular levels in eukaryotes through mutagenicity, molecular mimicry at metal binding sites and oxidative stress. The epigenome dictates expression of a gene's output through a number of regulatory steps involving chromatin remodeling, nucleosome unwinding, DNA accessibility, or nucleic acid modifications that ultimately impact the transcriptional and translational machinery. Several epigenetic enzymes exhibit zinc-dependence as zinc metalloenzymes and zinc finger proteins thus making them susceptible to deregulation through displacement by cadmium. In this review, we summarize the literature on cadmium-induced epigenetic mechanisms in mammalian kidneys and plants, compare similarities in the epigenetic defense between these bioaccumulators, and explore how future studies could advance our understanding of the cadmium-induced stress response and disruption to biological health.
Collapse
Affiliation(s)
- Stephanie Frings
- Center for Biotechnology, University of Bielefeld, 33615 Bielefeld, Germany; Plant Biotechnology, Faculty of Biology, Bielefeld University, 33615 Bielefeld, Germany
| | - Romy Schmidt-Schippers
- Center for Biotechnology, University of Bielefeld, 33615 Bielefeld, Germany; Plant Biotechnology, Faculty of Biology, Bielefeld University, 33615 Bielefeld, Germany
| | - Wing-Kee Lee
- Physiology and Pathophysiology of Cells and Membranes, Medical School OWL, Bielefeld University, 33615 Bielefeld, Germany.
| |
Collapse
|
|
7
|
Mirandari A, Parker H, Ashton-Key M, Stevens B, Walewska R, Stamatopoulos K, Bryant D, Oscier DG, Gibson J, Strefford JC. The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:877-901. [PMID: 39280243 PMCID: PMC11390296 DOI: 10.37349/etat.2024.00253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 05/08/2024] [Indexed: 09/18/2024] Open
Abstract
Splenic marginal zone lymphoma (SMZL) is a rare, predominantly indolent B-cell lymphoma constituting fewer than 2% of lymphoid neoplasms. However, around 30% of patients have a shorter survival despite currently available treatments and the prognosis is especially poor for the 5-15% of cases that transform to a large cell lymphoma. Mounting evidence suggests that the molecular pathogenesis of SMZL is critically shaped by microenvironmental triggering and cell-intrinsic aberrations. Immunogenetic investigations have revealed biases in the immunoglobulin gene repertoire, indicating a role of antigen selection. Furthermore, cytogenetic studies have identified recurrent chromosomal abnormalities such as deletion of the long arm of chromosome 7, though specific disease-associated genes remain elusive. Our knowledge of SMZL's mutational landscape, based on a limited number of cases, has identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways. These mutations can be clustered within patient subgroups with different patterns of chromosomal lesions, immunogenetic features, transcriptional signatures, immune microenvironments, and clinical outcomes. Regarding SMZL epigenetics, initial DNA methylation profiling has unveiled epigenetically distinct patient subgroups, including one characterized by elevated expression of Polycomb repressor complex 2 (PRC2) components. Furthermore, it has also demonstrated that patients with evidence of high historical cell division, inferred from methylation data, exhibit inferior treatment-free survival. This review provides an overview of our current understanding of SMZL's molecular basis and its implications for patient outcomes. Additionally, it addresses existing knowledge gaps, proposes future research directions, and discusses how a comprehensive molecular understanding of the disease will lead to improved management and treatment choices for patients.
Collapse
Affiliation(s)
- Amatta Mirandari
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Helen Parker
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Margaret Ashton-Key
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
- Department of Pathology, University Hospital Southampton NHS Foundation Trust, SO16 6YD Southampton, UK
| | - Benjamin Stevens
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Renata Walewska
- Department of Molecular Pathology, University Hospitals Dorset, SO16 6YD Bournemouth, UK
| | - Kostas Stamatopoulos
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, 57001 Thessaloniki, Greece
| | - Dean Bryant
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - David G Oscier
- Department of Molecular Pathology, University Hospitals Dorset, SO16 6YD Bournemouth, UK
| | - Jane Gibson
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Jonathan C Strefford
- Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| |
Collapse
|
|
8
|
Cao Q, Tian Y, Deng Z, Yang F, Chen E. Epigenetic Alteration in Colorectal Cancer: Potential Diagnostic and Prognostic Implications. Int J Mol Sci 2024; 25:3358. [PMID: 38542332 PMCID: PMC10969857 DOI: 10.3390/ijms25063358] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/01/2024] [Accepted: 03/12/2024] [Indexed: 01/03/2025] Open
Abstract
Colorectal cancer (CRC), a prevalent malignant tumor of the digestive system, ranks as the third and second in global incidence and mortality, respectively, in 2020, with 1.93 million new cases (≈10% of all cancers). There are 940,000 deaths (≈9.4% of all cancers), and the incidence of CRC in younger patients (under 50 years of age) has become a new trend. The pathogenesis of CRC is primarily attributed to a series of genetic and epigenetic abnormalities within normal colonic epithelial cells, coupled with the reshaping of the tumor microenvironment in the surrounding stroma. This process leads to the transformation of colorectal adenomas into invasive adenocarcinomas. Although genetic changes are known to be the primary driving force in the occurrence and progression of CRC, recent research indicates that epigenetic regulation serves as a crucial molecular marker in cancer, playing a significant role in the pathological and physiological control of interactions between genetics and the environment. This review discusses the current global epidemiology of CRC, its risk factors, and preventive treatment strategies. The current study explores the latest advancements in the epigenetic regulation of CRC, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These developments hold potential as screening tools, prognostic biomarkers, and therapeutic targets for CRC.
Collapse
Affiliation(s)
- Qing Cao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Ye Tian
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Zhiyi Deng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Fangfang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Erfei Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
- School of Medicine, Northwest University, Xi’an 710069, China
| |
Collapse
|
|
9
|
Lotfi E, Kholghi A, Golab F, Mohammadi A, Barati M. Circulating miRNAs and lncRNAs serve as biomarkers for early colorectal cancer diagnosis. Pathol Res Pract 2024; 255:155187. [PMID: 38377721 DOI: 10.1016/j.prp.2024.155187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 01/28/2024] [Accepted: 01/31/2024] [Indexed: 02/22/2024]
Abstract
BACKGROUND Colorectal cancer (CRC), the third most prevalent and lethal disease, accounted for approximately 1.9 million new cases and claimed nearly 861,000 lives in 2018. It is imperative to develop a minimally invasive diagnostic technique for early identification of CRC. This would facilitate the selection of patient populations most suitable for clinical trials, monitoring disease progression, assessing treatment effectiveness, and enhancing overall patient care. Utilizing blood as a biomarker source is advantageous due to its minimal discomfort for patients, enabling better integration into clinical and follow-up trials. Recent findings indicate that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are detectable in the blood of cancer patients, proving crucial in diagnosing various malignancies. METHODS In this case-control study, we collected plasma samples from 30 patients diagnosed with colorectal cancer (CRC) and 30 healthy volunteers. Following RNA extraction, we measured the expression levels of specific biomolecules, including miR-410, miR-211, miR-139, miR-197, lncRNA UICLM, lncRNA FEZF1-AS1, miR-129, lncRNA CCAT1, lncRNA BBOX1-AS1, and lncRNA LINC00698, using real-time quantitative polymerase chain reaction (RT-qPCR). The obtained data underwent analysis using the Mann-Whitney test for non-parametric data and the T-test for parametric data. RESULTS The level of miR-410, miR-211, miR-139, miR-197, lncRNA UICLM, lncRNA FEZF1-AS1 were significantly higher in patients with CRC than healthy controls (p < .05). Meanwhile, the level of miR-129, lncRNA CCAT1, lncRNA BBOX1-AS1, and lncRNA LINC00698 were higher in healthy controls than in CRC patients (p < .05). CONCLUSION MicroRNA (miRNA) and long noncoding RNAs (lncRNAs) have recently emerged as detectable entities in the blood of cancer patients, playing crucial roles in diagnosing various malignancies. However, their specific relevance in the diagnosis of colorectal cancer (CRC) remains underexplored. This study aimed to investigate miRNA and lncRNA profiles in the plasma fraction of human blood to discern significant differences in content and expression levels between CRC patients and healthy individuals. Our cohort comprised 30 CRC patients and 30 healthy controls, with no statistically significant differences (p < 0.05) in age or gender observed between the two groups. Noteworthy is the uniqueness of our study, as we identified a panel of three significant microRNAs and one significant lncRNA, providing a more reliable prediction compared to existing molecular markers in diagnosing CRC. The four genes examined, including miR-211, miR-129, miR-197, and lncRNA UICLM, demonstrated impeccable results in terms of sensitivity and specificity, suggesting their potential candidacy for inclusion in diagnostic panels. Further validation in a larger statistical population is recommended to confirm the robustness of these genes as promising markers for colorectal cancer diagnosis.
Collapse
Affiliation(s)
- Ehsan Lotfi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical sciences, Tehran, Iran
| | - Azam Kholghi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical sciences, Tehran, Iran
| | - Fereshteh Golab
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Mohammadi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical sciences, Tehran, Iran
| | - Mahmood Barati
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical sciences, Tehran, Iran.
| |
Collapse
|
|
10
|
Sheikhnia F, Maghsoudi H, Majidinia M. The Critical Function of microRNAs in Developing Resistance against 5- Fluorouracil in Cancer Cells. Mini Rev Med Chem 2024; 24:601-617. [PMID: 37642002 DOI: 10.2174/1389557523666230825144150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/06/2023] [Accepted: 07/13/2023] [Indexed: 08/31/2023]
Abstract
Although there have been significant advancements in cancer treatment, resistance and recurrence in patients make it one of the leading causes of death worldwide. 5-fluorouracil (5-FU), an antimetabolite agent, is widely used in treating a broad range of human malignancies. The cytotoxic effects of 5-FU are mediated by the inhibition of thymidylate synthase (TYMS/TS), resulting in the suppression of essential biosynthetic activity, as well as the misincorporation of its metabolites into RNA and DNA. Despite its huge benefits in cancer therapy, the application of 5-FU in the clinic is restricted due to the occurrence of drug resistance. MicroRNAs (miRNAs) are small, non-coding RNAs that act as negative regulators in many gene expression processes. Research has shown that changes in miRNA play a role in cancer progression and drug resistance. This review examines the role of miRNAs in 5-FU drug resistance in cancers.
Collapse
Affiliation(s)
- Farhad Sheikhnia
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Hossein Maghsoudi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| |
Collapse
|
|
11
|
Hussen BM, Abdullah ST, Abdullah SR, Younis YM, Hidayat HJ, Rasul MF, Mohamadtahr S. Exosomal non-coding RNAs: Blueprint in colorectal cancer metastasis and therapeutic targets. Noncoding RNA Res 2023; 8:615-632. [PMID: 37767111 PMCID: PMC10520679 DOI: 10.1016/j.ncrna.2023.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is ranked as the world's third-most prevalent cancer, and metastatic CRC considerably increases cancer-related fatalities globally. A number of complex mechanisms that are strictly controlled at the molecular level are involved in metastasis, which is the primary reason for death in people with CRC. Recently, it has become clear that exosomes, which are small extracellular vesicles released by non-tumorous and tumorigenic cells, play a critical role as communication mediators among tumor microenvironment (TME). To facilitate communication between the TME and cancer cells, non-coding RNAs (ncRNAs) play a crucial role and are recognized as potent regulators of gene expression and cellular processes, such as metastasis and drug resistance. NcRNAs are now recognized as potent regulators of gene expression and many hallmarks of cancer, including metastasis. Exosomal ncRNAs, like miRNAs, circRNAs, and lncRNAs, have been demonstrated to influence a number of cellular mechanisms that contribute to CRC metastasis. However, the molecular mechanisms that link exosomal ncRNAs with CRC metastasis are not well understood. This review highlights the essential roles that exosomal ncRNAs play in the progression of CRC metastatic disease and explores the therapeutic choices that are open to patients who have CRC metastases. However, exosomal ncRNA treatment strategy development is still in its early phases; consequently, additional investigation is required to improve delivery methods and find novel therapeutic targets as well as confirm the effectiveness and safety of these therapies in preclinical and clinical contexts.
Collapse
Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Biomedical Sciences, College of Science, Cihan University-Erbil, Erbil, Kurdistan Region, 44001, Iraq
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Sara Tharwat Abdullah
- Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Snur Rasool Abdullah
- Medical Laboratory Science, College of Health Sciences, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Yousif Mohammed Younis
- Department of Nursing, College of Nursing, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University-Erbil, Kurdistan Region, Iraq
| | - Mohammed Fatih Rasul
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Sayran Mohamadtahr
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| |
Collapse
|
|
12
|
Ravindran F, Mhatre A, Koroth J, Narayan S, Choudhary B. Curcumin modulates cell type-specific miRNA networks to induce cytotoxicity in ovarian cancer cells. Life Sci 2023; 334:122224. [PMID: 38084671 DOI: 10.1016/j.lfs.2023.122224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 09/27/2023] [Accepted: 10/27/2023] [Indexed: 12/18/2023]
Abstract
AIM To understand the epigenetic role of curcumin, a natural polyphenolic compound extracted from the spice Curcuma longa in inducing cytotoxicity in two molecularly distinct ovarian cancer cell lines: PA1 and A2780. MATERIALS AND METHODS An integrated mRNA-miRNA sequence analysis was performed to determine the curcumin-induced mRNA-miRNA regulatory networks in the induction of cytotoxicity. The miRNA-mRNA pathways, the miRNAs and their targets implicated in apoptosis, autophagy, DNA damage, and stemness markers were validated. Gene/miRNA expressions were validated using qPCR and protein expressions by western blotting. Curcumin-induced oncogenic /tumor-suppressor miRNAs were profiled utilising the oncomiRdb database. Similarly, the expressions of oncogenes/tumor suppressor genes were profiled and correlated with the TCGA ovarian cancer dataset. A dual luciferase assay was performed to investigate the interaction of miR-199a-5p to its direct target, DDR1. KEY FINDINGS The expression of several miRNAs demonstrated an inverse correlation with their respective direct targets. In curcumin-treated PA1 cells, miR-335-5p target ATG5 (autophagic), and OCT4 (pluripotent gene) were downregulated, miR-32a target PTEN (tumor suppressor) was upregulated, miR-1285 target P53 (tumor suppressor) was upregulated, and both miR-182-5p and miR-503-3p target BCL2, were down-regulated. Contrastingly, in curcumin-treated A2780 cells, miR-181a-3p target ATG5, miR-30a-5p, and miR-216a target BECN1 (autophagic) were upregulated, and miR-129a-5p target BCL2 were downregulated. The reversal of the oncomiR/TSmiR profile revealed suppression of oncogenic processes by curcumin. Curcumin treatment induced a moderate cisplatin-sensitisation effect and impaired epithelial-to-mesenchymal transition (EMT) characteristics. Curcumin also regulated the miR-199a-5p/DDR1 axis with a decrease in collagen deposition. SIGNIFICANCE The activity of curcumin is cell-type specific. Distinct miRNA regulatory networks were activated to induce multiple modes of cellular cytotoxicity in these ovarian cancer cells. This study further highlights the molecular mechanism of curcumin action in ovarian cancers establishing its candidacy as a promising drug candidate.
Collapse
Affiliation(s)
- Febina Ravindran
- Institute of Bioinformatics and Applied Biotechnology, Electronic city phase 1, Bangalore, India
| | - Anisha Mhatre
- Institute of Bioinformatics and Applied Biotechnology, Electronic city phase 1, Bangalore, India
| | - Jinsha Koroth
- Institute of Bioinformatics and Applied Biotechnology, Electronic city phase 1, Bangalore, India
| | - Suchitra Narayan
- Institute of Bioinformatics and Applied Biotechnology, Electronic city phase 1, Bangalore, India
| | - Bibha Choudhary
- Institute of Bioinformatics and Applied Biotechnology, Electronic city phase 1, Bangalore, India.
| |
Collapse
|
|
13
|
Ebrahimi N, Hakimzadeh A, Bozorgmand F, Speed S, Manavi MS, Khorram R, Farahani K, Rezaei-Tazangi F, Mansouri A, Hamblin MR, Aref AR. Role of non-coding RNAs as new therapeutic targets in regulating the EMT and apoptosis in metastatic gastric and colorectal cancers. Cell Cycle 2023; 22:2302-2323. [PMID: 38009668 PMCID: PMC10730205 DOI: 10.1080/15384101.2023.2286804] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 05/11/2023] [Accepted: 08/01/2023] [Indexed: 11/29/2023] Open
Abstract
Colorectal cancer (CRC) and gastric cancer (GC), are the two most common cancers of the gastrointestinal tract, and are serious health concerns worldwide. The discovery of more effective biomarkers for early diagnosis, and improved patient prognosis is important. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), can regulate cellular processes such as apoptosis and the epithelial-mesenchymal transition (EMT) leading to progression and resistance of GC and CRC tumors. Moreover these pathways (apoptosis and EMT) may serve as therapeutic targets, to prevent metastasis, and to overcome drug resistance. A subgroup of ncRNAs is common to both GC and CRC tumors, suggesting that they might be used as biomarkers or therapeutic targets. In this review, we highlight some ncRNAs that can regulate EMT and apoptosis as two opposite mechanisms in cancer progression and metastasis in GC and CRC. A better understanding of the biological role of ncRNAs could open up new avenues for the development of personalized treatment plans for GC and CRC patients.
Collapse
Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | - Ali Hakimzadeh
- Department of Medical Biotechnologies, University of Siena, Tuscany, Italy
| | - Farima Bozorgmand
- Department of Medical Nanotechnology, Faculty of Advanced Sciences and Technology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Sepehr Speed
- Medical Campus, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | | | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kobra Farahani
- Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Atena Mansouri
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Reza Aref
- Xsphera Biosciences, Translational Medicine group, Boston, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
14
|
Elshafie NO, Gribskov M, Lichti NI, Sayedahmed EE, Childress MO, dos Santos AP. miRNome expression analysis in canine diffuse large B-cell lymphoma. Front Oncol 2023; 13:1238613. [PMID: 37711209 PMCID: PMC10499539 DOI: 10.3389/fonc.2023.1238613] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/04/2023] [Indexed: 09/16/2023] Open
Abstract
Introduction Lymphoma is a common canine cancer with translational relevance to human disease. Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype, contributing to almost fifty percent of clinically recognized lymphoma cases. Identifying new biomarkers capable of early diagnosis and monitoring DLBCL is crucial for enhancing remission rates. This research seeks to advance our knowledge of the molecular biology of DLBCL by analyzing the expression of microRNAs, which regulate gene expression by negatively impacting gene expression via targeted RNA degradation or translational repression. The stability and accessibility of microRNAs make them appropriate biomarkers for the diagnosis, prognosis, and monitoring of diseases. Methods We extracted and sequenced microRNAs from ten fresh-frozen lymph node tissue samples (six DLBCL and four non-neoplastic). Results Small RNA sequencing data analysis revealed 35 differently expressed miRNAs (DEMs) compared to controls. RT-qPCR confirmed that 23/35 DEMs in DLBCL were significantly upregulated (n = 14) or downregulated (n = 9). Statistical significance was determined by comparing each miRNA's average expression fold-change (2-Cq) between the DLCBL and healthy groups by applying the unpaired parametric Welch's 2-sample t-test and false discovery rate (FDR). The predicted target genes of the DEMs were mainly enriched in the PI3K-Akt-MAPK pathway. Discussion Our data point to the potential value of miRNA signatures as diagnostic biomarkers and serve as a guideline for subsequent experimental studies to determine the targets and functions of these altered miRNAs in canine DLBCL.
Collapse
Affiliation(s)
- Nelly O. Elshafie
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
| | - Michael Gribskov
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
| | - Nathanael I. Lichti
- Bindley Bioscience Center, Purdue University, West Lafayette, IN, United States
| | - Ekramy. E. Sayedahmed
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
| | - Michael O. Childress
- Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, United States
| | - Andrea P. dos Santos
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
| |
Collapse
|
|
15
|
Boicean A, Birsan S, Ichim C, Boeras I, Roman-Filip I, Blanca G, Bacila C, Fleaca RS, Dura H, Roman-Filip C. Has-miR-129-5p's Involvement in Different Disorders, from Digestive Cancer to Neurodegenerative Diseases. Biomedicines 2023; 11:2058. [PMID: 37509697 PMCID: PMC10377727 DOI: 10.3390/biomedicines11072058] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/13/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
At present, it is necessary to identify specific biochemical, molecular, and genetic markers that can reliably aid in screening digestive cancer and correlate with the degree of disease development. Has-miR-129-5p is a small, non-coding molecule of RNA, circulating in plasma, gastric juice, and other biological fluids; it plays a protective role in tumoral growth, metastasis, etc. Furthermore, it is involved in various diseases, from the development of digestive cancer in cases of downregulation to neurodegenerative diseases and depression. Methods: We examined meta-analyses, research, and studies related to miR-129-5-p involved in digestive cancer and its implications in cancer processes, as well as metastasis, and described its implications in neurological diseases. Conclusions: Our review outlines that miR-129-5p is a significant controller of different pathways, genes, and proteins and influences different diseases. Some important pathways include the WNT and PI3K/AKT/mTOR pathways; their dysregulation results in digestive neoplasia and neurodegenerative diseases.
Collapse
Affiliation(s)
- Adrian Boicean
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania
| | - Sabrina Birsan
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania
| | - Cristian Ichim
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania
| | - Ioana Boeras
- Molecular Biology Laboratory of the Applied Ecology Research Center, Faculty of Sciences, Lucian Blaga University of Sibiu, 550012 Sibiu, Romania
| | - Iulian Roman-Filip
- Department of Neurology, "George Emil Palade" University of Medicine, Pharmacy, Sciences and Technology, 540136 Targu Mures, Romania
| | - Grama Blanca
- Faculty of Social Sciences, Lucian Blaga University of Sibiu, 550012 Sibiu, Romania
| | - Ciprian Bacila
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania
| | - Radu Sorin Fleaca
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania
| | - Horatiu Dura
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania
| | - Corina Roman-Filip
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania
| |
Collapse
|
|
16
|
Development of a 5-FU modified miR-129 mimic as a therapeutic for non-small cell lung cancer. Mol Ther Oncolytics 2023; 28:277-292. [PMID: 36911069 PMCID: PMC9995506 DOI: 10.1016/j.omto.2023.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 02/15/2023] [Indexed: 02/19/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths in the United States with non-small cell lung cancer (NSCLC) accounting for most cases. Despite advances in cancer therapeutics, the 5-year survival rate has remained poor due to several contributing factors, including its resistance to therapeutics. Therefore, there is a pressing need to develop therapeutics that can overcome resistance. Non-coding RNAs, including microRNAs (miRNAs), have been found to contribute to cancer resistance and therapeutics by modulating the expression of several targets involving multiple key mechanisms. In this study, we investigated the therapeutic potential of miR-129 modified with 5-fluorouracil (5-FU) in NSCLC. Our results show that 5-FU modified miR-129 (5-FU-miR-129) inhibits proliferation, induces apoptosis, and retains function as an miRNA in NSCLC cell lines A549 and Calu-1. Notably, we observed that 5-FU-miR-129 was able to overcome resistance to tyrosine kinase inhibitors and chemotherapy in cell lines resistant to erlotinib or 5-FU. Furthermore, we observed that the inhibitory effect of 5-FU-miR-129 can also be achieved in NSCLC cells under vehicle-free conditions. Finally, 5-FU-miR-129 inhibited NSCLC tumor growth and extended survival in vivo without toxic side effects. Altogether, our results demonstrate the potential of 5-FU-miR-129 as a highly potent cancer therapeutic in NSCLC.
Collapse
|
|
17
|
Ko B, Hanna M, Yu M, Grady WM. Epigenetic Alterations in Colorectal Cancer. EPIGENETICS AND HUMAN HEALTH 2023:331-361. [DOI: 10.1007/978-3-031-42365-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
18
|
Yuen JG, Fesler A, Hwang GR, Chen LB, Ju J. Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics. Mol Ther 2022; 30:3450-3461. [PMID: 35933584 PMCID: PMC9637772 DOI: 10.1016/j.ymthe.2022.07.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 06/20/2022] [Accepted: 07/21/2022] [Indexed: 11/24/2022] Open
Abstract
MicroRNA (miRNAs) are pleiotropic post-transcriptional modulators of gene expression. Their inherently pleiotropic nature makes miRNAs strong candidates for the development of cancer therapeutics, yet despite their potential, there remains a challenge to deliver nucleic acid-based therapies into cancer cells. We developed a novel approach to modify miRNAs by replacing the uracil bases with 5-fluorouracil (5-FU) in the guide strand of tumor suppressor miRNAs, thereby combining the therapeutic effect of 5-FU with tumor-suppressive effect of miRNAs to create a potent, multi-targeted therapeutic molecule without altering its native RNAi function. To demonstrate the general applicability of this approach to other tumor-suppressive miRNAs, we screened a panel of 12 novel miRNA mimetics in several cancer types, including leukemia, breast, gastric, lung, and pancreatic cancer. Our results show that 5-FU-modified miRNA mimetics have increased potency (low nanomolar range) in inhibiting cancer cell proliferation and that these mimetics can be delivered into cancer cells without delivery vehicle both in vitro and in vivo, thus representing significant advancements in the development of therapeutic miRNAs for cancer. This work demonstrates the potential of fluoropyrimidine modifications that can be broadly applicable and may serve as a platform technology for future miRNA and nucleic acid-based therapeutics.
Collapse
Affiliation(s)
- John G Yuen
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | | | - Ga-Ram Hwang
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Lan-Bo Chen
- Curamir Therapeutics Inc., Woburn, MA 01801, USA
| | - Jingfang Ju
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Curamir Therapeutics Inc., Woburn, MA 01801, USA.
| |
Collapse
|
|
19
|
The Features of Immune Checkpoint Gene Regulation by microRNA in Cancer. Int J Mol Sci 2022; 23:ijms23169324. [PMID: 36012588 PMCID: PMC9409052 DOI: 10.3390/ijms23169324] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 02/06/2023] Open
Abstract
Currently, the search for new promising tools of immunotherapy continues. In this regard, microRNAs (miRNAs) that influence immune checkpoint (IC) gene expression in tumor and T-cells and may be important regulators of immune cells are considered. MiRNAs regulate gene expression by blocking mRNA translation. An important feature of miRNA is its ability to affect the expression of several genes simultaneously, which corresponds to the trend toward the use of combination therapy. The article provides a list of miRNAs acting simultaneously on several ICs and miRNAs that, in addition to IC, can regulate the expression of targeted therapy genes. There is dependence of miRNA interactions with IC genes on the type of cancer. The analysis of the accumulated data demonstrates that only about 14% (95% CI: 9.8–20.1%) of the studied miRNAs regulate the expression of specific IC in more than one type of cancer. That is, there is tumor specificity in the miRNA action on ICs. A number of miRNAs demonstrated high efficiency in vitro and in vivo. This indicates the potential of miRNAs as promising agents for cancer immunotherapy. Additional studies of the miRNA–gene interaction features and the search for an optimal miRNA mimic structure are necessary.
Collapse
|
|
20
|
Zichittella C, Barreca MM, Cordaro A, Corrado C, Alessandro R, Conigliaro A. Mir-675-5p supports hypoxia-induced drug resistance in colorectal cancer cells. BMC Cancer 2022; 22:567. [PMID: 35596172 PMCID: PMC9123752 DOI: 10.1186/s12885-022-09666-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 04/28/2022] [Indexed: 12/15/2022] Open
Abstract
Background The uncontrolled proliferation of cancer cells determines hypoxic conditions within the neoplastic mass with consequent activation of specific molecular pathways that allow cells to survive despite oxygen deprivation. The same molecular pathways are often the cause of chemoresistance. This study aims to investigate the role of the hypoxia-induced miR-675-5p in 5-Fluorouracil (5-FU) resistance on colorectal cancer (CRC) cells. Methods CRC cell lines were treated with 5-Fu and incubated in normoxic or hypoxic conditions; cell viability has been evaluated by MTT assay. MiR-675-5p levels were analysed by RT-PCR and loss and gain expression of the miRNA has been obtained by the transfection of miRNA antagomir or miRNA mimic. Total protein expression of different apoptotic markers was analysed through western blot assay. MirWalk 2.0 database search engine was used to investigate the putative targets of the miR-675-5p involved in the apoptotic process. Finally, the luciferase assay was done to confirm Caspase-3 as a direct target of the miR-675-5p. Results Our data demonstrated that hypoxia-induced miR-675-5p counteracts the apoptotic signal induced by 5-FU, thus taking part in the drug resistance response. We showed that the apoptotic markers, cleaved PARP and cleaved caspase-3, increased combining miR-675-5p inhibition with 5-FU treatment. Moreover, we identified pro-caspase-3 among the targets of the miR-675-5p. Conclusion Our data demonstrate that the inhibition of hypoxia-induced miR-675-5p combined with 5-FU treatment can enhances drug efficacy in both prolonged hypoxia and normoxia, indicating a possible strategy to partially overcome chemoresistance. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09666-2.
Collapse
Affiliation(s)
- Chiara Zichittella
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Biology and Genetics, University of Palermo, 90133, Palermo, Italy
| | - Maria Magdalena Barreca
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Biology and Genetics, University of Palermo, 90133, Palermo, Italy.,Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128, Palermo, Italy
| | - Aurora Cordaro
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Biology and Genetics, University of Palermo, 90133, Palermo, Italy
| | - Chiara Corrado
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Biology and Genetics, University of Palermo, 90133, Palermo, Italy
| | - Riccardo Alessandro
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Biology and Genetics, University of Palermo, 90133, Palermo, Italy.,Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146, Palermo, Italy
| | - Alice Conigliaro
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Biology and Genetics, University of Palermo, 90133, Palermo, Italy.
| |
Collapse
|
|
21
|
MicroRNAs and drug resistance in colorectal cancer with special focus on 5-fluorouracil. Mol Biol Rep 2022; 49:5165-5178. [PMID: 35212928 DOI: 10.1007/s11033-022-07227-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 02/03/2022] [Indexed: 02/08/2023]
Abstract
Colorectal cancer is globally one of the most common cancers in all age groups. The current chemotherapy combinations for colorectal cancer treatment include 5-fluorouracil-based regimens; however, drug resistance remains one of the main reasons for chemotherapy failure and disease recurrence. Many studies have determined colorectal cancer chemoresistance mechanisms such as drug efflux, cell cycle arrest, DNA damage repair, apoptosis, autophagy, vital enzymes, epigenetic, epithelial-mesenchymal transition, stem cells, and immune system suppression. Several microRNAs affect drug resistance by regulating the drug resistance-related target genes in colorectal cancer. These drug resistance-related miRNAs may be used as promising biomarkers for predicting drug response or as potential therapeutic targets for treating patients with colorectal cancer. This work reviews and discuss the role of selected microRNAs in 5-fluorouracil resistance and their molecular mechanisms in colorectal cancer.
Collapse
|
|
22
|
Liu B, Hu J, Zhao H, Zhao L, Pan S. MicroRNA-155-5p Contributes to 5-Fluorouracil Resistance Through Down-Regulating TP53INP1 in Oral Squamous Cell Carcinoma. Front Oncol 2022; 11:706095. [PMID: 35070952 PMCID: PMC8770267 DOI: 10.3389/fonc.2021.706095] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 12/15/2021] [Indexed: 11/13/2022] Open
Abstract
The anticancer drug 5-fluorouracil (5-FU) resistance is a major obstacle to reducing the effectiveness of cancer treatment, and its detailed mechanism has not been fully elucidated. Here, in 5-FU-resistant human oral squamous cell carcinoma (OSCC) HSC3 cells (HSC3/5-FU), the levels of 21 miRNA candidates were detected using RT-PCR and miR-155-5p level increased strikingly in HSC3/5-FU cells compared to HSC3 cells. Compared with HSC3 cells, the CCK-8 assay showed that the HSC3/5-FU cells transfected with miR-155-5p inhibitors decreased 5-FU IC50. Ectopic expression of miR-155-5p in HSC3 and HSC4 cells increased 5-FU IC50 (CCK-8 assay), migration (wound-healing and transwell assays) and invasion (transwell assay) abilities. Seven miR-155-5p target candidates were discovered by miRNA prediction algorithms (miRDB, Targetscan, and miRWalk), and the RT-PCR results showed that in HSC3/5-FU cells TP53INP1 was of the lowest mRNA expression level compared with HSC3 cells. The RT-PCR and Western blotting assays showed that ectopic expression of miR-155-5p in HSC3 and HSC4 cells decreased TP53INP1 expression level. Furthermore, the luciferase reporter and RNA pull-down assays determined the interference effect of miR-155-5p on TP53INP1 expression. The enhancement of cell viability (CCK-8 assay), migration (wound-healing and transwell assays) and invasion (transwell assay) by miR-155-5p after 5-FU treatment was reversed by TP53INP1 overexpression. After treatment with 5-FU, HSC3-miR-155-5p tumor-bearing nude mice presented growing tumors, while HSC3-TP53INP1 group possessed shrinking tumors. In conclusion, these results lead to the proposal that miR-155-5p enhances 5-FU resistance by decreasing TP53INP1 expression in OSCC.
Collapse
Affiliation(s)
- Bowen Liu
- Outpatient Department of Oral and Maxillofacial Surgery, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Jingchao Hu
- Department of Periodontics, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Han Zhao
- Multi-disciplinary Treatment Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Li Zhao
- Department of Prosthodontics, Stomatological Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Shiyuan Pan
- Department of Dentistry, Chongqing Huamei Plastic Surgery Hospital, Chongqing, China
| |
Collapse
|
|
23
|
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: 2] [Impact Index Per Article: 0.7] [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.
Collapse
|
|
24
|
Lahooti B, Poudel S, Mikelis CM, Mattheolabakis G. MiRNAs as Anti-Angiogenic Adjuvant Therapy in Cancer: Synopsis and Potential. Front Oncol 2021; 11:705634. [PMID: 34956857 PMCID: PMC8695604 DOI: 10.3389/fonc.2021.705634] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
Angiogenesis is a key mechanism for tumor growth and metastasis and has been a therapeutic target for anti-cancer treatments. Intensive vascular growth is concomitant with the rapidly proliferating tumor cell population and tumor outgrowth. Current angiogenesis inhibitors targeting either one or a few pro-angiogenic factors or a range of downstream signaling molecules provide clinical benefit, but not without significant side effects. miRNAs are important post-transcriptional regulators of gene expression, and their dysregulation has been associated with tumor progression, metastasis, resistance, and the promotion of tumor-induced angiogenesis. In this mini-review, we provide a brief overview of the current anti-angiogenic approaches, their molecular targets, and side effects, as well as discuss existing literature on the role of miRNAs in angiogenesis. As we highlight specific miRNAs, based on their activity on endothelial or cancer cells, we discuss their potential for anti-angiogenic targeting in cancer as adjuvant therapy and the importance of angiogenesis being evaluated in such combinatorial approaches.
Collapse
Affiliation(s)
- Behnaz Lahooti
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, United States
| | - Sagun Poudel
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, United States
| | - Constantinos M. Mikelis
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, United States
- Department of Pharmacy, University of Patras, Patras, Greece
| | - George Mattheolabakis
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, United States
| |
Collapse
|
|
25
|
Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
Collapse
Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| |
Collapse
|
|
26
|
Kim JK, Qu X, Chen CT, Smith JJ, Sanchez-Vega F, Garcia-Aguilar J. Identifying Diagnostic MicroRNAs and Investigating Their Biological Implications in Rectal Cancer. JAMA Netw Open 2021; 4:e2136913. [PMID: 34860243 PMCID: PMC8642786 DOI: 10.1001/jamanetworkopen.2021.36913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
IMPORTANCE Accurate clinical staging is important in rectal cancer because it determines the appropriate treatment and prognosis. Despite the use of multiple diagnostic imaging tools, it is sometimes difficult to clinically distinguish stage I tumors from stage II or III locally advanced disease. Identification of differentiating microRNAs (miRNAs) between these 2 groups may improve the clinical diagnostic power and provide insight into the biology of tumor progression. OBJECTIVES To investigate differences in the expression of miRNAs in stage I vs stage II or III rectal cancers and integrate matched mRNA profiling data to identify possible functional roles of these miRNAs. DESIGN, SETTING, AND PARTICIPANTS The primary tumor specimens from patients who were enrolled in 2 prospective clinical trials between March 24, 2004, and November 16, 2012 (American College of Surgeons Oncology Group [ACOSOG] Z6041 and Timing of Rectal Cancer Response to Chemoradiation [TIMING]) were sequenced to arrive at a set of 127 cases (41 stage I and 86 stage II or III tumors) with matched miRNA and messenger RNA (mRNA) profiling data. These findings were also evaluated in an independent cohort of 127 patient specimens (29 stage I and 98 stage II or III tumors) from The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) that also had matched miRNA and mRNA data. Data analysis was performed from September 1, 2019, to September 1, 2020. MAIN OUTCOMES AND MEASURES Alterations in miRNA expression between stage I and stage II or III tumors and their potential gene targets. RESULTS A total of 254 pretreatment rectal adenocarcinoma specimens were analyzed in this study as 2 distinct cohorts: 127 samples in the ACOSOG/TIMING (stage I group: 27 [66%] male; mean [SD] age, 64.4 [10.8] years; stage II or III group: 47 [55%] male; mean [SD] age, 57.0 [11.4] years), and another 127 samples from TCGA-READ (stage I group: 17 [59%] male; mean [SD] age, 63.6 [12.0] years; stage II or III group: 48 [49%] male; mean [SD] age, 64.5 [11.4] years). A total of 19 miRNAs were overexpressed in stage II or III vs stage I tumors in both cohorts. This miRNA signature had an excellent discriminative value for distinguishing stage II or III from stage I rectal tumors (area under the curve, 0.88; 95% CI, 0.83-0.94 in ACOSOG/TIMING cohort and area under the curve, 0.84; 95% CI, 0.77-0.91 in the TCGA-READ cohort). Integrative analysis revealed 3 miRNA-mRNA pairs that exhibited significant correlations in both cohorts: miR-31-5p-SATB2, miR-143-3p-KLF5, and miR-204-5p-EZR. CONCLUSIONS AND RELEVANCE This diagnostic study found that many of the dysregulated miRNAs in stage II or III vs stage I rectal cancers have biological implications for tumor progression. The results of this study suggest that these miRNAs could assist as diagnostic biomarkers to better identify patients with locally advanced rectal cancer.
Collapse
Affiliation(s)
- Jin K. Kim
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York
| | - Xuan Qu
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York
| | - Chin-Tung Chen
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York
| | - J. Joshua Smith
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York
| | - Francisco Sanchez-Vega
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York
| | - Julio Garcia-Aguilar
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York
| |
Collapse
|
|
27
|
Patil N, Abba ML, Zhou C, Chang S, Gaiser T, Leupold JH, Allgayer H. Changes in Methylation across Structural and MicroRNA Genes Relevant for Progression and Metastasis in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13235951. [PMID: 34885060 DOI: 10.3390/cancers13235951] [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: 11/10/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 12/12/2022] Open
Abstract
MiRs are important players in cancer and primarily genetic/transcriptional means of regulating their gene expression are known. However, epigenetic changes modify gene expression significantly. Here, we evaluated genome-wide methylation changes focusing on miR genes from primary CRC and corresponding normal tissues. Differentially methylated CpGs spanning CpG islands, open seas, and north and south shore regions were evaluated, with the largest number of changes observed within open seas and islands. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed several of these miRs to act in important cancer-related pathways, including phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) pathways. We found 18 miR genes to be significantly differentially methylated, with MIR124-2, MIR124-3, MIR129-2, MIR137, MIR34B, MIR34C, MIR548G, MIR762, and MIR9-3 hypermethylated and MIR1204, MIR17, MIR17HG, MIR18A, MIR19A, MIR19B1, MIR20A, MIR548F5, and MIR548I4 hypomethylated in CRC tumor compared with normal tissue, most of these miRs having been shown to regulate steps of metastasis. Generally, methylation changes were distributed evenly across all chromosomes with predominance for chromosomes 1/2 and protein-coding genes. Interestingly, chromosomes abundantly affected by methylation changes globally were rarely affected by methylation changes within miR genes. Our findings support additional mechanisms of methylation changes affecting (miR) genes that orchestrate CRC progression and metastasis.
Collapse
Affiliation(s)
- Nitin Patil
- Department of Experimental Surgery-Cancer Metastasis, Mannheim Medical Faculty, Ruprecht Karls University of Heidelberg, 68167 Mannheim, Germany
| | - Mohammed L Abba
- Department of Experimental Surgery-Cancer Metastasis, Mannheim Medical Faculty, Ruprecht Karls University of Heidelberg, 68167 Mannheim, Germany
| | - Chan Zhou
- Department of Experimental Surgery-Cancer Metastasis, Mannheim Medical Faculty, Ruprecht Karls University of Heidelberg, 68167 Mannheim, Germany
| | - Shujian Chang
- Department of Experimental Surgery-Cancer Metastasis, Mannheim Medical Faculty, Ruprecht Karls University of Heidelberg, 68167 Mannheim, Germany
| | - Timo Gaiser
- Institute of Pathology, Mannheim Medical Faculty, Ruprecht Karls University of Heidelberg, Theodor Kutzer Ufer 1-3, 68167 Mannheim, Germany
| | - Jörg H Leupold
- Department of Experimental Surgery-Cancer Metastasis, Mannheim Medical Faculty, Ruprecht Karls University of Heidelberg, 68167 Mannheim, Germany
| | - Heike Allgayer
- Department of Experimental Surgery-Cancer Metastasis, Mannheim Medical Faculty, Ruprecht Karls University of Heidelberg, 68167 Mannheim, Germany
| |
Collapse
|
|
28
|
Regulatory role of miR-129 and miR-384-5p on apoptosis induced by oxygen and glucose deprivation in PC12 cell. Exp Brain Res 2021; 240:97-111. [PMID: 34661743 DOI: 10.1007/s00221-021-06236-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 09/25/2021] [Indexed: 10/20/2022]
Abstract
This study aimed to establish the role of miR-129 and miR-384-5p in cerebral ischemia-induced apoptosis. Using PC12 cells transfected with miR-129 or miR-384-5p mimics or inhibitors, oxygen glucose deprivation (OGD) conditions were applied for 4 h to simulate transient cerebral ischemia. Apoptotic phenotypes were assessed via lactate dehydrogenase (LDH) assay, MTT cell metabolism assay, and fluorescence-activated cell sorting (FACS). The effect of miR overexpression and inhibition was evaluated by protein and mRNA detection of bcl-2 and caspase-3, critical apoptosis factors. Finally, the direct relationship of miR-129 and bcl-2 and miR-384-5p and caspase-3 was measured by luciferase reporter assay. The overexpression of miR-384-5p and miR-129 deficiency significantly enhanced cell viability, reduced LDH release, and inhibited apoptosis. By contrast, overexpression of miR-129 and miR-384-5p deficiency aggravated hypoxia-induced apoptosis and cell injury. miR-129 overexpression significantly reduced mRNA and protein levels of bcl-2 and miR-129 inhibition significantly increased mRNA and protein levels of bcl-2 in hypoxic cells.miR-384-5p overexpression significantly reduced protein levels of caspase-3 while miR-384-5p deficiency significantly increased protein levels of caspase-3. However, no changes were observed in caspase-3 mRNA in either transfection paradigm. Finally, luciferase reporter assay confirmed caspase-3 to be a direct target of miR-384-5p; however, no binding activity was detected between bcl-2 and miR-129.Transient cerebral ischemia induces differential expression of miR-129 and miR-384-5p which influences apoptosis by regulating apoptotic factors caspase-3 and bcl-2, thereby participating in the pathological mechanism of cerebral ischemia, and becoming potential targets for the treatment of ischemic cerebral injury in the future.
Collapse
|
|
29
|
Xu S, Li W, Wu J, Lu Y, Xie M, Li Y, Zou J, Zeng T, Ling H. The role of miR-129-5p in cancer: a novel therapeutic target. Curr Mol Pharmacol 2021; 15:647-657. [PMID: 34521336 DOI: 10.2174/1874467214666210914122010] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/30/2021] [Accepted: 06/25/2021] [Indexed: 11/22/2022]
Abstract
MiRNA-129-5p belongs to the microRNA-129 (miRNA-129) family. MiRNA-129-5p is expressed in many tissues and organs of the human body, and it regulates a wide range of biological functions. The abnormal expression of miRNA-129-5p is related to the occurrence and development of a variety of malignant tumors. MiRNA-129-5p plays an important role in the tumorigenesis process and functions by promoting or inhibiting tumors. However, the role of miRNA-129-5p in cancer remains controversial. This article reviews the different biological functions of miRNA-129-5p in cancer and provides ideas for research in this field to guide the development of targeted therapies and drugs for malignant tumors.
Collapse
Affiliation(s)
- Shan Xu
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China)，College of Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001. China
| | - Wei Li
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China)，College of Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001. China
| | - Jing Wu
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China)，College of Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001. China
| | - Yuru Lu
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China)，College of Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001. China
| | - Ming Xie
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China)，College of Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001. China
| | - Yanlan Li
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China)，College of Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001. China
| | - Juan Zou
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China)，College of Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001. China
| | - Tiebing Zeng
- Hunan Province Cooperative innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405], Hengyang, Hunan 421001. China
| | - Hui Ling
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China)，College of Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001. China
| |
Collapse
|
|
30
|
Crudele F, Bianchi N, Astolfi A, Grassilli S, Brugnoli F, Terrazzan A, Bertagnolo V, Negrini M, Frassoldati A, Volinia S. The Molecular Networks of microRNAs and Their Targets in the Drug Resistance of Colon Carcinoma. Cancers (Basel) 2021; 13:cancers13174355. [PMID: 34503164 PMCID: PMC8431668 DOI: 10.3390/cancers13174355] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/19/2021] [Accepted: 08/22/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary We systematically reviewed the recent scientific publications describing the role of microRNAs in the regulation of drug resistance in colon cancer. To clarify the intricate web of resulting genetic and biochemical interactions, we used a machine learning approach aimed at creating: (i) networks of validated miRNA/target interactions involved in drug resistances and (ii) drug-centric networks, from which we identified the major clusters of proteins affected by drugs used in the treatment of colon cancer. Finally, to facilitate a high-level interpretation of these molecular interactions, we determined the cellular pathways related with drug resistance and regulated by the miRNAs in colon cancer. Abstract Drug resistance is one of the major forces driving a poor prognosis during the treatment and progression of human colon carcinomas. The molecular mechanisms that regulate the diverse processes underlying drug resistance are still under debate. MicroRNAs (miRNAs) are a subgroup of non-coding RNAs increasingly found to be associated with the regulation of tumorigenesis and drug resistance. We performed a systematic review of the articles concerning miRNAs and drug resistance in human colon cancer published from 2013 onwards in journals with an impact factor of 5 or higher. First, we built a network with the most studied miRNAs and targets (as nodes) while the drug resistance/s are indicated by the connections (edges); then, we discussed the most relevant miRNA/targets interactions regulated by drugs according to the network topology and statistics. Finally, we considered the drugs as nodes in the network, to allow an alternative point of view that could flow through the treatment options and the associated molecular pathways. A small number of microRNAs and proteins appeared as critically involved in the most common drugs used for the treatment of patients with colon cancer. In particular, the family of miR-200, miR34a, miR-155 and miR-17 appear as the most relevant microRNAs. Thus, regulating these miRNAs could be useful for interfering with some drug resistance mechanisms in colorectal carcinoma.
Collapse
Affiliation(s)
- Francesca Crudele
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (F.C.); (N.B.); (A.A.); (S.G.); (F.B.); (A.T.); (V.B.); (M.N.)
- Laboratory for Advanced Therapy Technologies (LTTA), Via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Nicoletta Bianchi
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (F.C.); (N.B.); (A.A.); (S.G.); (F.B.); (A.T.); (V.B.); (M.N.)
| | - Annalisa Astolfi
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (F.C.); (N.B.); (A.A.); (S.G.); (F.B.); (A.T.); (V.B.); (M.N.)
| | - Silvia Grassilli
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (F.C.); (N.B.); (A.A.); (S.G.); (F.B.); (A.T.); (V.B.); (M.N.)
- Laboratory for Advanced Therapy Technologies (LTTA), Via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Federica Brugnoli
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (F.C.); (N.B.); (A.A.); (S.G.); (F.B.); (A.T.); (V.B.); (M.N.)
| | - Anna Terrazzan
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (F.C.); (N.B.); (A.A.); (S.G.); (F.B.); (A.T.); (V.B.); (M.N.)
| | - Valeria Bertagnolo
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (F.C.); (N.B.); (A.A.); (S.G.); (F.B.); (A.T.); (V.B.); (M.N.)
| | - Massimo Negrini
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (F.C.); (N.B.); (A.A.); (S.G.); (F.B.); (A.T.); (V.B.); (M.N.)
- Laboratory for Advanced Therapy Technologies (LTTA), Via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Antonio Frassoldati
- Department of Oncology, Azienda Ospedaliero-Universitaria St. Anna di Ferrara, Via A. Moro 8, 44124 Ferrara, Italy;
| | - Stefano Volinia
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy; (F.C.); (N.B.); (A.A.); (S.G.); (F.B.); (A.T.); (V.B.); (M.N.)
- Laboratory for Advanced Therapy Technologies (LTTA), Via Fossato di Mortara 70, 44121 Ferrara, Italy
- Correspondence:
| |
Collapse
|
|
31
|
miR-129-5p Promotes Osteogenic Differentiation of BMSCs and Bone Regeneration via Repressing Dkk3. Stem Cells Int 2021; 2021:7435605. [PMID: 34326879 PMCID: PMC8302374 DOI: 10.1155/2021/7435605] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/12/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
Objective Accumulating evidence indicates that microRNAs (miRNAs) play crucial roles in osteogenic differentiation. However, the associated mechanisms remain elusive. This paper is aimed at exploring the role of miR-129-5p in regulating bone marrow mesenchymal stem cell (BMSC) differentiation and bone regeneration in vivo and in vitro. Methods BMSCs were transduced by miR-129-5p mimic, miR-129-5p inhibitor, and negative control lentivirus. The ability of BMSC differentiation to osteoblast was tested by alkaline phosphatase (ALP) and alizarin red staining (ARS). The expression of osteogenic genes (Runx2, Bmp2, and OCN) was examined via quantitative RT-PCR and western blot. A mouse model of calvaria defect was investigated by Micro-CT, immunohistochemistry, and histological examination. The luciferase reporter gene assay was performed to confirm the binding between Dkk3 and miR-129-5p. For the transfection experiments, lipofectamine 3000 was used to transfect pcDNA-Dkk3 into BMSCs to overexpress Dkk3. Coimmunoprecipitation and immunofluorescent localization assay were included for exploring the role of Dkk3 and β-catenin. Results miR-129-5p was induced in BMSCs and MSC cell line C3H10T1/2 cells under osteogenic medium. Overexpression of miR-129-5p significantly promoted osteogenic differentiation of BMSCs in vitro. Moreover, BMSCs transduced with miR-129-5p mimic exhibited better bone regeneration compared with BMSCs transduced with control counterpart in vivo. Luciferase and western blot data showed that Dickkopf3 (Dkk3) is a target gene of miR-129-5p and the expression of Dkk3 was inhibited in BMSCs transduced with miR-129-5p mimic but enhanced in BMSCs transduced with miR-129-5p inhibitor. In addition, Dkk3 interacted with β-catenin directly. Conclusions miR-129-5p promotes osteogenic differentiation of BMSCs and bone regeneration, and miR-129-5p/Dkk3 axis may be new potential targets for the treatment of bone defect and bone loss.
Collapse
|
|
32
|
MicroRNAs in Medullary Thyroid Carcinoma: A State of the Art Review of the Regulatory Mechanisms and Future Perspectives. Cells 2021; 10:cells10040955. [PMID: 33924120 PMCID: PMC8074316 DOI: 10.3390/cells10040955] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 12/17/2022] Open
Abstract
Medullary thyroid carcinoma (MTC) is a rare malignant neoplasia with a variable clinical course, with complete remission often difficult to achieve. Genetic alterations lead to fundamental changes not only in hereditary MTC but also in the sporadic form, with close correlations between mutational status and prognosis. In recent years, microRNAs (miRNAs) have become highly relevant as crucial players in MTC etiology. Current research has focused on their roles in disease carcinogenesis and development, but recent studies have expounded their potential as biomarkers and response predictors to novel biological drugs for advanced MTC. One such element which requires greater investigation is their mechanism of action and the molecular pathways involved in the regulation of gene expression. A more thorough understanding of these mechanisms will help realize the promising potential of miRNAs for MTC therapy and management.
Collapse
|
|
33
|
Ghafouri-Fard S, Abak A, Tondro Anamag F, Shoorei H, Fattahi F, Javadinia SA, Basiri A, Taheri M. 5-Fluorouracil: A Narrative Review on the Role of Regulatory Mechanisms in Driving Resistance to This Chemotherapeutic Agent. Front Oncol 2021; 11:658636. [PMID: 33954114 PMCID: PMC8092118 DOI: 10.3389/fonc.2021.658636] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/24/2021] [Indexed: 12/14/2022] Open
Abstract
5-fluorouracil (5-FU) is among the mostly administrated chemotherapeutic agents for a wide variety of neoplasms. Non-coding RNAs have a central impact on the determination of the response of patients to 5-FU. These transcripts via modulation of cancer-related pathways, cell apoptosis, autophagy, epithelial-mesenchymal transition, and other aspects of cell behavior can affect cell response to 5-FU. Modulation of expression levels of microRNAs or long non-coding RNAs may be a suitable approach to sensitize tumor cells to 5-FU treatment via modulating multiple biological signaling pathways such as Hippo/YAP, Wnt/β-catenin, Hedgehog, NF-kB, and Notch cascades. Moreover, there is an increasing interest in targeting these transcripts in various kinds of cancers that are treated by 5-FU. In the present article, we provide a review of the function of non-coding transcripts in the modulation of response of neoplastic cells to 5-FU.
Collapse
Affiliation(s)
- Soudeh Ghafouri-Fard
- Dental Research Center, Research Institute for Dental Sciences, Dental School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atefe Abak
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Faranak Fattahi
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, United States
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, United States
| | - Seyed Alireza Javadinia
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Abbas Basiri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
34
|
Rahimian N, Razavi ZS, Aslanbeigi F, Mirkhabbaz AM, Piroozmand H, Shahrzad MK, Hamblin MR, Mirzaei H. Non-coding RNAs related to angiogenesis in gynecological cancer. Gynecol Oncol 2021; 161:896-912. [PMID: 33781555 DOI: 10.1016/j.ygyno.2021.03.020] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023]
Abstract
Gynecological cancer affects the female reproductive system, including ovarian, uterine, endometrial, cervical, vulvar, and vaginal tumors. Non-coding RNAs (ncRNAs), and in particular microRNAs, function as regulatory molecules, which can control gene expression in a post-transcriptional manner. Normal physiological processes like cellular proliferation, differentiation, and apoptosis, and pathological processes such as oncogenesis and metastasis are regulated by microRNAs. Numerous reports have shown a direct role of microRNAs in the modulation of angiogenesis in gynecological cancer, via targeting pro-angiogenic factors and signaling pathways. Understanding the molecular mechanism involved in the regulation of angiogenesis by microRNAs may lead to new treatment options. Recently the regulatory role of some long non-coding RNAs in gynecological cancer has also been explored, but the information on this function is more limited. The aim of this article is to explore the pathways responsible for angiogenesis, and to what extent ncRNAs may be employed as biomarkers or therapeutic targets in gynecological cancer.
Collapse
Affiliation(s)
- Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | | | | | | | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohammad Karim Shahrzad
- Department of Internal Medicine and endocrinology, Shohadae Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| |
Collapse
|
|
35
|
The Multifaceted Role and Utility of MicroRNAs in Indolent B-Cell Non-Hodgkin Lymphomas. Biomedicines 2021; 9:biomedicines9040333. [PMID: 33806113 PMCID: PMC8064455 DOI: 10.3390/biomedicines9040333] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/14/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023] Open
Abstract
Normal B-cell development is a tightly regulated complex procedure, the deregulation of which can lead to lymphomagenesis. One common group of blood cancers is the B-cell non-Hodgkin lymphomas (NHLs), which can be categorized according to the proliferation and spread rate of cancer cells into indolent and aggressive ones. The most frequent indolent B-cell NHLs are follicular lymphoma and marginal zone lymphoma. MicroRNAs (miRNAs) are small non-coding RNAs that can greatly influence protein expression. Based on the multiple interactions among miRNAs and their targets, complex networks of gene expression regulation emerge, which normally are essential for proper B-cell development. Multiple miRNAs have been associated with B-cell lymphomas, as the deregulation of these complex networks can lead to such pathological states. The aim of the present review is to summarize the existing information regarding the multifaceted role of miRNAs in indolent B-cell NHLs, affecting the main B-cell subpopulations. We attempt to provide insight into their biological function, the complex miRNA-mRNA interactions, and their biomarker utility in these malignancies. Lastly, we address the limitations that hinder the investigation of the role of miRNAs in these lymphomas and discuss ways that these problems could be overcome in the future.
Collapse
|
|
36
|
Du G, Yu X, Chen Y, Cai W. MiR-1-3p Suppresses Colorectal Cancer Cell Proliferation and Metastasis by Inhibiting YWHAZ-Mediated Epithelial-Mesenchymal Transition. Front Oncol 2021; 11:634596. [PMID: 33718221 PMCID: PMC7952857 DOI: 10.3389/fonc.2021.634596] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 01/21/2021] [Indexed: 12/24/2022] Open
Abstract
Background Colorectal cancer (CRC) is regarded as one of the most common malignancies in the world. MiR-1-3p was reported to be a tumor suppressor in CRC. However, the mechanisms have not been fully elucidated. Methods To identify CRC-associated miRNA, microarray data set GSE30454 was downloaded from the Gene Expression Omnibus database (GEO), and miR-1-3p was screened out as a candidate. The expression of miR-1-3p was detected using quantitative real-time polymerase chain reaction (qRT-PCR) in CRC cell lines and tissues. CCK-8 assay and transwell invasion assay were performed to determine CRC cell line proliferation and invasion, respectively. The levels of YWHAZ and EMT-associated proteins were detected using western blotting. Results Bioinformatic analysis showed that miR-1-3p was downregulated in CRC tissues, which is verified by our experimental validation. The overexpression of miR-1-3p significantly suppressed CRC cell proliferation and invasion. Further studies showed that YWHAZ was a direct target of miR-1-3p and mediated epithelial-mesenchymal transition (EMT) modulated by miR-1-3p. Conclusion Our results demonstrated that miR-1-3p suppresses colorectal cancer cell proliferation and metastasis through regulating YWHAZ-mediated EMT, which may support a novel therapeutic strategy for CRC patients.
Collapse
Affiliation(s)
- Guanghong Du
- Department of Geriatrics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xuelian Yu
- Department of Geriatrics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yun Chen
- Department of Geriatrics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Wangting Cai
- Organ transplant center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| |
Collapse
|
|
37
|
MicroRNA-Based Therapeutics for Drug-Resistant Colorectal Cancer. Pharmaceuticals (Basel) 2021; 14:ph14020136. [PMID: 33567635 PMCID: PMC7915952 DOI: 10.3390/ph14020136] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/29/2021] [Accepted: 02/04/2021] [Indexed: 12/13/2022] Open
Abstract
Although therapeutic approaches for patients with colorectal cancer (CRC) have improved in the past decades, the problem of drug resistance still persists and acts as a major obstacle for effective therapy. Many studies have shown that drug resistance is related to reduced drug uptake, modification of drug targets, and/or transformation of cell cycle checkpoints. A growing body of evidence indicates that several microRNAs (miRNAs) may contribute to the drug resistance to chemotherapy, targeted therapy, and immunotherapy by regulating the drug resistance-related target genes in CRC. These drug resistance-related miRNAs may be used as promising biomarkers for predicting drug response or as potential therapeutic targets for treating patients with CRC. In this review, we summarized the recent discoveries regarding anti-cancer drug-related miRNAs and their molecular mechanisms in CRC. Furthermore, we discussed the challenges associated with the clinical application of miRNAs as biomarkers for the diagnosis of drug-resistant patients and as therapeutic targets for CRC treatment.
Collapse
|
|
38
|
Hwang GR, Yuen JG, Ju J. Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development. Int J Mol Sci 2021; 22:ijms22041624. [PMID: 33562727 PMCID: PMC7915611 DOI: 10.3390/ijms22041624] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
Resistance to cancer treatment is one of the major challenges currently faced when treating gastrointestinal (GI) cancers. A major contributing factor to this resistance is the presence of cancer stem cells (CSCs) in GI cancers (e.g., colorectal, pancreatic, gastric, liver cancer). Non-coding RNAs, such as microRNAs (miRNAs), have been found to regulate several key targets that are responsible for cancer stemness, and function as oncogenic miRNAs (oncomiRs) or tumor suppressor miRNAs. As a result, several miRNAs have been found to alter, or be altered by, the expression of CSC-defining markers and their related pathways. These miRNAs can be utilized to affect stemness in multiple ways, including directly targeting CSCs and enhancing the efficacy of cancer therapeutics. This review highlights current studies regarding the roles of miRNAs in GI CSCs, and efforts towards the development of cancer therapeutics.
Collapse
|
|
39
|
Zhang N, Hu X, Du Y, Du J. The role of miRNAs in colorectal cancer progression and chemoradiotherapy. Biomed Pharmacother 2021; 134:111099. [PMID: 33338745 DOI: 10.1016/j.biopha.2020.111099] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/17/2020] [Accepted: 12/02/2020] [Indexed: 02/07/2023] Open
|
|
40
|
Shan S, Lu Y, Zhang X, Shi J, Li H, Li Z. Inhibitory effect of bound polyphenol from foxtail millet bran on miR-149 methylation increases the chemosensitivity of human colorectal cancer HCT-8/Fu cells. Mol Cell Biochem 2021; 476:513-523. [PMID: 33011952 DOI: 10.1007/s11010-020-03906-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 09/07/2020] [Indexed: 12/24/2022]
Abstract
Nature polyphenols widely present in plants and foods are promising candidates in cancer chemotherapy. Emerging evidence has shown that plant polyphenols regulate the expression of miRNAs to exert the anti-Multidrug resistance (MDR) activity, which partly attributes to their regulation on miRNAs methylation. Our previous study found that bound polyphenol from foxtail millet bran (BPIS) had potential as an anti-MDR agent for colorectal cancer (CRC), but its mechanism remains unclear. The present findings demonstrated that BPIS upregulated the expression of miR-149 by reducing the methylation of its CpG islands, which subsequently induced the cell cycle arrest in G2/M phase, resulting in enhancing the chemo-sensitivity of HCT-8/Fu cells. Mechanically, BPIS and its active components (FA and p-CA) reduced miR-149 methylation by inhibiting the expression levels of DNA methyltransferases, promoting a remarkable increase of miR-149 expression. Further, the increased miR-149 induced cell cycle arrest in G2/M phase by inhibiting the expression of Akt, Cyclin B1 and CDK1, thus increasing the chemosensitivity of HCT-8/Fu cells. Additionally, a strong inducer of DNA de-methylation (5-aza-dc) treatment markedly increased the chemosensitivity of CRC through elevating miR-149 expression, which indicates the hypermethylation of miR-149 may be the key cause of drug resistance in CRC. The study indicates that the enhanced chemosensitivity of BPIS on CRC is mainly attributed to the increase of miR-149 expression induced by methylation inhibition.
Collapse
Affiliation(s)
- Shuhua Shan
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China
| | - Yang Lu
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China
| | - Xiaoli Zhang
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China
| | - Jiangying Shi
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China
| | - Hanqing Li
- School of Life Science, Shanxi University, Taiyuan, China
| | - Zhuoyu Li
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China.
- School of Life Science, Shanxi University, Taiyuan, China.
| |
Collapse
|
|
41
|
Wang B, Li Y, You C. miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway. Diabetes Metab Syndr Obes 2021; 14:153-163. [PMID: 33488104 PMCID: PMC7815084 DOI: 10.2147/dmso.s285179] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 12/12/2020] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Glucose fluctuations have an adverse effect on several diabetes-related complications, especially for the nervous system, but the underlying mechanisms are not clear. MicroRNAs are critical regulators of posttranscription in many physiological processes, such as apoptosis. Our study clarified the neuroprotective effects of miR-129-3p targeting mitochondrial calcium uniporter (MCU) in glucose fluctuation-mediated neuronal damage and the specific mechanisms involved. METHODS The expression of MCU and miR-129-3p was examined by real-time PCR and Western blot in the glucose fluctuation cell model. Dual-luciferase reporter assay was performed to confirm the transcriptional regulation of miR-129-3p by MCU. Fluorescent probe and assay kit assay was used to determine oxidative stress condition. Mitochondrial-dependent intrinsic apoptotic factors were examined by flow cytometry assay, enzyme-linked immunosorbent assay (ELISA), and gene and protein expression assays. RESULTS We found an upregulation of MCU and downregulation of miR-129-3p in glucose fluctuation-treated primary hippocampal neuronal cells, and miR-129-3p directly targeted MCU. miR-129-3p overexpression produced a dramatic reduction in calcium overload, reactive oxygen species (ROS) generation, GSH-to-GSSG ratio, MMP-2 expression in the mitochondrial-dependent intrinsic apoptosis pathway and an increase in MnSOD activity. Increasing MCU expression rescued the effects of miR-129-3p overexpression. miR-129-3p downregulation produced a significant increase in calcium overload, reactive oxygen species (ROS) generation, MMP-2 expression, cytochrome c release and cell apoptosis, and antioxidant N-acetyl cysteine (NAC) rescued the effects of miR-129-3p downregulation. CONCLUSION Therefore, miR-129-3p suppressed glucose fluctuation-mediated neuronal damage by targeting MCU via a mitochondrial-dependent intrinsic apoptotic pathway. The miR-129-3p/MCU axis may be a promising therapeutic target for glucose fluctuation-mediated neuronal damage.
Collapse
Affiliation(s)
- Bo Wang
- Department of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan610041, People’s Republic of China
- Department of Neurosurgery, Kunming Medical University First Affiliated Hospital, Kunming, Yunnan650032, People’s Republic of China
| | - Yang Li
- Intensive Care Unit, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan610041, People’s Republic of China
| | - Chao You
- Department of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan610041, People’s Republic of China
- Correspondence: Chao You Department of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan610041, People’s Republic of ChinaTel +86 28-85422026 Email
| |
Collapse
|
|
42
|
Wang H. MicroRNA, Diabetes Mellitus and Colorectal Cancer. Biomedicines 2020; 8:biomedicines8120530. [PMID: 33255227 PMCID: PMC7760221 DOI: 10.3390/biomedicines8120530] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 12/11/2022] Open
Abstract
Diabetes mellitus (DM) is an endocrinological disorder that is due to either the pancreas not producing enough insulin, or the body does not respond appropriately to insulin. There are many complications of DM such as retinopathy, nephropathy, and peripheral neuropathy. In addition to these complications, DM was reported to be associated with different cancers. In this review, we discuss the association between DM and colorectal cancer (CRC). CRC is the third most commonly diagnosed cancer worldwide that mostly affects older people, however, its incidence and mortality are rising among young people. We discuss the relationship between DM and CRC based on their common microRNA (miRNA) biomarkers. miRNAs are non-coding RNAs playing important functions in cell differentiation, development, regulation of cell cycle, and apoptosis. miRNAs can inhibit cell proliferation and induce apoptosis in CRC cells. miRNAs also can improve glucose tolerance and insulin sensitivity. Therefore, investigating the common miRNA biomarkers of both DM and CRC can shed a light on how these two diseases are correlated and more understanding of the link between these two diseases can help the prevention of both DM and CRC.
Collapse
Affiliation(s)
- Hsiuying Wang
- Institute of Statistics, National Chiao Tung University, Hsinchu 30010, Taiwan
| |
Collapse
|
|
43
|
Duan L, Yang W, Feng W, Cao L, Wang X, Niu L, Li Y, Zhou W, Zhang Y, Liu J, Zhang H, Zhao Q, Hong L, Fan D. Molecular mechanisms and clinical implications of miRNAs in drug resistance of colorectal cancer. Ther Adv Med Oncol 2020; 12:1758835920947342. [PMID: 32922521 PMCID: PMC7450467 DOI: 10.1177/1758835920947342] [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: 11/13/2019] [Accepted: 07/13/2020] [Indexed: 12/12/2022] Open
Abstract
Systemic chemotherapy is identified as a curative approach to prolong the survival time of patients with colorectal cancer (CRC). Although great progress in therapeutic approaches has been achieved during the last decades, drug resistance still extensively persists and serves as a major hurdle to effective anticancer therapy for CRC. The mechanism of multidrug resistance remains unclear. Recently, mounting evidence suggests that a great number of microRNAs (miRNAs) may contribute to drug resistance in CRC. Certain of these miRNAs may thus be used as promising biomarkers for predicting drug response to chemotherapy or serve as potential targets to develop personalized therapy for patients with CRC. This review mainly summarizes recent advances in miRNAs and the molecular mechanisms underlying miRNA-mediated chemoresistance in CRC. We also discuss the potential role of drug resistance-related miRNAs as potential biomarkers (diagnostic and prognostic value) and envisage the future orientation and challenges in translating the findings on miRNA-mediated chemoresistance of CRC into clinical applications.
Collapse
Affiliation(s)
- Lili Duan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Wanli Yang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Weibo Feng
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Lu Cao
- Department of Biomedical Engineering, Fourth Military Medical University, Xi'an, China
| | - Xiaoqian Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Liaoran Niu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yiding Li
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Wei Zhou
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yujie Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Jinqiang Liu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Hongwei Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Qingchuan Zhao
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Liu Hong
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| |
Collapse
|
|
44
|
Ahadi A. The significance of microRNA deregulation in colorectal cancer development and the clinical uses as a diagnostic and prognostic biomarker and therapeutic agent. Noncoding RNA Res 2020; 5:125-134. [PMID: 32954092 PMCID: PMC7476809 DOI: 10.1016/j.ncrna.2020.08.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/19/2020] [Accepted: 08/19/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most widely recognized and deadly malignancies worldwide. Although death rates have declined over the previous decade, mainly because of enhanced screening or potential treatment alternatives, CRC remains the third leading cause of cancer-related mortality globally, with an estimated incidence of over 1 million new cases and approximately 600 000 deaths estimated yearly. Therefore, many scientific efforts are put into the development of new diagnostic biomarkers for CRC. MicroRNAs (miRNAs), one of the epigenetics categories, have demonstrated significant roles in carcinogenesis and progression through regulating epithelial-mesenchymal transition (EMT), oncogenic signaling pathways, and metastasis. Dysregulation of miRNAs expression has been reported in many cancers, including CRC. The expression profile of miRNAs is reproducibly altered in CRC, and their expression patterns are associated with diagnosis, prognosis, and therapeutic outcomes in CRC. Recently, many studies were conducted on the dysregulation of miRNAs as a diagnostic and prognostic biomarker in CRC. Among them, some miRNAs, which include miR-21, miR-34 family, miR-155, miR-224, and miR-378, have been more studied in CRC with more prominent roles in diagnosis, prognosis, and therapy. In the present review, we summarized the latest information regarding the dysregulated miRNAs in CRC and the advantages of using miRNAs as a biomarker for CRC diagnosis, treatment, and their function in different signaling pathways involved in CRC progression. Moreover, we described the translation of miRNA research to potential therapeutic applications in the management of CRC in clinical settings.
Collapse
Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
45
|
Vaghari-Tabari M, Majidinia M, Moein S, Qujeq D, Asemi Z, Alemi F, Mohamadzadeh R, Targhazeh N, Safa A, Yousefi B. MicroRNAs and colorectal cancer chemoresistance: New solution for old problem. Life Sci 2020; 259:118255. [PMID: 32818543 DOI: 10.1016/j.lfs.2020.118255] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 08/01/2020] [Accepted: 08/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies with a significant mortality rate. Despite the great advances in cancer treatment in the last few decades, effective treatment of CRC is still under challenge. One of the main problems associated with CRC treatment is the resistance of cancer cells to chemotherapy drugs. METHODS Many studies have been carried out to identify CRC chemoresistance mechanisms, and shed light on the role of ATP-binding cassette transporters (ABC transporters), enzymes as thymidylate synthase, some signaling pathways, and cancer stem cells (CSC) in chemoresistance and failed CRC chemotherapies. Other studies have also been recently carried out to find solutions to overcome chemoresistance. Some of these studies have identified the role of miRNAs in chemoresistance of the CRC cells and the effective use of these micro-molecules to CRC treatment. RESULTS Considering the results of these studies, more focus on miRNAs likely leads to a proper solution to overcome CRC chemoresistance. CONCLUSION The current study has reviewed the related literature while discussing the efficacy of miRNAs as potential clinical tools for overcoming CRC chemoresistance and reviewing the most important chemoresistance mechanisms in CRC cells.
Collapse
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
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Soheila Moein
- Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, 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
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Forough Alemi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Mohamadzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nilofar Targhazeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Safa
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam; Faculty of Medicine, Zabol University of Medical Sciences, Zabol, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
46
|
Wang H. MicroRNAs and Apoptosis in Colorectal Cancer. Int J Mol Sci 2020; 21:ijms21155353. [PMID: 32731413 PMCID: PMC7432330 DOI: 10.3390/ijms21155353] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/25/2020] [Accepted: 07/27/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer death in the world, and its incidence is rising in developing countries. Treatment with 5-Fluorouracil (5-FU) is known to improve survival in CRC patients. Most anti-cancer therapies trigger apoptosis induction to eliminate malignant cells. However, de-regulated apoptotic signaling allows cancer cells to escape this signaling, leading to therapeutic resistance. Treatment resistance is a major challenge in the development of effective therapies. The microRNAs (miRNAs) play important roles in CRC treatment resistance and CRC progression and apoptosis. This review discusses the role of miRNAs in contributing to the promotion or inhibition of apoptosis in CRC and the role of miRNAs in modulating treatment resistance in CRC cells.
Collapse
Affiliation(s)
- Hsiuying Wang
- Institute of Statistics, National Chiao Tung University, Hsinchu 30010, Taiwan
| |
Collapse
|
|
47
|
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: 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: 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.
Collapse
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
| |
Collapse
|
|
48
|
LncRNA NEAT1/miR-129/Bcl-2 signaling axis contributes to HDAC inhibitor tolerance in nasopharyngeal cancer. Aging (Albany NY) 2020; 12:14174-14188. [PMID: 32692721 PMCID: PMC7425502 DOI: 10.18632/aging.103427] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 05/25/2020] [Indexed: 01/05/2023]
Abstract
Histone deacetylase inhibitors (HDACis) - based therapeutic drug tolerance is one of the principal factors of poor prognosis of patients with nasopharyngeal cancer (NPC). Mechanisms of tolerance to HDACis are not well understood. Nowadays, dysregulation of long non-coding RNAs (LncRNAs) and microRNAs (miRNAs) has been reported to provide beneficial or inhibitory effects in drug-tolerance in various cancers. Herein, we established the HDAC inhibitor (SAHA)-tolerant NPC cell sublines, which had decreased apoptosis in response to SAHA treatment. We observed that the expression of miR-129 was significantly reduced in SAHA-tolerant NPC cells. Manipulating the expression of miR-129 overcame SAHA tolerance, and enhanced the SAHA-induced apoptosis. In terms of miR-129 downregulation, we identified that NEAT1 suppresses miR-129 expression. NEAT1 was found to be upregulated in SAHA tolerance cells. The depletion of NEAT1 phenocopied the effect of miR-129 overexpression, which also enhanced SAHA-induced apoptosis. Bcl-2 was the downstream target of miR-129 and contributed to SAHA tolerance in NPC. Our in vivo xenograft experiment confirmed that the administration of miR-129 or inhibition of Bcl-2 overcame the SAHA tolerance in NPC. In conclusion, NEAT1 increases in NPC tissues and manages to facilitate SAHA tolerance by modulating the miR-129/Bcl-2 axis, providing novel therapeutic targets for NPC treatment.
Collapse
|
|
49
|
Yu J, Zhang X, Ma Y, Li Z, Tao R, Chen W, Xiong S, Han X. MiR-129-5p Restrains Apatinib Resistance in Human Gastric Cancer Cells Via Downregulating HOXC10. Cancer Biother Radiopharm 2020; 36:95-105. [PMID: 32552008 DOI: 10.1089/cbr.2019.3107] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Background: Repeated administration of apatinib has resulted in serious drug resistance in gastric cancer (GC). Previous studies showed that miR-129-5p had a low expression in GC, and homeobox gene C10 (HOXC10), a carcinogenic gene, was highly expressed in GC, while the molecular mechanism of miR-129-5p involved in apatinib resistance in GC cells is still unclear. Materials and Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of miR-129-5p and HOXC10 in GC tissues or cell lines. The expression levels of associated proteins were detected by Western blot. Cell counting kit-8 (CCK-8), the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), and flow cytometry assays were conducted to detect cell viability, proliferation, and apoptosis of MGC-803/AP and AGS/AP cells in vitro. The dual-luciferase reporter assay was used to verify the targeted relationship between miR-129-5p and HOXC10. The xenograft model was established to examine the effect of miR-129-5p in vivo, and the HOXC10 protein expression in tumor xenograft was assessed by immunohistochemistry. Results: MiR-129-5p had a low expression in GC tissues and apatinib-resistant cell lines, while HOXC10 was highly expressed. Meanwhile, overexpression of miR-129-5p and knockdown of HOXC10 could enhance the chemosensitivity of MGC-803/AP and AGS/AP cells. Dual-luciferase reporter assay confirmed miR-129-5p targeted HOXC10 and downregulated its expression level. MiR-129-5p inhibited proliferation and promoted apoptosis of MGC-803/AP and AGS/AP cells by downregulating HOXC10. The experiment in vivo also confirmed that miR-129-5p reduced apatinib resistance in GC cells by targetedly inhibiting HOXC10. HOXC10 was upregulated in GC tumor xenograft tissues. Conclusion: miR-129-5p restrains apatinib-resistant of GC cells by regulating HOXC10.
Collapse
Affiliation(s)
- Jianping Yu
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
| | - Xiankun Zhang
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
| | - Youwei Ma
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
| | - Zhengkai Li
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
| | - Ruiyu Tao
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
| | - Weikai Chen
- Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, China
| | - Shimeng Xiong
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Xiaopeng Han
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
| |
Collapse
|
|
50
|
Asadi M, Shanehbandi D, Zafari V, Khaze V, Somi MH, Hashemzadeh S. Transcript Level of MicroRNA Processing Elements in Gastric Cancer. J Gastrointest Cancer 2020; 50:855-859. [PMID: 30168106 DOI: 10.1007/s12029-018-0154-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Aberrant expression of microRNAs (miRNAs) has been implicated in the etiopathogenesis and development of various cancers. Drosha and Dicer are the main components of the miRNA biosynthesis machine. Another enzyme, DGCR8, is the assistant of Drosha in the processing complex. Here, we tried to evaluate the mRNA transcript level of Drosha, Dicer, and DGCR8 genes in involved tissues from patients with gastric cancer. METHODS Fifty tumoral and their marginal tissues, as the control group, were obtained from patients with gastric cancer. After RNA extraction from tissues and cDNA synthesis, quantification of mRNA expression of Drosha, Dicer, and DGCR8 was conducted using SYBR Green master mix and real-time PCR. RESULTS It was observed that mRNA expression levels of Drosha, Dicer, and DGCR8 were significantly upregulated in tumoral tissues compared with marginal tissues. Upregulation of these genes was not correlated with clinical manifestations of the patients. CONCLUSIONS Upregulation of Drosha, Dicer, and DGCR8 plays a role in the development of cancer, probably through dysregulated the expression level of miRNAs.
Collapse
Affiliation(s)
- Milad Asadi
- Research Centers for Liver and Gastrointestinal Disease, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Venus Zafari
- Tuberculosis and Pulmonary Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Khaze
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hosein Somi
- Research Centers for Liver and Gastrointestinal Disease, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahriar Hashemzadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of General and Vascular Surgery, Imam Reza Educational Hospital, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|