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Zheng Y, Chen X, Huang Y, Lin X, Lin J, Mo Y, Gan L, Wei S, Wang Z, Song X, Tu Z. DDX27: An RNA helicase regulating cancer progression and therapeutic prospects. Int J Biol Macromol 2025; 313:144388. [PMID: 40394785 DOI: 10.1016/j.ijbiomac.2025.144388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2025] [Revised: 05/07/2025] [Accepted: 05/18/2025] [Indexed: 05/22/2025]
Abstract
DDX27, a member of the DEAD-box RNA helicase family, plays a crucial role in RNA metabolism, inflammation, and cancer progression. Elevated expression of DDX27 has been observed in multiple cancers, including oral squamous cell carcinoma (OSCC), breast cancer (BC), colorectal cancer (CRC), gastric cancer (GC), and hepatocellular carcinoma (HCC), where it is associated with poor prognosis, tumor growth, metastasis, and chemoresistance. DDX27 regulates the NF-κB signaling pathway, which is central to inflammation and tumor progression, and influences key cellular processes such as cell cycle regulation, apoptosis, migration, and stemness. Additionally, DDX27 promotes epithelial-mesenchymal transition (EMT), further contributing to metastasis. Its interactions with non-coding RNAs and various signaling pathways complicate treatment responses, making DDX27 a promising therapeutic target. This review explores the role of DDX27 as both a biomarker and therapeutic target, with potential strategies including small molecule inhibitors, RNA interference, and combination therapies with existing treatments such as NF-κB inhibitors or chemotherapy. Targeting DDX27 may help overcome resistance, reduce metastasis, and improve cancer treatment outcomes. Further research into its molecular mechanisms and interactions will be crucial for developing effective therapies, particularly for cancers with high metastatic potential.
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Affiliation(s)
- Yuantong Zheng
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Xinyi Chen
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Yunfei Huang
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Xuanli Lin
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Jiaxin Lin
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Yuting Mo
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Lu Gan
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Shuhua Wei
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Zhen Wang
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Xiaojuan Song
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Zhengchao Tu
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development (MOE), School of Pharmacy, Jinan University, Guangzhou 510632, PR China.
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Zhao J, Wang X, Wang J, You Y, Wang Q, Xu Y, Fan Y. Butyrate Metabolism-Related Gene Signature in Tumor Immune Microenvironment in Lung Adenocarcinoma: A Comprehensive Bioinformatics Study. Immun Inflamm Dis 2024; 12:e70087. [PMID: 39641239 PMCID: PMC11621860 DOI: 10.1002/iid3.70087] [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: 06/25/2024] [Revised: 10/21/2024] [Accepted: 11/18/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Experimental results have verified the suppressive impact of butyrate on tumor formation. Nevertheless, there is a limited understanding of the hidden function of butyrate metabolism within the tumor immune microenvironment (TIME) of lung adenocarcinoma (LUAD). This research aimed at digging the association between genes related to butyrate metabolism (butyrate metabolism-related genes [BMRGs) and immune infiltrates in LUAD patients. METHODS Through analyzing The Cancer Genome Atlas dataset (TCGA), the identification of 38 differentially expressed BMRGs was made between LUAD and normal samples. Later, a prognostic signature made up of nine BMRGs was made to evaluate the risk score of LUAD subjects. Notably, high-risk scores emerged as negative prognostic indicators for overall survival in LUAD subjects. Additionally, BMRGs displayed associations with immunocyte infiltration levels, immune pathway activities, and pivotal prognostic hub BMRGs. RESULTS One key prognostic BMRG, PTGDS, exhibited a robust correlation with T cells, the chemokine-related pathway, and the TCR signaling pathway. This study suggests that investigating the interplay between butyrate metabolism and T cells could present a promising novel approach to cancer treatment. OncoPredict analysis further unveiled distinct sensitivities of nine medicine in high- and low-risk groups, facilitating the selection of optimal treatment strategies for individual LUAD patients. CONCLUSIONS The study establishes that the BMRG signature serves as a sensitive predictive biomarker, providing profound insights into the crucial effect of butyrate metabolism in the context of LUAD TIME.
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Affiliation(s)
- Jing Zhao
- Department of Clinical Skills Training CenterXinqiao Hospital, Army Medical UniversityChongqingChina
| | - Xueyue Wang
- Department of PaediatricsGeneral Hospital of Xizang Military RegionXizangChina
| | - Jing Wang
- Department of Respiratory DiseaseXinqiao Hospital, Army Medical UniversityChongqingChina
| | - Yating You
- Department of Respiratory DiseaseXinqiao Hospital, Army Medical UniversityChongqingChina
| | - Qi Wang
- Department of Preventive MedicineXinqiao Hospital, Army Medical UniversityChongqingChina
| | - Yuan Xu
- Department of OrthopaedicsXinqiao Hospital, Army Medical UniversityChongqingChina
| | - Ye Fan
- Department of Respiratory DiseaseXinqiao Hospital, Army Medical UniversityChongqingChina
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Zhang R, Liu S, Mousavi SM. Cognitive Dysfunction and Exercise: From Epigenetic to Genetic Molecular Mechanisms. Mol Neurobiol 2024; 61:6279-6299. [PMID: 38286967 DOI: 10.1007/s12035-024-03970-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/19/2024] [Indexed: 01/31/2024]
Abstract
Maintaining good health is crucial, and exercise plays a vital role in achieving this goal. It offers a range of positive benefits for cognitive function, regardless of age. However, as our population ages and life expectancy increases, cognitive impairment has become a prevalent issue, often coexisting with age-related neurodegenerative conditions. This can result in devastating consequences such as memory loss, difficulty speaking, and confusion, greatly hindering one's ability to lead an ordinary life. In addition, the decrease in mental capacity has a significant effect on an individual's physical and emotional well-being, greatly reducing their overall level of contentment and causing a significant financial burden for communities. While most current approaches aim to slow the decline of cognition, exercise offers a non-pharmacological, safe, and accessible solution. Its effects on cognition are intricate and involve changes in the brain's neural plasticity, mitochondrial stability, and energy metabolism. Moreover, exercise triggers the release of cytokines, playing a significant role in the body-brain connection and its impact on cognition. Additionally, exercise can influence gene expression through epigenetic mechanisms, leading to lasting improvements in brain function and behavior. Herein, we summarized various genetic and epigenetic mechanisms that can be modulated by exercise in cognitive dysfunction.
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Affiliation(s)
- Runhong Zhang
- Department of Physical Education, Luliang University, Lishi, 033000, Shanxi, China.
| | - Shangwu Liu
- Department of Physical Education, Luliang University, Lishi, 033000, Shanxi, China
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Ghorbani M, Namazi S, Dehghani M, Razi F, Khalvati B, Dehshahri A. Gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the neurokinin-1 receptor antagonist-based antiemetic regimens: a candidate-gene association study in breast cancer patients. Cancer Chemother Pharmacol 2024; 94:237-250. [PMID: 38678150 DOI: 10.1007/s00280-024-04661-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 02/20/2024] [Indexed: 04/29/2024]
Abstract
PURPOSE The current candidate gene association study aims to investigate tag SNPs from the TACR1 gene as pharmacogenetic predictors of response to the antiemetic guidelines-recommended, NK-1 receptor antagonist-based, triple antiemetic regimens. METHODS A set of eighteen tag SNPs of TACR1 were genotyped in breast cancer patients receiving anthracycline and cyclophosphamide (with/without docetaxel) applying real-time PCR-HRMA. Data analysis for 121 ultimately enrolled patients was initiated by defining haplotype blocks using PHASE v.2.1. The association of each tag SNP and haplotype alleles with failure to achieve the defined antiemetic regimen efficacy endpoints was tested using PLINK (v.1.9 and v.1.07, respectively) based on the logistic regression, adjusting for the previously known chemotherapy-induced nausea and vomiting (CINV) prognostic factors. All reported p-values were corrected using the permutation test (n = 100,000). RESULTS Four variants of rs881, rs17010730, rs727156, and rs3755462, as well as haplotypes containing the mentioned variants, were significantly associated with failure to achieve at least one of the defined efficacy endpoints. Variant annotation via in-silico studies revealed that the non-seed sequence variant, rs881, is located in the miRNA (hsa-miR-613) binding site. The other three variants or a variant in complete linkage disequilibrium with them overlap a region of high H3K9ac-promoter-like signature or regions of high enhancer-like signature in the brain or gastrointestinal tissue. CONCLUSION Playing an essential role in regulating TACR1 expression, gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the NK-1 receptor antagonist-based, triple antiemetic regimens. If clinically approved, modifying the NK-1 receptor antagonist dose leads to better management of CINV in risk-allele carriers.
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Affiliation(s)
- Marziyeh Ghorbani
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soha Namazi
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mehdi Dehghani
- Department of Hematology and Medical Oncology, Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farideh Razi
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahman Khalvati
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
- Biological Mass Spectrometry Center, Stony Brook Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Ali Dehshahri
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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Sarkar N, Mishra R, Gopal C, Kumar A. miR-617 interacts with the promoter of DDX27 and positively regulates its expression: implications for cancer therapeutics. Front Oncol 2024; 14:1411539. [PMID: 38939334 PMCID: PMC11208480 DOI: 10.3389/fonc.2024.1411539] [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: 04/03/2024] [Accepted: 05/31/2024] [Indexed: 06/29/2024] Open
Abstract
Background Pervasive transcription of the eukaryotic genome generates noncoding RNAs (ncRNAs), which regulate messenger RNA (mRNA) stability and translation. MicroRNAs (miRNAs/miRs) represent a group of well-studied ncRNAs that maintain cellular homeostasis. Thus, any aberration in miRNA expression can cause diseases, including carcinogenesis. According to microRNA microarray analyses, intronic miR-617 is significantly downregulated in oral squamous cell carcinoma (OSCC) tissues compared to normal oral tissues. Methods The miR-617-mediated regulation of DDX27 is established by performing experiments on OSCC cell lines, patient samples, and xenograft nude mice model. Overexpression plasmid constructs, bisulphite sequencing PCR, bioinformatics analyses, RT-qPCR, Western blotting, dual-luciferase reporter assay, and cell-based assays are utilized to delineate the role of miR-617 in OSCC. Results The present study shows that miR-617 has an anti-proliferative role in OSCC cells and is partly downregulated in OSCC cells due to the hypermethylation of its independent promoter. Further, we demonstrate that miR-617 upregulates DDX27 gene by interacting with its promoter in a dose-dependent and sequence-specific manner, and this interaction is found to be biologically relevant in OSCC patient samples. Subsequently, we show that miR-617 regulates cell proliferation, apoptosis, and anchorage-independent growth of OSCC cells by modulating DDX27 levels. Besides, our study shows that miR-617 exerts its effects through the PI3K/AKT/MTOR pathway via regulating DDX27 levels. Furthermore, the OSCC xenograft study in nude mice shows the anti-tumorigenic potential of miR-617. Conclusion miR-617-mediated upregulation of DDX27 is a novel mechanism in OSCC and underscores the therapeutic potential of synthetic miR-617 mimics in cancer therapeutics. To the best of our knowledge, miR-617 is the 15th example of a miRNA that upregulates the expression of a protein-coding gene by interacting with its promoter.
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Affiliation(s)
- Neelanjana Sarkar
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore, India
| | - Radha Mishra
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore, India
| | - Champaka Gopal
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - Arun Kumar
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore, India
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Orang A, Marri S, McKinnon RA, Petersen J, Michael MZ. Restricting Colorectal Cancer Cell Metabolism with Metformin: An Integrated Transcriptomics Study. Cancers (Basel) 2024; 16:2055. [PMID: 38893174 PMCID: PMC11171104 DOI: 10.3390/cancers16112055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/13/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms by which metformin slows colorectal cancer cell proliferation by investigating metformin-associated microRNA (miRNA) and target gene pairs implicated in signalling pathways. METHODS The present study analysed changes in miRNAs and the coding transcriptome in CRC cells treated with a sublethal dose of metformin, followed by the contextual validation of potential miRNA-target gene pairs. RESULTS Analyses of small RNA and transcriptome sequencing data revealed 104 miRNAs and 1221 mRNAs to be differentially expressed in CRC cells treated with metformin for 72 h. Interaction networks between differentially expressed miRNAs and putative target mRNAs were identified. Differentially expressed genes were mainly implicated in metabolism and signalling processes, such as the PI3K-Akt and MAPK/ERK pathways. Further validation of potential miRNA-target mRNA pairs revealed that metformin induced miR-2110 and miR-132-3p to target PIK3R3 and, consequently, regulate CRC cell proliferation, cell cycle progression and the PI3K-Akt signalling pathway. Metformin also induced miR-222-3p and miR-589-3p, which directly target STMN1 to inhibit CRC cell proliferation and cell cycle progression. CONCLUSIONS This study identified novel changes in the coding transcriptome and small non-coding RNAs associated with metformin treatment of CRC cells. Integration of these datasets highlighted underlying mechanisms by which metformin impedes cell proliferation in CRC. Importantly, it identified the post-transcriptional regulation of specific genes that impact both metabolism and cell proliferation.
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Affiliation(s)
- Ayla Orang
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Shashikanth Marri
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Ross A. McKinnon
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Janni Petersen
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Nutrition and Metabolism, South Australia Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Michael Z. Michael
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Bedford Park, SA 5042, Australia
- Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, SA 5042, Australia
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Hartman TJ, Christie J, Wilson A, Ziegler TR, Methe B, Flanders WD, Rolls BJ, Loye Eberhart B, Li JV, Huneault H, Cousineau B, Perez MR, O'Keefe SJD. Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer trial study protocol: a randomised clinical trial of fibre-rich legumes targeting the gut microbiome, metabolome and gut transit time of overweight and obese patients with a history of noncancerous adenomatous polyps. BMJ Open 2024; 14:e081379. [PMID: 38316601 PMCID: PMC10860035 DOI: 10.1136/bmjopen-2023-081379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 01/15/2024] [Indexed: 02/07/2024] Open
Abstract
INTRODUCTION Recently published studies support the beneficial effects of consuming fibre-rich legumes, such as cooked dry beans, to improve metabolic health and reduce cancer risk. In participants with overweight/obesity and a history of colorectal polyps, the Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer randomised clinical trial will test whether a high-fibre diet featuring legumes will simultaneously facilitate weight reduction and suppress colonic mucosal biomarkers of colorectal cancer (CRC). METHODS/DESIGN This study is designed to characterise changes in (1) body weight; (2) biomarkers of insulin resistance and systemic inflammation; (3) compositional and functional profiles of the faecal microbiome and metabolome; (4) mucosal biomarkers of CRC risk and (5) gut transit. Approximately 60 overweight or obese adults with a history of noncancerous adenomatous polyps within the previous 3 years will be recruited and randomised to one of two weight-loss diets. Following a 1-week run-in, participants in the intervention arm will receive preportioned high-fibre legume-rich entrées for two meals/day in months 1-3 and one meal/day in months 4-6. In the control arm, entrées will replace legumes with lean protein sources (eg, chicken). Both groups will receive in-person and written guidance to include nutritionally balanced sides with energy intake to lose 1-2 pounds per week. ETHICS AND DISSEMINATION The National Institutes of Health fund this ongoing 5-year study through a National Cancer Institute grant (5R01CA245063) awarded to Emory University with a subaward to the University of Pittsburgh. The study protocol was approved by the Emory Institutional Review Board (IRB approval number: 00000563). TRIAL REGISTRATION NUMBER NCT04780477.
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Affiliation(s)
- Terryl J Hartman
- Department of Epidemiology, Rollins School of Public Health and Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
- Nutrition and Health Sciences, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Jennifer Christie
- Department of Medicine, Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Annette Wilson
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Thomas R Ziegler
- Department of Medicine, Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Barbara Methe
- Pulmonary, Allergy and Critical Care Medicine, Center for the Microbiome and Medicine, University of Pittsburg, Pittsburgh, Pennsylvania, USA
| | - William Dana Flanders
- Department of Biostatistics and Bioinformatics, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Barbara J Rolls
- Department of Nutritional Sciences, The Pennsylvania State University, State College, Pennsylvania, USA
| | - Blaine Loye Eberhart
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jia V Li
- Section of Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Commonwealth Building, Hammersmith Hospital Campus, Imperial College London, South Kensington, London, UK
| | - Helaina Huneault
- Nutrition and Health Sciences, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Ben Cousineau
- Nutrition and Health Sciences, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Miriam R Perez
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Stephen J D O'Keefe
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Cheng J, Zhou J. Unraveling the gut health puzzle: exploring the mechanisms of butyrate and the potential of High-Amylose Maize Starch Butyrate (HAMSB) in alleviating colorectal disturbances. Front Nutr 2024; 11:1285169. [PMID: 38304546 PMCID: PMC10830644 DOI: 10.3389/fnut.2024.1285169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 01/02/2024] [Indexed: 02/03/2024] Open
Abstract
Colorectal disturbances encompass a variety of disorders that impact the colon and rectum, such as colitis and colon cancer. Butyrate, a short-chain fatty acid, plays a pivotal role in supporting gut health by nourishing colonocytes, promoting barrier function, modulating inflammation, and fostering a balanced microbiome. Increasing colorectal butyrate concentration may serve as a critical strategy to improve colon function and reduce the risk of colorectal disturbances. Butyrylated high-amylose maize starch (HAMSB) is an edible ingredient that efficiently delivers butyrate to the colon. HAMSB is developed by esterifying a high-amylose starch backbone with butyric anhydride. With a degree of substitution of 0.25, each hydroxy group of HAMSB is substituted by a butyryl group in every four D-glucopyranosyl units. In humans, the digestibility of HAMSB is 68% (w/w), and 60% butyrate molecules attached to the starch backbone is absorbed by the colon. One clinical trial yielded two publications, which showed that HAMSB significantly reduced rectal O6-methyl-guanine adducts and epithelial proliferation induced by the high protein diet. Fecal microbial profiles were assessed in three clinical trials, showing that HAMSB supplementation was consistently linked to increased abundance of Parabacteroides distasonis. In animal studies, HAMSB was effective in reducing the risk of diet- or AOM-induced colon cancer by reducing genetic damage, but the mechanisms differed. HAMSB functioned through affecting cecal ammonia levels by modulating colon pH in diet-induced cancer, while it ameliorated chemical-induced colon cancer through downregulating miR19b and miR92a expressions and subsequently activating the caspase-dependent apoptosis. Furthermore, animal studies showed that HAMSB improved colitis via regulating the gut immune modulation by inhibiting histone deacetylase and activating G protein-coupled receptors, but its role in bacteria-induced colon colitis requires further investigation. In conclusion, HAMSB is a food ingredient that may deliver butyrate to the colon to support colon health. Further clinical trials are warranted to validate earlier findings and determine the minimum effective dose of HAMSB.
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Affiliation(s)
- Junrui Cheng
- Global Scientific and Regulatory Department, Ingredion Incorporated, Bridgewater, NJ, United States
| | - Jing Zhou
- Global Scientific and Regulatory Department, Ingredion Incorporated, Bridgewater, NJ, United States
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Chen Y, Liu F, Chen X, Li W, Li K, Cai H, Wang S, Wang H, Xu K, Zhang C, Ye S, Shen Y, Mou T, Cai S, Zhou J, Yu J. microRNA-622 upregulates cell cycle process by targeting FOLR2 to promote CRC proliferation. BMC Cancer 2024; 24:26. [PMID: 38166756 PMCID: PMC10763126 DOI: 10.1186/s12885-023-11766-6] [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: 08/03/2023] [Accepted: 12/15/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Epigenetic alterations contribute greatly to the development and progression of colorectal cancer, and effect of aberrant miR-622 expression is still controversial. This study aimed to discover miR-622 regulation in CRC proliferation. METHODS miR-622 expression and prognosis were analyzed in clinical CRC samples from Nanfang Hospital. miR-622 regulation on cell cycle and tumor proliferation was discovered, and FOLR2 was screened as functional target of miR-622 using bioinformatics analysis, which was validated via dual luciferase assay and gain-of-function and loss-of-function experiments both in vitro and in vivo. RESULTS miR-622 overexpression in CRC indicated unfavorable prognosis and it regulated cell cycle to promote tumor growth both in vitro and in vivo. FOLR2 is a specific, functional target of miR-622, which negatively correlates with signature genes in cell cycle process to promote CRC proliferation. CONCLUSIONS miR-622 upregulates cell cycle process by targeting FOLR2 to promote CRC proliferation, proposing a novel mechanism and treatment target in CRC epigenetic regulation of miR-622.
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Affiliation(s)
- Yuehong Chen
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Feng Liu
- Department of Colorectal and Anal Surgery Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510515, China
| | - Xinhua Chen
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Wenyi Li
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Kejun Li
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Hailang Cai
- Department of Radiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Shunyi Wang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Honglei Wang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ke Xu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Chenxi Zhang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Shengzhi Ye
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yunhao Shen
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Tingyu Mou
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Shumin Cai
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
- Department of Critical Care Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
| | - Jianwei Zhou
- Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Avenue North, Guangzhou, 510515, China.
| | - Jiang Yu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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Chorawala MR, Postwala H, Prajapati BG, Shah Y, Shah A, Pandya A, Kothari N. Impact of the microbiome on colorectal cancer development. COLORECTAL CANCER 2024:29-72. [DOI: 10.1016/b978-0-443-13870-6.00021-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Wang T, Tian S, Tikhonova EB, Karamyshev AL, Wang JJ, Zhang F, Wang D. The Enrichment of miRNA-Targeted mRNAs in Translationally Less Active over More Active Polysomes. BIOLOGY 2023; 12:1536. [PMID: 38132362 PMCID: PMC10741098 DOI: 10.3390/biology12121536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 12/03/2023] [Accepted: 12/13/2023] [Indexed: 12/23/2023]
Abstract
miRNAs moderately inhibit the translation and enhance the degradation of their target mRNAs via cognate binding sites located predominantly in the 3'-untranslated regions (UTR). Paradoxically, miRNA targets are also polysome-associated. We studied the polysome association by the comparative translationally less-active light- and more-active heavy-polysome profiling of a wild type (WT) human cell line and its isogenic mutant (MT) with a disrupted DICER1 gene and, thus, mature miRNA production. As expected, the open reading frame (ORF) length is a major determinant of light- to heavy-polysome mRNA abundance ratios, but is rendered less powerful in WT than in MT cells by miRNA-regulatory activities. We also observed that miRNAs tend to target mRNAs with longer ORFs, and that adjusting the mRNA abundance ratio with the ORF length improves its correlation with the 3'-UTR miRNA-binding-site count. In WT cells, miRNA-targeted mRNAs exhibit higher abundance in light relative to heavy polysomes, i.e., light-polysome enrichment. In MT cells, the DICER1 disruption not only significantly abrogated the light-polysome enrichment, but also narrowed the mRNA abundance ratio value range. Additionally, the abrogation of the enrichment due to the DICER1 gene disruption, i.e., the decreases of the ORF-length-adjusted mRNA abundance ratio from WT to MT cells, exhibits a nearly perfect linear correlation with the 3'-UTR binding-site count. Transcription factors and protein kinases are the top two most enriched mRNA groups. Taken together, the results provide evidence for the light-polysome enrichment of miRNA-targeted mRNAs to reconcile polysome association and moderate translation inhibition, and that ORF length is an important, though currently under-appreciated, transcriptome regulation parameter.
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Affiliation(s)
- Tingzeng Wang
- Department of Environmental Toxicology, and The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX 79416, USA; (T.W.); (S.T.)
| | - Shuangmei Tian
- Department of Environmental Toxicology, and The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX 79416, USA; (T.W.); (S.T.)
| | - Elena B. Tikhonova
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (E.B.T.); (A.L.K.)
| | - Andrey L. Karamyshev
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (E.B.T.); (A.L.K.)
| | - Jing J. Wang
- Department of Cancer Biology and Genetics, James Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
| | - Fangyuan Zhang
- Department of Mathematics and Statistics, Texas Tech University, Lubbock, TX 79416, USA;
| | - Degeng Wang
- Department of Environmental Toxicology, and The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX 79416, USA; (T.W.); (S.T.)
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12
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Fattahi M, Shahrabi S, Saadatpour F, Rezaee D, Beyglu Z, Delavari S, Amrolahi A, Ahmadi S, Bagheri-Mohammadi S, Noori E, Majidpoor J, Nouri S, Aghaei-Zarch SM, Falahi S, Najafi S, Le BN. microRNA-382 as a tumor suppressor? Roles in tumorigenesis and clinical significance. Int J Biol Macromol 2023; 250:125863. [PMID: 37467828 DOI: 10.1016/j.ijbiomac.2023.125863] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 06/30/2023] [Accepted: 07/15/2023] [Indexed: 07/21/2023]
Abstract
MicroRNAs (miRNAs) are small single-stranded RNAs belonging to a class of non-coding RNAs with an average length of 18-22 nucleotides. Although not able to encode any protein, miRNAs are vastly studied and found to play role in various human physiologic as well as pathological conditions. A huge number of miRNAs have been identified in human cells whose expression is straightly regulated with crucial biological functions, while this number is constantly increasing. miRNAs are particularly studied in cancers, where they either can act with oncogenic function (oncomiRs) or tumor-suppressors role (referred as tumor-suppressor/oncorepressor miRNAs). miR-382 is a well-studied miRNA, which is revealed to play regulatory roles in physiological processes like osteogenic differentiation, hematopoietic stem cell differentiation and normal hematopoiesis, and liver progenitor cell differentiation. Notably, miR-382 deregulation is reported in pathologic conditions, such as renal fibrosis, muscular dystrophies, Rett syndrome, epidural fibrosis, atrial fibrillation, amelogenesis imperfecta, oxidative stress, human immunodeficiency virus (HIV) replication, and various types of cancers. The majority of oncogenesis studies have claimed miR-382 downregulation in cancers and suppressor impact on malignant phenotype of cancer cells in vitro and in vivo, while a few studies suggest opposite findings. Given the putative role of this miRNA in regulation of oncogenesis, assessment of miR-382 expression is suggested in a several clinical investigations as a prognostic/diagnostic biomarker for cancer patients. In this review, we have an overview to recent studies evaluated the role of miR-382 in oncogenesis as well as its clinical potential.
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Affiliation(s)
- Mehdi Fattahi
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam; School of Engineering & Technology, Duy Tan University, Da Nang, Vietnam
| | - Saeid Shahrabi
- Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Saadatpour
- Pharmaceutical Biotechnology Lab, Department of Microbiology, School of Biology and Center of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran
| | - Delsuz Rezaee
- School of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran
| | - Zahra Beyglu
- Department of Genetics, Qom Branch, Islamic Azad University, Qom, Iran
| | - Sana Delavari
- Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Anita Amrolahi
- Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shirin Ahmadi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeid Bagheri-Mohammadi
- Department of Physiology and Neurophysiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Effat Noori
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jamal Majidpoor
- Department of Anatomy, Faculty of Medicine, Infectious Disease Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Shadi Nouri
- Department of Radiology, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Seyed Mohsen Aghaei-Zarch
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Shahab Falahi
- Zoonotic Diseases Research Center, Ilam University of Medical Sciences, Ilam, Iran.
| | - Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Binh Nguyen Le
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam; School of Engineering & Technology, Duy Tan University, Da Nang, Vietnam
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13
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Chen J, Cai Z, Hu J, Zhou L, Zhang P, Xu X. MicroRNA-375 in extracellular vesicles - novel marker for esophageal cancer diagnosis. Medicine (Baltimore) 2023; 102:e32826. [PMID: 36749234 PMCID: PMC9901947 DOI: 10.1097/md.0000000000032826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND MicroRNAs have been confirmed to function as diagnostic biomarkers for esophageal cancer (EC). This study aimed to investigate the diagnostic potential of miR-375 in the plasma or extracellular vesicles (EVs) of esophageal cancers (ECs). METHODS miRNAs with diagnostic potential were identified through public database searches and validated through clinical sample testing. The diagnostic value of miR-375 in plasma and EVs was evaluated via receiver operating characteristic analysis and area under the curve. In addition, expression and survival analyses of the top ten target genes of miR-375 were conducted using the cancer genome atlas database. RESULTS MiR-375 was identified as a potential biomarker for ECs by searching the gene expression omnibus database. Results of clinical sample measurements showed that miR-375 in plasma or EVs was significantly different between ECs and controls ( P < .01), but did not differ by gender or age. receiver operating characteristic analysis demonstrated that miR-375 in EVs could function as a diagnostic marker for ECs, with a higher area under the curve (0.852) than that in plasma. The expression and survival analysis of the top ten target genes for miR-375 showed that only EIF4G3 was significantly associated with survival ( P < .05). CONCLUSION This research shows that miR-375, particularly in EVs, could serve as a biomarker for the diagnosis of ECs.
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Affiliation(s)
- Jie Chen
- Department of Thoracic Surgery, The Naval Medical Center of PLA, Second Military Medical University, Shanghai, China
| | - Zhigang Cai
- Department of Thoracic Surgery, The Naval Medical Center of PLA, Second Military Medical University, Shanghai, China
| | - Jing Hu
- Department of Thoracic Surgery, The Naval Medical Center of PLA, Second Military Medical University, Shanghai, China
| | - Lixia Zhou
- Department of Cardiology, The Naval Medical Center of PLA, Second Military Medical University, Shanghai, China
| | - Peili Zhang
- Department of Critical Medicine, The Naval Medical Center of PLA, Second Military Medical University, Shanghai, China
| | - Xiaoping Xu
- Department of Thoracic Surgery, The Naval Medical Center of PLA, Second Military Medical University, Shanghai, China
- * Correspondence: Xiaoping Xu, Department of Thoracic Surgery, the Naval Medical Center of PLA, Second Military Medical University, Shanghai, China (e-mail: )
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14
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Morelli E, Fulciniti M, Samur MK, Ribeiro CF, Wert-Lamas L, Henninger JE, Gullà A, Aktas-Samur A, Todoerti K, Talluri S, Park WD, Federico C, Scionti F, Amodio N, Bianchi G, Johnstone M, Liu N, Gramegna D, Maisano D, Russo NA, Lin C, Tai YT, Neri A, Chauhan D, Hideshima T, Shammas MA, Tassone P, Gryaznov S, Young RA, Anderson KC, Novina CD, Loda M, Munshi NC. A MIR17HG-derived long noncoding RNA provides an essential chromatin scaffold for protein interaction and myeloma growth. Blood 2023; 141:391-405. [PMID: 36126301 PMCID: PMC10082365 DOI: 10.1182/blood.2022016892] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 09/08/2022] [Accepted: 09/13/2022] [Indexed: 01/31/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) can drive tumorigenesis and are susceptible to therapeutic intervention. Here, we used a large-scale CRISPR interference viability screen to interrogate cell-growth dependency to lncRNA genes in multiple myeloma (MM) and identified a prominent role for the miR-17-92 cluster host gene (MIR17HG). We show that an MIR17HG-derived lncRNA, named lnc-17-92, is the main mediator of cell-growth dependency acting in a microRNA- and DROSHA-independent manner. Lnc-17-92 provides a chromatin scaffold for the functional interaction between c-MYC and WDR82, thus promoting the expression of ACACA, which encodes the rate-limiting enzyme of de novo lipogenesis acetyl-coA carboxylase 1. Targeting MIR17HG pre-RNA with clinically applicable antisense molecules disrupts the transcriptional and functional activities of lnc-17-92, causing potent antitumor effects both in vitro and in vivo in 3 preclinical animal models, including a clinically relevant patient-derived xenograft NSG mouse model. This study establishes a novel oncogenic function of MIR17HG and provides potent inhibitors for translation to clinical trials.
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Affiliation(s)
- Eugenio Morelli
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Mariateresa Fulciniti
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Mehmet K. Samur
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Caroline F. Ribeiro
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY
| | - Leon Wert-Lamas
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA
| | - Jon E. Henninger
- Whitehead Institute of Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA
| | - Annamaria Gullà
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Anil Aktas-Samur
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Katia Todoerti
- Department of Hematology, Fondazione Cà Granda IRCCS Policlinico, Milan, Italy
| | - Srikanth Talluri
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- VA Boston Healthcare System, Boston, MA
| | - Woojun D. Park
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Cinzia Federico
- Department of Clinical and Experimental Medicine, Magna Graecia University, Catanzaro, Italy
| | - Francesca Scionti
- Department of Clinical and Experimental Medicine, Magna Graecia University, Catanzaro, Italy
- Clinical Research Development and Phase I Unit, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Nicola Amodio
- Department of Clinical and Experimental Medicine, Magna Graecia University, Catanzaro, Italy
| | - Giada Bianchi
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Megan Johnstone
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
| | - Na Liu
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
| | - Doriana Gramegna
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Domenico Maisano
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Nicola A. Russo
- Istituto di Ricerche Genetiche “G. Salvatore,” Biogem s.c.ar.l., Avellino, Italy
| | - Charles Lin
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Yu-Tzu Tai
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Antonino Neri
- Department of Hematology, Fondazione Cà Granda IRCCS Policlinico, Milan, Italy
- Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
- Scientific Directorate, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy
| | - Dharminder Chauhan
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Teru Hideshima
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Masood A. Shammas
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- VA Boston Healthcare System, Boston, MA
| | - Pierfrancesco Tassone
- Department of Clinical and Experimental Medicine, Magna Graecia University, Catanzaro, Italy
| | | | - Richard A. Young
- Whitehead Institute of Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA
| | - Kenneth C. Anderson
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Carl D. Novina
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA
| | - Massimo Loda
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY
| | - Nikhil C. Munshi
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- VA Boston Healthcare System, Boston, MA
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15
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Ali SR, Humphreys KJ, Simpson K, McKinnon RA, Meech R, Michael MZ. Functional high-throughput screen identifies microRNAs that promote butyrate-induced death in colorectal cancer cells. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 30:30-47. [PMID: 36189423 PMCID: PMC9485215 DOI: 10.1016/j.omtn.2022.08.037] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 08/24/2022] [Indexed: 12/24/2022]
Abstract
The gut fermentation product butyrate displays anti-cancer properties in the human proximal colon, including the ability to inhibit proliferation and induce apoptosis in colorectal cancer (CRC) cells. A natural histone deacetylase inhibitor (HDACi), butyrate can alter histone acetylation patterns in CRC cells, and thereby regulate global gene expression, including the non-coding transcriptome and microRNAs (miRNAs). Dysregulated miRNA expression affects CRC development and progression; however, the interplay between miRNA activity and butyrate response remains to be elucidated. A high-throughput functional screen was employed to identify miRNAs that can act as enhancers of the anti-cancer properties of butyrate. Validation studies confirmed that several miRNAs, including miR-125b, miR-181a, miR-593, and miR-1227, enhanced apoptosis, decreased proliferation, and promoted cell-cycle arrest in the presence of butyrate. Pathway analyses of predicted miRNA target genes highlighted their likely involvement in critical cancer-related growth pathways, including WNT and PI3K signaling. Several cancer-associated miRNA targets, including TRIM29, COX2, PIK3R3, CCND1, MET, EEF2K, DVL3, and NUP62 were synergistically regulated by the combination of cognate miRNAs and butyrate. Overall, this study has exposed the potential of miRNAs to act as enhancers of the anti-cancer effects of HDAC inhibition and identifies specific miRNAs that might be exploited for therapeutic benefit.
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16
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Elghzaly AA, Sun C, Looger LL, Hirose M, Salama M, Khalil NM, Behiry ME, Hegazy MT, Hussein MA, Salem MN, Eltoraby E, Tawhid Z, Alwasefy M, Allam W, El-Shiekh I, Elserafy M, Abdelnaser A, Hashish S, Shebl N, Shahba AA, Elgirby A, Hassab A, Refay K, El-Touchy HM, Youssef A, Shabacy F, Hashim AA, Abdelzaher A, Alshebini E, Fayez D, El-Bakry SA, Elzohri MH, Abdelsalam EN, El-Khamisy SF, Ibrahim S, Ragab G, Nath SK. Genome-wide association study for systemic lupus erythematosus in an egyptian population. Front Genet 2022; 13:948505. [PMID: 36324510 PMCID: PMC9619055 DOI: 10.3389/fgene.2022.948505] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 09/30/2022] [Indexed: 04/11/2024] Open
Abstract
Systemic lupus erythematosus (SLE) susceptibility has a strong genetic component. Genome-wide association studies (GWAS) across trans-ancestral populations show both common and distinct genetic variants of susceptibility across European and Asian ancestries, while many other ethnic populations remain underexplored. We conducted the first SLE GWAS on Egyptians-an admixed North African/Middle Eastern population-using 537 patients and 883 controls. To identify novel susceptibility loci and replicate previously known loci, we performed imputation-based association analysis with 6,382,276 SNPs while accounting for individual admixture. We validated the association analysis using adaptive permutation tests (n = 109). We identified a novel genome-wide significant locus near IRS1/miR-5702 (Pcorrected = 1.98 × 10-8) and eight novel suggestive loci (Pcorrected < 1.0 × 10-5). We also replicated (Pperm < 0.01) 97 previously known loci with at least one associated nearby SNP, with ITGAM, DEF6-PPARD and IRF5 the top three replicated loci. SNPs correlated (r 2 > 0.8) with lead SNPs from four suggestive loci (ARMC9, DIAPH3, IFLDT1, and ENTPD3) were associated with differential gene expression (3.5 × 10-95 < p < 1.0 × 10-2) across diverse tissues. These loci are involved in cellular proliferation and invasion-pathways prominent in lupus and nephritis. Our study highlights the utility of GWAS in an admixed Egyptian population for delineating new genetic associations and for understanding SLE pathogenesis.
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Affiliation(s)
- Ashraf A. Elghzaly
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, El-Mansoura, Egypt
| | - Celi Sun
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
| | - Loren L. Looger
- Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, United States
| | - Misa Hirose
- Division of Genetics, Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
| | - Mohamed Salama
- Institute of Global Health and Human Ecology, The American University in Cairo, New Cairo, Egypt
| | - Noha M. Khalil
- Rheumatology and Clinical Immunology Unit, Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mervat Essam Behiry
- Rheumatology and Clinical Immunology Unit, Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Tharwat Hegazy
- Rheumatology and Clinical Immunology Unit, Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Ahmed Hussein
- Rheumatology and Clinical Immunology Unit, Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamad Nabil Salem
- Department of Internal Medicine, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt
| | - Ehab Eltoraby
- Department of Internal Medicine, Faculty of Medicine, Mansoura University, El-Mansoura, Egypt
| | - Ziyad Tawhid
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, El-Mansoura, Egypt
| | - Mona Alwasefy
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, El-Mansoura, Egypt
| | - Walaa Allam
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt
| | - Iman El-Shiekh
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt
| | - Menattallah Elserafy
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt
| | - Anwar Abdelnaser
- Institute of Global Health and Human Ecology, The American University in Cairo, New Cairo, Egypt
| | - Sara Hashish
- Institute of Global Health and Human Ecology, The American University in Cairo, New Cairo, Egypt
| | - Nourhan Shebl
- Institute of Global Health and Human Ecology, The American University in Cairo, New Cairo, Egypt
| | | | - Amira Elgirby
- Department of Internal Medicine, Faculty of Medicine, Alexandria University, Bab Sharqi, Egypt
| | - Amina Hassab
- Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Bab Sharqi, Egypt
| | - Khalida Refay
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | | | - Ali Youssef
- Department of Rheumatology and Immunology, Faculty of Medicine, Benha University Hospital, Benha, Egypt
| | - Fatma Shabacy
- Department of Rheumatology and Immunology, Faculty of Medicine, Benha University Hospital, Benha, Egypt
| | | | - Asmaa Abdelzaher
- Department of Clinical Pathology, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Emad Alshebini
- Department of Internal Medicine, Faculty of Medicine, Menoufia University, Al Minufiyah, Egypt
| | - Dalia Fayez
- Rheumatology and Clinical Immunology Unit, Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Samah A. El-Bakry
- Rheumatology and Clinical Immunology Unit, Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mona H. Elzohri
- Department of Internal Medicine, Faculty of Medicine, Assiut University, Asyut, Egypt
| | | | - Sherif F. El-Khamisy
- Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt
- The Healthy Lifespan Institute, University of Sheffield, Sheffield, United Kingdom
- The Institute of Cancer Therapeutics, University of Bradford, Bradford, United Kingdom
| | - Saleh Ibrahim
- Division of Genetics, Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
| | - Gaafar Ragab
- Rheumatology and Clinical Immunology Unit, Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Swapan K. Nath
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
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17
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The Role of miR-29 Family in TGF-β Driven Fibrosis in Glaucomatous Optic Neuropathy. Int J Mol Sci 2022; 23:ijms231810216. [PMID: 36142127 PMCID: PMC9499597 DOI: 10.3390/ijms231810216] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 08/30/2022] [Accepted: 09/02/2022] [Indexed: 11/17/2022] Open
Abstract
Primary open angle glaucoma (POAG), a chronic optic neuropathy, remains the leading cause of irreversible blindness worldwide. It is driven in part by the pro-fibrotic cytokine transforming growth factor beta (TGF-β) and leads to extracellular matrix remodelling at the lamina cribrosa of the optic nerve head. Despite an array of medical and surgical treatments targeting the only known modifiable risk factor, raised intraocular pressure, many patients still progress and develop significant visual field loss and eventual blindness. The search for alternative treatment strategies targeting the underlying fibrotic transformation in the optic nerve head and trabecular meshwork in glaucoma is ongoing. MicroRNAs are small non-coding RNAs known to regulate post-transcriptional gene expression. Extensive research has been undertaken to uncover the complex role of miRNAs in gene expression and miRNA dysregulation in fibrotic disease. MiR-29 is a family of miRNAs which are strongly anti-fibrotic in their effects on the TGF-β signalling pathway and the regulation of extracellular matrix production and deposition. In this review, we discuss the anti-fibrotic effects of miR-29 and the role of miR-29 in ocular pathology and in the development of glaucomatous optic neuropathy. A better understanding of the role of miR-29 in POAG may aid in developing diagnostic and therapeutic strategies in glaucoma.
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18
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In silico Prediction of Deleterious Single Nucleotide Polymorphism in S100A4 Metastatic Gene: Potential Early Diagnostic Marker. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:4202623. [PMID: 35965620 PMCID: PMC9357733 DOI: 10.1155/2022/4202623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/20/2022] [Accepted: 06/27/2022] [Indexed: 11/17/2022]
Abstract
S100A4 protein overexpression has been reported in different types of cancer and plays a key role by interacting with the tumor suppressor protein Tp53. Single nucleotide polymorphisms (SNP) in S100A4 could directly influence the biomolecular interaction with the tumor suppressor protein Tp53 due to their aberrant conformations. Hence, the study was designed to predict the deleterious SNP and its effect on the S100A4 protein structure and function. Twenty-one SNP data sets were screened for nonsynonymous mutations and subsequently subjected to deleterious mutation prediction using different computational tools. The screened deleterious mutations were analyzed for their changes in functionality and their interaction with the tumor suppressor protein Tp53 by protein-protein docking analysis. The structural effects were studied using the 3DMissense mutation tool to estimate the solvation energy and torsion angle of the screened mutations on the predicted structures. In our study, 21 deleterious nonsynonymous mutations were screened, including F72V, E74G, L5P, D25E, N65S, A28V, A8D, S20L, L58P, and K26N were found to be remarkably conserved by exhibiting the interaction either with the EF-hand 1 or EF-hand 2 domain. The solvation and torsion values significantly deviated for the mutant-type structures with S20L, N65S, and F72L mutations and showed a marked reduction in their binding affinity with the Tp53 protein. Hence, these deleterious mutations might serve as prospective targets for diagnosing and developing personalized treatments for cancer and other related diseases.
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Rajasekaran S, Khan E, Ching SR, Khan M, Siddiqui J, Gradia DF, Lin C, Bouley SJ, Mercadante D, Manning AL, Gerber AP, Walker J, Miles W. PUMILIO competes with AUF1 to control DICER1 RNA levels and miRNA processing. Nucleic Acids Res 2022; 50:7048-7066. [PMID: 35736218 PMCID: PMC9262620 DOI: 10.1093/nar/gkac499] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 05/27/2022] [Indexed: 12/24/2022] Open
Abstract
DICER1 syndrome is a cancer pre-disposition disorder caused by mutations that disrupt the function of DICER1 in miRNA processing. Studying the molecular, cellular and oncogenic effects of these mutations can reveal novel mechanisms that control cell homeostasis and tumor biology. Here, we conduct the first analysis of pathogenic DICER1 syndrome allele from the DICER1 3'UTR. We find that the DICER1 syndrome allele, rs1252940486, abolishes interaction with the PUMILIO RNA binding protein with the DICER1 3'UTR, resulting in the degradation of the DICER1 mRNA by AUF1. This single mutational event leads to diminished DICER1 mRNA and protein levels, and widespread reprogramming of miRNA networks. The in-depth characterization of the rs1252940486 DICER1 allele, reveals important post-transcriptional regulatory events that control DICER1 levels.
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Affiliation(s)
- Swetha Rajasekaran
- Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA
| | - Eshan Khan
- Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA
| | - Samuel R Ching
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Misbah Khan
- Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA
| | - Jalal K Siddiqui
- Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA
| | - Daniela F Gradia
- Department of Microbial Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK
- Department of Genetics, Federal University of Parana, Curitiba, Brazil
| | - Chenyu Lin
- Department of Cancer Biology and Genetics, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA
| | - Stephanie J Bouley
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Dayna L Mercadante
- Bioinformatics and Computational Biology Program, Worcester Polytechnic Institute, 100 Institute Road, Worcester, MA 01609, USA
| | - Amity L Manning
- Bioinformatics and Computational Biology Program, Worcester Polytechnic Institute, 100 Institute Road, Worcester, MA 01609, USA
- Department of Biology and Biotechnology, Worcester Polytechnic Institute, 100 Institute Road, Worcester, MA 01609, USA
| | - André P Gerber
- Department of Microbial Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK
| | - James A Walker
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Wayne O Miles
- To whom correspondence should be addressed. Tel: +1 614 366 2869;
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EpisomiR, a New Family of miRNAs, and Its Possible Roles in Human Diseases. Biomedicines 2022; 10:biomedicines10061280. [PMID: 35740302 PMCID: PMC9220071 DOI: 10.3390/biomedicines10061280] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/24/2022] [Accepted: 05/26/2022] [Indexed: 11/26/2022] Open
Abstract
MicroRNAs (miRNAs) are synthesized through a canonical pathway and play a role in human diseases, such as cancers and cardiovascular, neurodegenerative, psychiatric, and chronic inflammatory diseases. The development of sequencing technologies has enabled the identification of variations in noncoding miRNAs. These miRNA variants, called isomiRs, are generated through a non-canonical pathway, by several enzymes that alter the length and sequence of miRNAs. The isomiR family is, now, expanding further to include episomiRs, which are miRNAs with different modifications. Since recent findings have shown that isomiRs reflect the cell-specific biological function of miRNAs, knowledge about episomiRs and isomiRs can, possibly, contribute to the optimization of diagnosis and therapeutic technology for precision medicine.
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Su Y, Zheng Q, Zhu L, Gu X, Lu J, Li L. Functions and underlying mechanisms of miR-650 in human cancers. Cancer Cell Int 2022; 22:132. [PMID: 35331235 PMCID: PMC8944108 DOI: 10.1186/s12935-022-02551-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 03/13/2022] [Indexed: 01/27/2023] Open
Abstract
MicroRNAs (miRNAs) are one type of noncoding RNAs that interfere with mRNA translation to downregulate gene expression, which results in posttranscriptional gene silencing. Over the past two decades, miRNAs have been widely reported to impact the progression of malignant tumours by interfering with cancer initiation and progression; therefore, miRNAs represent potential new diagnostic and therapeutic tools. miR-650 is a newly identified miR, and increasing studies have demonstrated that miR-650 plays critical roles in cancer progression, such as mediating the Wnt signalling pathway/AXIN1 (axis inhibition protein 1) axis in hepatocellular carcinoma. Nevertheless, associations between the expression patterns and molecular mechanisms of miR-650 in cancer have not been comprehensively described. In this article, we review the existing evidence regarding the mechanisms by which miR-650 expression is altered and their relation to cancer. Moreover, the promising clinical application of miR-650 for diagnosis and treatment is highlighted.
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Affiliation(s)
- Yuanshuai Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, Hangzhou, 310003, China
| | - Qiuxian Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, Hangzhou, 310003, China
| | - Lingxiao Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, Hangzhou, 310003, China
| | - Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, Hangzhou, 310003, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, Hangzhou, 310003, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, Hangzhou, 310003, China.
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Rihane FE, Erguibi D, Lamsisi M, Chehab F, Ennaji MM. RETRACTED ARTICLE: Upregulation of miR-21 Expression in Gastric Cancer and Its Clinicopathological Feature Association. J Gastrointest Cancer 2022; 53:236. [PMID: 34907506 DOI: 10.1007/s12029-021-00691-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2021] [Indexed: 12/29/2022]
Affiliation(s)
- Fatima Ezzahra Rihane
- Laboratory of Genetic and Molecular Pathology, Faculty of Medicine & Pharmacy Casablanca, University Hassan II of Casablanca, Casablanca, Morocco
- Laboratory of Virology, Microbiology, Quality, Biotechnologies/Ecotoxicology and Biodiversity, Faculty of Sciences & Technologies Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco
| | - Driss Erguibi
- Service of Digestive Cancers Surgery and Liver Transplant, Department of Surgery, Ibn Rochd University Hospital Center, Faculty of Medicine & Pharmacy Casablanca, University Hassan II of Casablanca, Casablanca, Morocco
| | - Maryame Lamsisi
- Laboratory of Virology, Microbiology, Quality, Biotechnologies/Ecotoxicology and Biodiversity, Faculty of Sciences & Technologies Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco
| | - Farid Chehab
- Service of Digestive Cancers Surgery and Liver Transplant, Department of Surgery, Ibn Rochd University Hospital Center, Faculty of Medicine & Pharmacy Casablanca, University Hassan II of Casablanca, Casablanca, Morocco
| | - Moulay Mustapha Ennaji
- Laboratory of Virology, Microbiology, Quality, Biotechnologies/Ecotoxicology and Biodiversity, Faculty of Sciences & Technologies Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco.
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Dinami R, Petti E, Porru M, Rizzo A, Ganci F, Sacconi A, Ostano P, Chiorino G, Trusolino L, Blandino G, Ciliberto G, Zizza P, Biroccio A. TRF2 cooperates with CTCF for controlling the oncomiR-193b-3p in colorectal cancer. Cancer Lett 2022; 533:215607. [PMID: 35240232 DOI: 10.1016/j.canlet.2022.215607] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 02/11/2022] [Accepted: 02/24/2022] [Indexed: 12/14/2022]
Abstract
The Telomeric Repeat binding Factor 2 (TRF2), a key protein involved in telomere integrity, is over-expressed in several human cancers and promotes tumor formation and progression. Recently, TRF2 has been also found outside telomeres where it can affect gene expression. Here we provide evidence that TRF2 is able to modulate the expression of microRNAs (miRNAs), small non-coding RNAs altered in human tumors. Among the miRNAs regulated by TRF2, we focused on miR-193b-3p, an oncomiRNA that positively correlates with TRF2 expression in human colorectal cancer patients from The Cancer Genome Atlas dataset. At the mechanistic level, the control of miR-193b-3p expression requires the cooperative activity between TRF2 and the chromatin organization factor CTCF. We found that CTCF physically interacts with TRF2, thus driving the proper positioning of TRF2 on a binding site located upstream the miR-193b-3p host-gene. The binding of TRF2 on the identified region is necessary for promoting the expression of miR-193b3p which, in turn, inhibits the translation of the onco-suppressive methyltransferase SUV39H1 and promotes tumor cell proliferation. The translational relevance of the oncogenic properties of miR-193b-3p was confirmed in patients, in whom the association between TRF2 and miR-193b-3p has a prognostic value.
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Affiliation(s)
- Roberto Dinami
- Oncogenomic and Epigenetic Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome, 00144, Italy
| | - Eleonora Petti
- Oncogenomic and Epigenetic Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome, 00144, Italy
| | - Manuela Porru
- Oncogenomic and Epigenetic Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome, 00144, Italy
| | - Angela Rizzo
- Oncogenomic and Epigenetic Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome, 00144, Italy
| | - Federica Ganci
- Oncogenomic and Epigenetic Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome, 00144, Italy
| | - Andrea Sacconi
- Oncogenomic and Epigenetic Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome, 00144, Italy
| | - Paola Ostano
- Cancer Genomics Lab, Fondazione Edo ed Elvo Tempia, via Malta 3, Biella, 13900, Italy
| | - Giovanna Chiorino
- Cancer Genomics Lab, Fondazione Edo ed Elvo Tempia, via Malta 3, Biella, 13900, Italy
| | - Livio Trusolino
- Department of Oncology, University of Torino, Strada Provinciale 142, Candiolo, TO, 10060, Italy; Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute, FPO - IRCCS, Strada Provinciale 142, Candiolo, TO, 10060, Italy
| | - Giovanni Blandino
- Oncogenomic and Epigenetic Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome, 00144, Italy
| | - Gennaro Ciliberto
- Scientific Direction, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome, 00144, Italy
| | - Pasquale Zizza
- Oncogenomic and Epigenetic Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome, 00144, Italy.
| | - Annamaria Biroccio
- Oncogenomic and Epigenetic Unit, IRCCS - Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome, 00144, Italy.
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Kansal V, Agarwal A, Harbour A, Farooqi H, Singh VK, Prasad R. Regular Intake of Green Tea Polyphenols Suppresses the Development of Nonmelanoma Skin Cancer through miR-29-Mediated Epigenetic Modifications. J Clin Med 2022; 11:jcm11020398. [PMID: 35054091 PMCID: PMC8777720 DOI: 10.3390/jcm11020398] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/26/2021] [Accepted: 01/10/2022] [Indexed: 12/11/2022] Open
Abstract
Previously, we and others have shown that the regular intake of green tea polyphenols (GTPs) reduces ultraviolet B (UVB) radiation-induced skin cancer by targeting multiple signaling pathways, including DNA damage, DNA repair, immunosuppression, and inflammation. Here, we determine the effect of GTPs on UVB-induced epigenetic changes, emphasizing DNA hypermethylation in UV-exposed skin and tumors and their association with miR-29, a key regulator of DNA methyltransferases (DNMTs). Skin cancer was induced in SKH-1 hairless mice following repeated exposures of UVB radiation (180 mJ/cm2, three times/week, 24 weeks) with or without GTPs supplementation (0.2%) in drinking water. Regular intake of GTPs inhibited tumor growth by hindering the cascade of DNA hypermethylation events. GTPs supplementation significantly blocked UVB-induced DNA hypermethylation in the skin (up to 35%; p < 0.0001) and in tumors (up to 50%; p < 0.0001). Experimental results showed that the levels of DNA hypermethylation were higher in GTPs-treated mice than in the control group. The expressions of miR-29a, miR-29b, and miR-29c were markedly decreased in UV-induced skin tumors, and GTPs administration blocked UVB-induced miR-29s depletion. Furthermore, these observations were verified using the in vitro approach in human skin cancer cells (A431) followed by treatment with GTPs or mimics of miR-29c. Increased levels of miR-29 were observed in GTPs-treated A431 cells, resulting in increased TET activity and decreased DNA hypermethylation. In conclusion, UVB-mediated miR-29 depletion promotes DNA hypermethylation and leads to enhanced tumor growth by silencing tumor suppressors. Regular intake of GTPs rescued UVB-induced miR-29 depletion and prevented tumor growth by maintaining reduced DNA hypermethylation and activating tumor suppressors. Our observations suggest that miR-based strategies and regular consumption of GTPs could minimize the risk of UVB-induced skin cancers and contribute to better management of NMSCs.
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Affiliation(s)
- Vikash Kansal
- Department of Otolaryngology, Emory University, Atlanta, GA 30322, USA;
| | - Anshu Agarwal
- Department of Zoology, Agra College, Agra 282001, India;
- Department of Biotechnology, Hamdard University, New Delhi 110048, India
| | - Angela Harbour
- College of Medicine, Florida State University, Tallahassee, FL 32304, USA;
| | - Humaira Farooqi
- Department of Biotechnology, Hamdard University, New Delhi 110048, India
- Correspondence: (H.F.); (V.K.S.); (R.P.)
| | - Vijay Kumar Singh
- Department of Zoology, Agra College, Agra 282001, India;
- Correspondence: (H.F.); (V.K.S.); (R.P.)
| | - Ram Prasad
- Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence: (H.F.); (V.K.S.); (R.P.)
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Zhou R, Luo Z, Yin G, Yu L, Zhong H. MiR-556-5p modulates migration, invasion, and epithelial-mesenchymal transition in breast cancer cells via targeting PTHrP. J Mol Histol 2022; 53:297-308. [PMID: 35000027 DOI: 10.1007/s10735-021-10056-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 12/29/2021] [Indexed: 01/19/2023]
Abstract
Breast cancer bone metastases may block normal bone remodeling and promote bone degradation, during which several signaling pathways and small non-coding miRNAs might all play a role. miRNAs and target mRNAs that might be associated with breast cancer bone metastasis were analyzed and selected using bioinformatics analyses based on online data. The 3' untranslated region of key factors associated with breast cancer metastasis were examined for candidate miRNA binding site using Targetscan. The predicted binding was validated. The specific effects of single miRNA and dynamic effects of the miRNA-mRNA axis on breast cancer cell metastasis were investigated. miR-556-5p was downregulated in breast cancer samples according to online datasets and experimental analyses. In breast cancer cells, miR-556-5p overexpression inhibited, whereas miR-556-5p inhibition promoted cancer cell invasion and migration. Among key factors associated with breast cancer bone metastasis, parathyroid hormone related protein (PTHrP) 3'UTR possessed miR-556-5p binding site. Through direct binding, miR-556-5p negatively regulated PTHrP expression. In breast cancer cell lines, miR-556-5p inhibition promoted, whereas PTHrP silencing suppressed cancer cell migration, invasion, and epithelial-mesenchymal transition; the effects of miR-556-5p inhibition were partially reversed by PTHrP silencing. In summary, miR-556-5p targets PTHrP to modulate the cell migration and invasion of breast cancer.
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Affiliation(s)
- Rongjun Zhou
- Department of Surgery, Changsha Hospital for Maternal and Child Health Care, No. 416 Chengnan East Road, Yuhua District, Changsha, 410007, Hunan, China.
| | - Zhen Luo
- Department of General Surgery, The First Hospital of Changsha, Changsha, 410005, Hunan, China
| | - Guanqun Yin
- Department of Surgery, Changsha Hospital for Maternal and Child Health Care, No. 416 Chengnan East Road, Yuhua District, Changsha, 410007, Hunan, China
| | - Lanting Yu
- Department of Surgery, Changsha Hospital for Maternal and Child Health Care, No. 416 Chengnan East Road, Yuhua District, Changsha, 410007, Hunan, China
| | - Hao Zhong
- Department of Surgery, Changsha Hospital for Maternal and Child Health Care, No. 416 Chengnan East Road, Yuhua District, Changsha, 410007, Hunan, China
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Kaller M, Hünten S, Siemens H, Hermeking H. Analysis of the p53/microRNA Network in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1385:187-228. [DOI: 10.1007/978-3-031-08356-3_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Changes in Exosomal miRNA Composition in Thyroid Cancer Cells after Prolonged Exposure to Real Microgravity in Space. Int J Mol Sci 2021; 22:ijms222312841. [PMID: 34884646 PMCID: PMC8657878 DOI: 10.3390/ijms222312841] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
As much as space travel and exploration have been a goal since humankind looked up to the stars, the challenges coming with it are manifold and difficult to overcome. Therefore, researching the changes the human organism undergoes following exposure to weightlessness, on a cellular or a physiological level, is imperative to reach the goal of exploring space and new planets. Building on the results of our CellBox-1 experiment, where thyroid cancer cells were flown to the International Space Station, we are now taking advantage of the newest technological opportunities to gain more insight into the changes in cell–cell communication of these cells. Analyzing the exosomal microRNA composition after several days of microgravity might elucidate some of the proteomic changes we have reported earlier. An array scan of a total of 754 miRNA targets revealed more than 100 differentially expressed miRNAs in our samples, many of which have been implicated in thyroid disease in other studies.
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Isca C, Piacentini F, Mastrolia I, Masciale V, Caggia F, Toss A, Piombino C, Moscetti L, Barbolini M, Maur M, Dominici M, Omarini C. Circulating and Intracellular miRNAs as Prognostic and Predictive Factors in HER2-Positive Early Breast Cancer Treated with Neoadjuvant Chemotherapy: A Review of the Literature. Cancers (Basel) 2021; 13:cancers13194894. [PMID: 34638377 PMCID: PMC8508299 DOI: 10.3390/cancers13194894] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNA) are small noncoding RNAs that can act as both oncogene and tumor suppressors. Deregulated miRNA expression has been detected in human cancers, including breast cancer (BC). Considering their important roles in tumorigenesis, miRNAs have been investigated as potential prognostic and diagnostic biomarkers. Neoadjuvant setting is an optimal model to investigate in vivo the mechanism of treatment resistance. In the management of human epidermal growth factor receptor-2 (HER2)-positive early BC, the anti-HER2-targeted therapies have drastically changed the survival outcomes. Despite this, growing drug resistance due to the pressure of therapy is relatively frequent. In the present review, we focused on the main miRNAs involved in HER2-positive BC tumorigenesis and discussed the recent evidence on their predictive and prognostic value.
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Affiliation(s)
- Chrystel Isca
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, 41124 Modena, Italy; (C.I.); (F.P.); (F.C.); (A.T.); (C.P.); (M.B.); (M.D.)
| | - Federico Piacentini
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, 41124 Modena, Italy; (C.I.); (F.P.); (F.C.); (A.T.); (C.P.); (M.B.); (M.D.)
| | - Ilenia Mastrolia
- Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (I.M.); (V.M.)
| | - Valentina Masciale
- Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (I.M.); (V.M.)
| | - Federica Caggia
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, 41124 Modena, Italy; (C.I.); (F.P.); (F.C.); (A.T.); (C.P.); (M.B.); (M.D.)
| | - Angela Toss
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, 41124 Modena, Italy; (C.I.); (F.P.); (F.C.); (A.T.); (C.P.); (M.B.); (M.D.)
| | - Claudia Piombino
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, 41124 Modena, Italy; (C.I.); (F.P.); (F.C.); (A.T.); (C.P.); (M.B.); (M.D.)
| | - Luca Moscetti
- Division of Medical Oncology, Department of Oncology-Hematology, University Hospital of Modena, 41124 Modena, Italy; (L.M.); (M.M.)
| | - Monica Barbolini
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, 41124 Modena, Italy; (C.I.); (F.P.); (F.C.); (A.T.); (C.P.); (M.B.); (M.D.)
| | - Michela Maur
- Division of Medical Oncology, Department of Oncology-Hematology, University Hospital of Modena, 41124 Modena, Italy; (L.M.); (M.M.)
| | - Massimo Dominici
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, 41124 Modena, Italy; (C.I.); (F.P.); (F.C.); (A.T.); (C.P.); (M.B.); (M.D.)
- Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (I.M.); (V.M.)
| | - Claudia Omarini
- Division of Medical Oncology, Department of Oncology-Hematology, University Hospital of Modena, 41124 Modena, Italy; (L.M.); (M.M.)
- Correspondence: ; Tel.: +39-059-4222845
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MiR-137 Targets the 3' Untranslated Region of MSH2: Potential Implications in Lynch Syndrome-Related Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13184662. [PMID: 34572889 PMCID: PMC8470766 DOI: 10.3390/cancers13184662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/13/2021] [Accepted: 09/15/2021] [Indexed: 11/17/2022] Open
Abstract
Mismatch Repair (MMR) gene dysregulation plays a fundamental role in Lynch Syndrome (LS) pathogenesis, a form of hereditary colorectal cancer. Loss or overexpression of key MMR genes leads to genome instability and tumorigenesis; however, the mechanisms controlling MMR gene expression are unknown. One such gene, MSH2, exerts an important role, not only in MMR, but also in cell proliferation, apoptosis, and cell cycle control. In this study, we explored the functions and underlying molecular mechanisms of increased MSH2 expression related to a c.*226A>G variant in the 3'untranslated (UTR) region of MSH2 that had been previously identified in a subject clinically suspected of LS. Bioinformatics identified a putative binding site for miR-137 in this region. To verify miRNA targeting specificity, we performed luciferase gene reporter assays using a MSH2 3'UTR psiCHECK-2 vector in human SW480 cells over-expressing miR-137, which showed a drastic reduction in luciferase activity (p > 0.0001). This effect was abolished by site-directed mutagenesis of the putative miR-137 seed site. Moreover, in these cells we observed that miR-137 levels were inversely correlated with MSH2 expression levels. These results were confirmed by results in normal and tumoral tissues from the patient carrying the 3'UTR c.*226A>G variant in MSH2. Finally, miR-137 overexpression in SW480 cells significantly suppressed cell proliferation in a time- and dose-dependent manner (p < 0.0001), supporting a role for MSH2 in apoptosis and cell proliferation processes. Our findings suggest miR-137 helps control MSH2 expression via its 3'UTR and that dysregulation of this mechanism appears to promote tumorigenesis in colon cells.
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Hozaka Y, Kita Y, Yasudome R, Tanaka T, Wada M, Idichi T, Tanabe K, Asai S, Moriya S, Toda H, Mori S, Kurahara H, Ohtsuka T, Seki N. RNA-Sequencing Based microRNA Expression Signature of Colorectal Cancer: The Impact of Oncogenic Targets Regulated by miR-490-3p. Int J Mol Sci 2021; 22:ijms22189876. [PMID: 34576039 PMCID: PMC8469425 DOI: 10.3390/ijms22189876] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/08/2021] [Accepted: 09/10/2021] [Indexed: 12/24/2022] Open
Abstract
To elucidate novel aspects of the molecular pathogenesis of colorectal cancer (CRC), we have created a new microRNA (miRNA) expression signature based on RNA-sequencing. Analysis of the signature showed that 84 miRNAs were upregulated, and 70 were downregulated in CRC tissues. Interestingly, our signature indicated that both guide and passenger strands of some miRNAs were significantly dysregulated in CRC tissues. These findings support our earlier data demonstrating the involvement of miRNA passenger strands in cancer pathogenesis. Our study focused on downregulated miR-490-3p and investigated its tumor-suppressive function in CRC cells. We successfully identified a total of 38 putative oncogenic targets regulated by miR-490-3p in CRC cells. Among these targets, the expression of three genes (IRAK1: p = 0.0427, FUT1: p = 0.0468, and GPRIN2: p = 0.0080) significantly predicted 5-year overall survival of CRC patients. Moreover, we analyzed the direct regulation of IRAK1 by miR-490-3p, and its resultant oncogenic function in CRC cells. Thus, we have clarified a part of the molecular pathway of CRC based on the action of tumor-suppressive miR-490-3p. This new miRNA expression signature of CRC will be a useful tool for elucidating new molecular pathogenesis in this disease.
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Affiliation(s)
- Yuto Hozaka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (Y.H.); (Y.K.); (R.Y.); (T.T.); (M.W.); (T.I.); (K.T.); (H.T.); (S.M.); (H.K.); (T.O.)
| | - Yoshiaki Kita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (Y.H.); (Y.K.); (R.Y.); (T.T.); (M.W.); (T.I.); (K.T.); (H.T.); (S.M.); (H.K.); (T.O.)
| | - Ryutaro Yasudome
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (Y.H.); (Y.K.); (R.Y.); (T.T.); (M.W.); (T.I.); (K.T.); (H.T.); (S.M.); (H.K.); (T.O.)
| | - Takako Tanaka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (Y.H.); (Y.K.); (R.Y.); (T.T.); (M.W.); (T.I.); (K.T.); (H.T.); (S.M.); (H.K.); (T.O.)
| | - Masumi Wada
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (Y.H.); (Y.K.); (R.Y.); (T.T.); (M.W.); (T.I.); (K.T.); (H.T.); (S.M.); (H.K.); (T.O.)
| | - Tetsuya Idichi
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (Y.H.); (Y.K.); (R.Y.); (T.T.); (M.W.); (T.I.); (K.T.); (H.T.); (S.M.); (H.K.); (T.O.)
| | - Kan Tanabe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (Y.H.); (Y.K.); (R.Y.); (T.T.); (M.W.); (T.I.); (K.T.); (H.T.); (S.M.); (H.K.); (T.O.)
| | - Shunichi Asai
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
| | - Shogo Moriya
- Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
| | - Hiroko Toda
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (Y.H.); (Y.K.); (R.Y.); (T.T.); (M.W.); (T.I.); (K.T.); (H.T.); (S.M.); (H.K.); (T.O.)
| | - Shinichiro Mori
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (Y.H.); (Y.K.); (R.Y.); (T.T.); (M.W.); (T.I.); (K.T.); (H.T.); (S.M.); (H.K.); (T.O.)
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (Y.H.); (Y.K.); (R.Y.); (T.T.); (M.W.); (T.I.); (K.T.); (H.T.); (S.M.); (H.K.); (T.O.)
| | - Takao Ohtsuka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; (Y.H.); (Y.K.); (R.Y.); (T.T.); (M.W.); (T.I.); (K.T.); (H.T.); (S.M.); (H.K.); (T.O.)
| | - Naohiko Seki
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
- Correspondence: ; Tel.: +81-43-226-2971
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Competing Endogenous RNA of Snail and Zeb1 UTR in Therapeutic Resistance of Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22179589. [PMID: 34502497 PMCID: PMC8431469 DOI: 10.3390/ijms22179589] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/25/2021] [Accepted: 08/31/2021] [Indexed: 12/30/2022] Open
Abstract
The epithelial-mesenchymal transition (EMT) comprises an important biological mechanism not only for cancer progression but also in the therapeutic resistance of cancer cells. While the importance of the protein abundance of EMT-inducers, such as Snail (SNAI1) and Zeb1 (ZEB1), during EMT progression is clear, the reciprocal interactions between the untranslated regions (UTRs) of EMT-inducers via a competing endogenous RNA (ceRNA) network have received little attention. In this study, we found a synchronized transcript abundance of Snail and Zeb1 mediated by a non-coding RNA network in colorectal cancer (CRC). Importantly, the trans-regulatory ceRNA network in the UTRs of EMT inducers is mediated by competition between tumor suppressive miRNA-34 (miR-34) and miRNA-200 (miR-200). Furthermore, the ceRNA network consisting of the UTRs of EMT inducers and tumor suppressive miRs is functional in the EMT phenotype and therapeutic resistance of colon cancer. In The Cancer Genome Atlas (TCGA) samples, we also found genome-wide ceRNA gene sets regulated by miR-34a and miR-200 in colorectal cancer. These results indicate that the ceRNA networks regulated by the reciprocal interaction between EMT gene UTRs and tumor suppressive miRs are functional in CRC progression and therapeutic resistance.
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Rahmadi A, Fasyah I, Sudigyo D, Budiarto A, Mahesworo B, Hidayat AA, Pardamean B. Comparative study of predicted miRNA between Indonesia and China (Wuhan) SARS-CoV-2: a bioinformatics analysis. Genes Genomics 2021; 43:1079-1086. [PMID: 34152577 PMCID: PMC8215323 DOI: 10.1007/s13258-021-01119-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/05/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Several reports on the discovery of SARS-CoV-2 mutations and variations in Indonesia COVID-19 cases led to genomic dysregulation with the first pandemic cases in Wuhan, China. MicroRNA (miRNA) plays an important role in this genetic regulation and contributes to the enhancement of viral RNA binding through the host mRNA. OBJECTIVE This research is aimed to detect miRNA targets of SARS-CoV-2 and examines their role in Indonesia cases against Wuhan cases. METHODS SARS-CoV-2 sequences were obtained from GISAID ( https://www.gisaid.org/ ), NCBI ( https://ncbi.nlm.nih.gov ), and National Genomics Data Center ( https://bigd.big.ac.cn/gwh/ ) databases. MiRDB ( https://github.com/gbnegrini/mirdb-custom-target-search ) was used to annotate and predict target human mature miRNAs. For statistical analysis, we utilized a series chi-square test to obtain significant miRNA. DIANA-miRPath v3.0 ( http://www.microrna.gr/miRPathv3 ) analyzed the Gene Ontology of mature miRNAs. RESULT The statistical results detected five significant miRNAs. Two miRNAs: hsa-miR-4778-5p and hsa-miR-4531 were consistently found in the majority of Wuhan samples, while they were only found in less than half of the Indonesia samples. The other three miRNA, hsa-miR-6844, hsa-miR-627-5p, and hsa-miR-3674, were discovered in most samples in both groups but with a significant difference ratio. Among these five significant miRNA targets, hsa-miR-6844 is the only miRNA that has an association with the ORF1ab gene of SARS-CoV-2. CONCLUSION The Gene Ontology analysis of five significant miRNA targets indicates a significant role in inflammation and the immune system. The specific detection of host miRNAs in this study shows that there are differences in the characteristics of SARS-CoV-2 between Indonesia and Wuhan.
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Affiliation(s)
- Agus Rahmadi
- Faculty of Medicine, Universitas Muhammadiyah Prof. DR. Hamka, Jakarta, 12130, Indonesia
| | - Ismaily Fasyah
- Faculty of Medicine, Universitas Muhammadiyah Prof. DR. Hamka, Jakarta, 12130, Indonesia
| | - Digdo Sudigyo
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, 11480, Indonesia.
| | - Arif Budiarto
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, 11480, Indonesia
- School of Computer Science, Bina Nusantara University, Jakarta, 11480, Indonesia
| | - Bharuno Mahesworo
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, 11480, Indonesia
| | - Alam Ahmad Hidayat
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, 11480, Indonesia
| | - Bens Pardamean
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, 11480, Indonesia
- BINUS Graduate Program-Master of Computer Science Program, Bina Nusantara University, Jakarta, 11480, Indonesia
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MiR-325 Promotes Oxaliplatin-Induced Cytotoxicity Against Colorectal Cancer Through the HSPA12B/PI3K/AKT/Bcl-2 Pathway. Dig Dis Sci 2021; 66:2651-2660. [PMID: 32914380 DOI: 10.1007/s10620-020-06579-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 08/21/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Oxaliplatin is one of the most effective chemotherapeutic drugs used for the treatment of colorectal cancer (CRC). However, intervention that attenuates the resistance of oxaliplatin is still required in the treatment of CRC. AIMS To investigate the role of miR-325 in changing the oxaliplatin sensitivity to CRC cells. METHODS Expression of miR-325 in colorectal cancer tissues and cell lines was measured by using qRT-PCR analysis. Cytotoxicity of oxaliplatin to control or miR-325-overexpressed HT29 and SW480 cells was evaluated by CCK-8 assays. Luciferase reporter assay was used to confirm the regulation of miR-325 on HSPA12B. Flow cytometry was performed to detect the mitochondrial membrane potential and cell apoptosis. RESULTS Expression of miR-325 was decreased in colorectal cancer tissues and cell lines. However, overexpression of miR-325 can decrease the 50% inhibiting concentration of oxaliplatin to colorectal cancer cell lines HT29 and SW480. Mechanically, we confirmed that miR-325 targeted HSPA12B in colorectal cancer. Therefore, overexpression of miR-325 inhibited the phosphorylation of PI3K and AKT and decreased the expression of Bcl-2 to promote the oxaliplatin-induced mitochondrial apoptosis in colorectal cancer. CONCLUSIONS MiR-325 sensitizes the colorectal cancer cells to oxaliplatin-induced cytotoxicity through the HSPA12B/PI3K/AKT/Bcl-2 pathway.
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The Clinical Assessment of MicroRNA Diagnostic, Prognostic, and Theranostic Value in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13122916. [PMID: 34208056 PMCID: PMC8230660 DOI: 10.3390/cancers13122916] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/29/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary MiRNAs are of great interest within colorectal cancers in diagnosis, prognosis, and within the field of personalized treatments; they are present within different biological fluids such as blood and can lead to specific information for daily clinical use. Herein, we review the current literature focusing on miRNAs as potential diagnostic and prognostic biomarkers in patients treated for colorectal cancers. Detection and analysis of miRNA expression are cost-effective and lead to high sensitivity and specificity rates. However, it is now necessary to highlight the most sensitive and specific miRNAs for each goal, either diagnostic, prognostic, or theranostic, thanks to multicentric prospective studies. Abstract MiRNAs have recently become a subject of great interest within cancers and especially colorectal cancers in diagnosis, prognosis, and therapy decisions; herein we review the current literature focusing on miRNAs in colorectal cancers, and we discuss future challenges to use this tool on a daily clinical basis. In liquid biopsies, miRNAs seem easily accessible and can give important information toward each step of the management of colorectal cancers. However, it is now necessary to highlight the most sensitive and specific miRNAs for each goal thanks to multicentric prospective studies. Conclusions: by their diversity and the feasibility of their use, miRNAs are getting part of the armamentarium of healthcare management of colorectal cancers.
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Souza MDA, Ramos-Sanchez EM, Muxel SM, Lagos D, Reis LC, Pereira VRA, Brito MEF, Zampieri RA, Kaye PM, Floeter-Winter LM, Goto H. miR-548d-3p Alters Parasite Growth and Inflammation in Leishmania (Viannia) braziliensis Infection. Front Cell Infect Microbiol 2021; 11:687647. [PMID: 34178725 PMCID: PMC8224172 DOI: 10.3389/fcimb.2021.687647] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/24/2021] [Indexed: 12/21/2022] Open
Abstract
American Tegumentary Leishmaniasis (ATL) is an endemic disease in Latin America, mainly caused in Brazil by Leishmania (Viannia) braziliensis. Clinical manifestations vary from mild, localized cutaneous leishmaniasis (CL) to aggressive mucosal disease. The host immune response strongly determines the outcome of infection and pattern of disease. However, the pathogenesis of ATL is not well understood, and host microRNAs (miRNAs) may have a role in this context. In the present study, miRNAs were quantified using qPCR arrays in human monocytic THP-1 cells infected in vitro with L. (V.) braziliensis promastigotes and in plasma from patients with ATL, focusing on inflammatory response-specific miRNAs. Patients with active or self-healed cutaneous leishmaniasis patients, with confirmed parasitological or immunological diagnosis, were compared with healthy controls. Computational target prediction of significantly-altered miRNAs from in vitro L. (V.) braziliensis-infected THP-1 cells revealed predicted targets involved in diverse pathways, including chemokine signaling, inflammatory, cellular proliferation, and tissue repair processes. In plasma, we observed distinct miRNA expression in patients with self-healed and active lesions compared with healthy controls. Some miRNAs dysregulated during THP-1 in vitro infection were also found in plasma from self-healed patients, including miR-548d-3p, which was upregulated in infected THP-1 cells and in plasma from self-healed patients. As miR-548d-3p was predicted to target the chemokine pathway and inflammation is a central to the pathogenesis of ATL, we evaluated the effect of transient transfection of a miR-548d-3p inhibitor on L. (V.) braziliensis infected-THP-1 cells. Inhibition of miR-548d-3p reduced parasite growth early after infection and increased production of MCP1/CCL2, RANTES/CCL5, and IP10/CXCL10. In plasma of self-healed patients, MCP1/CCL2, RANTES/CCL5, and IL-8/CXCL8 concentrations were significantly decreased and MIG/CXCL9 and IP-10/CXCL10 increased compared to patients with active disease. These data suggest that by modulating miRNAs, L. (V.) braziliensis may interfere with chemokine production and hence the inflammatory processes underpinning lesion resolution. Our data suggest miR-548d-3p could be further evaluated as a prognostic marker for ATL and/or as a host-directed therapeutic target.
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Affiliation(s)
- Marina de Assis Souza
- Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo (IMTSP/USP), São Paulo, Brazil
| | - Eduardo Milton Ramos-Sanchez
- Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo (IMTSP/USP), São Paulo, Brazil.,Departamento de Salud Publica, Facultad de Ciencias de La Salud, Universidad Nacional Toribio Rodriguez de Mendoza de Amazonas, Chachapoyas, Peru
| | | | - Dimitris Lagos
- York Biomedical Research Institute, Hull York Medical School, University of York, York, United Kingdom
| | - Luiza Campos Reis
- Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo (IMTSP/USP), São Paulo, Brazil
| | | | | | | | - Paul Martin Kaye
- York Biomedical Research Institute, Hull York Medical School, University of York, York, United Kingdom
| | | | - Hiro Goto
- Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo (IMTSP/USP), São Paulo, Brazil.,Departamento de Medicina Preventiva, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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Lin X, Lai X, Feng W, Yu X, Gu Q, Zheng X. MiR-30a sensitized lung cancer against neoadjuvant chemotherapy by depressing autophagy. Jpn J Clin Oncol 2021; 51:675-684. [PMID: 33537721 DOI: 10.1093/jjco/hyaa272] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 12/11/2020] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE This study was aimed at exploring whether miR-30a enhanced sensitivity of non-small-cell lung cancer (NSCLC) cells against neoadjuvant chemotherapy through an autophagy-dependent way. METHODS We totally recruited 304 NSCLC patients who have underwent chemotherapy, as well as 185 NSCLC patients who did not receive chemotherapy. NSCLC cell lines (i.e. H1299 and H460) were also purchased, and they were transfected by miR-30a mimic/inhibitor. Furthermore, cisplatin (DDP)/pemetrexed (PEM) resistance of NSCLC cells was assessed utilizing MTT assay, and autophagic proteins isolated from NSCLC tissues and cells were quantitated by western blotting. RESULTS Lowly expressed miR-30a was reflective of lymph node metastasis, advanced TNM stage and poor 5-year survival among NSCLC patients treated by neoadjuvant chemotherapy (i.e. combined treatment of DDP and PEM) (P < 0.05). Moreover, DDP combined with PEM attenuated viability and proliferation, but, on the contrary, promoted autophagy of H1299 and H460 cell lines (P < 0.05). However, miR-30a undermined resistance of NSCLC cells against DDP and PEM (P < 0.05), and it suppressed DDP/PEM-induced autophagy and promoted DDP/PEM-triggered apoptosis of NSCLC cells (P < 0.05). CONCLUSIONS Intentionally elevating miR-30a expression was conducive to improving NSCLC prognosis after neoadjuvant chemotherapy, for its depressing drug-caused autophagy and resistance.
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Affiliation(s)
| | | | | | | | | | - Xiao Zheng
- Department of Thoracic Radiotherapy, The Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou City, China
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Long non‑coding RNA‑DUXAP8 regulates TOP2A in the growth and metastasis of osteosarcoma via microRNA‑635. Mol Med Rep 2021; 24:511. [PMID: 33982765 PMCID: PMC8134877 DOI: 10.3892/mmr.2021.12150] [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: 11/21/2020] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
Osteosarcoma (OS) is a malignant disease with high morbidity and mortality rates in children and adolescents. Evidence has indicated that long non-coding RNAs (lncRNAs) may serve important roles in human cancer progression, including OS. In the present study, the role of lnc-double homeobox A pseudogene 8 (DUXAP8) in the development of OS was identified. The expression of lncRNA-DUXAP8 was determined by reverse transcription-quantitative polymerase chain reaction in OS tissues. Cell proliferation was evaluated using Cell Counting kit-8 and colony formation assays, and Transwell assays were conducted to measure cell invasion. Cell migration was evaluated using a wound healing assay. The binding site between lnc-DUXAP8 and miR-635 RNAs was investigated using a luciferase reporter assay. The expression of lnc-DUXAP8 was significantly upregulated in OS samples and OS cell lines compared with normal tissues. High expression of lncRNA DUXAP8 was associated with shorter overall survival times. Knockdown of lncRNA DUXAP8 inhibited proliferation, migration and invasion in OS cells. Notably, mechanistic investigation revealed that lncRNA DUXAP8 predominantly acted as a competing endogenous RNA in OS by regulating the miR-635/topoisomerase alpha 2 (TOP2A) axis. lncRNA DUXAP8 is upregulated in OS, and lncRNA DUXAP8-knockdown serves a vital antitumor role in OS cell progression through the miR-635/TOP2A axis. The results of the present study suggested that lncRNA DUXAP8 may be a novel, promising biomarker for the diagnosis and prognosis of OS.
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Fiala O, Sorejs O, Hosek P, Liska V, Vycital O, Bruha J, Kucera R, Topolcan O, Finek J, Maceckova D, Pitule P. Association of miR-125b, miR-17 and let-7c Dysregulations With Response to Anti-epidermal Growth Factor Receptor Monoclonal Antibodies in Patients With Metastatic Colorectal Cancer. Cancer Genomics Proteomics 2021; 17:605-613. [PMID: 32859639 DOI: 10.21873/cgp.20217] [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: 05/31/2020] [Revised: 06/21/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIM MicroRNAs (miRs) play an important role in the regulation of cancer-related processes and are promising candidates for cancer biomarkers. The aim of the study was to evaluate the association of response to anti-EGFR monoclonal antibodies (mAbs) with selected miR expression profiles, including miR-125b, let-7c, miR-99a, miR-17, miR-143 and miR-145 in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS This retrospective study included 46 patients with mCRC harbouring wild-type RAS gene treated with cetuximab or panitumumab combined with chemotherapy in first- or second-line therapy. The miR expression was assessed using qRT-PCR. RESULTS Down-regulation of miR-125b and let-7c and up-regulation of miR-17 were found in the tumour tissue (p=0.0226, p=0.0040, p<0.0001). Objective response rate (ORR) was associated with up-regulation of miR-125b (p=0.0005). Disease control rate (DCR) was associated with up-regulation of miR-125b and let-7c (p=0.0383 and p=0.0255) and down-regulation of miR-17 (p=0.0464). MiR-125b showed correlation with progression-free and overall survival (p=0.055 and p=0.006). CONCLUSION The results show that up-regulation of miR-125b is associated with higher ORR and DCR and longer survival; let-7c up-regulation and miR-17 down-regulation are associated with higher DCR in mCRC patients treated with anti-EGFR mAbs.
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Affiliation(s)
- Ondrej Fiala
- Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic .,Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ondrej Sorejs
- Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic.,Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Petr Hosek
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Vaclav Liska
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.,Department of Surgery, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ondrej Vycital
- Department of Surgery, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Jan Bruha
- Department of Surgery, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Radek Kucera
- Department of Immunochemistry Diagnostics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ondrej Topolcan
- Department of Immunochemistry Diagnostics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Jindrich Finek
- Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
| | - Diana Maceckova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Pavel Pitule
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
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Xie X, Pang M, Liang S, Lin Y, Zhao Y, Qiu D, Liu J, Dong Y, Liu Y. Cellular microRNAs influence replication of H3N2 canine influenza virus in infected cells. Vet Microbiol 2021; 257:109083. [PMID: 33894663 DOI: 10.1016/j.vetmic.2021.109083] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 04/18/2021] [Indexed: 12/17/2022]
Abstract
MicroRNAs (miRNAs) are known to play important regulatory roles in host-virus interactions. Avian-origin H3N2 canine influenza virus (CIV) has emerged as the most prevalent subtype among dogs in Asia since 2007. To evaluate the roles of host miRNAs in H3N2 CIV infection, here, miRNA profiles obtained from primary canine bronchiolar epithelial cells (CBECs) and canine alveolar macrophages (CAMCs) were compared between infected and mock-infected cells with the H3N2 CIV JS/10. It was found that the expressions of cfa-miR-125b and cfa-miR-151, which have been reported to be associated with innate immunity and inflammatory response, were significantly decreased in CIV-infected canine primary cells. Bioinformatics prediction indicated that 5' seed regions of the two miRNAs are partially complementary to the mRNAs of nucleoprotein (NP) and non-structural protein 1 (NS1) of JS/10. As determined by virus titration, quantitative real-time PCR (qRT-PCR) and western blotting, overexpression of the two miRNAs inhibited CIV replication in cell culture, while their inhibition facilitated this replication, suggesting that the two miRNAs could act as negative regulators of CIV replication. Our findings support the notion that some cellular miRNAs can influence the outcome of virus infection, which helps to elucidate the resistance of host cells to viral infection and to clarify the pathogenesis of H3N2 CIV.
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Affiliation(s)
- Xing Xie
- Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China; Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, 210014, China
| | - Maoda Pang
- Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China; Institute of Food Safety and Nutrition, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, China
| | - Shan Liang
- Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yan Lin
- Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yanbing Zhao
- Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Dong Qiu
- Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China; Jiangsu Provincial Animal Disease Control Center, Nanjing, 210036, China
| | - Jin Liu
- Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yuhao Dong
- Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yongjie Liu
- Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China.
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Khoei SG, Sadeghi H, Samadi P, Najafi R, Saidijam M. Relationship between Sphk1/S1P and microRNAs in human cancers. Biotechnol Appl Biochem 2021; 68:279-287. [PMID: 32275078 DOI: 10.1002/bab.1922] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 04/04/2020] [Indexed: 12/12/2022]
Abstract
Sphingosine kinases type 1 (SphK1) is a key enzyme in the phosphorylation of sphingosine to sphingosine 1-phosphate (S1P). Different abnormalities in SphK1 functions may correspond with poor prognosis in various cancers. Additionally, upregulated SphK1/S1P could promote cancer cell proliferation, angiogenesis, mobility, invasion, and metastasis. MicroRNAs as conserved small noncoding RNAs play major roles in cancer initiation, progression, metastasis, etc. Their posttranscriptionally mechanisms could affect the development of cancer growth or tumorigenesis suppression. The growing number of studies has described that various microRNAs can be regulated by SphK1, and its expression level can also be regulated by microRNAs. In this review, the relationship of SphK1 and microRNA functions and their interaction in human malignancies have been discussed. Based on them novel treatment strategies can be introduced.
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Affiliation(s)
- Saeideh Gholamzadeh Khoei
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hamid Sadeghi
- Department of Microbiology and Virology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Pouria Samadi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rezvan Najafi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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Zarrilli G, Galuppini F, Angerilli V, Munari G, Sabbadin M, Lazzarin V, Nicolè L, Biancotti R, Fassan M. miRNAs Involved in Esophageal Carcinogenesis and miRNA-Related Therapeutic Perspectives in Esophageal Carcinoma. Int J Mol Sci 2021; 22:3640. [PMID: 33807389 PMCID: PMC8037581 DOI: 10.3390/ijms22073640] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play a pivotal role in many aspects of cell biology, including cancer development. Within esophageal cancer, miRNAs have been proved to be involved in all phases of carcinogenesis, from initiation to metastatic spread. Several miRNAs have been found to be dysregulated in esophageal premalignant lesions, namely Barrett's esophagus, Barrett's dysplasia, and squamous dysplasia. Furthermore, numerous studies have investigated the alteration in the expression levels of many oncomiRNAs and tumor suppressor miRNAs in esophageal squamous cell carcinoma and esophageal adenocarcinoma, thus proving how miRNAs are able modulate crucial regulatory pathways of cancer development. Considering these findings, miRNAs may have a role not only as a diagnostic and prognostic tool, but also as predictive biomarker of response to anti-cancer therapies and as potential therapeutic targets. This review aims to summarize several studies on the matter, focusing on the possible diagnostic-therapeutic implications.
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Affiliation(s)
- Giovanni Zarrilli
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.Z.); (F.G.); (V.A.); (M.S.); (V.L.); (L.N.); (R.B.)
| | - Francesca Galuppini
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.Z.); (F.G.); (V.A.); (M.S.); (V.L.); (L.N.); (R.B.)
| | - Valentina Angerilli
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.Z.); (F.G.); (V.A.); (M.S.); (V.L.); (L.N.); (R.B.)
| | - Giada Munari
- Veneto Institute of Oncology-IOV-IRCCS, 35128 Padua, Italy;
| | - Marianna Sabbadin
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.Z.); (F.G.); (V.A.); (M.S.); (V.L.); (L.N.); (R.B.)
| | - Vanni Lazzarin
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.Z.); (F.G.); (V.A.); (M.S.); (V.L.); (L.N.); (R.B.)
| | - Lorenzo Nicolè
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.Z.); (F.G.); (V.A.); (M.S.); (V.L.); (L.N.); (R.B.)
| | - Rachele Biancotti
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.Z.); (F.G.); (V.A.); (M.S.); (V.L.); (L.N.); (R.B.)
| | - Matteo Fassan
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.Z.); (F.G.); (V.A.); (M.S.); (V.L.); (L.N.); (R.B.)
- Veneto Institute of Oncology-IOV-IRCCS, 35128 Padua, Italy;
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Stevens MT, Saunders BM. Targets and regulation of microRNA-652-3p in homoeostasis and disease. J Mol Med (Berl) 2021; 99:755-769. [PMID: 33712860 DOI: 10.1007/s00109-021-02060-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/23/2021] [Accepted: 03/01/2021] [Indexed: 12/14/2022]
Abstract
microRNA are small non-coding RNA molecules which inhibit gene expression by binding mRNA, preventing its translation. As important regulators of gene expression, there is increasing interest in microRNAs as potential diagnostic biomarkers and therapeutic targets. Studies investigating the role of one of the miRNA-miR-652-3p-detail diverse roles for this miRNA in normal cell homoeostasis and disease states, including cancers, cardiovascular disease, mental health, and central nervous system diseases. Here, we review recent literature surrounding miR-652-3p, discussing its known target genes and their relevance to disease progression. These studies demonstrate that miR-652-3p targets LLGL1 and ZEB1 to modulate cell polarity mechanisms, with impacts on cancer metastasis and asymmetric cell division. Inhibition of the NOTCH ligand JAG1 by miR-652-3p can have diverse effects on angiogenesis and immune cell regulation. Investigation of miR-652-3p and other dysregulated miRNAs identified a number of pathways potentially regulated by miR-652-3p. This review demonstrates that miR-652-3p has great promise as a diagnostic or therapeutic target due to its activity across multiple cellular systems.
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Affiliation(s)
- Maxwell T Stevens
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
| | - Bernadette M Saunders
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.
- Centenary Institute, The University of Sydney, Sydney, NSW, Australia.
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Xu P, Jia S, Wang K, Fan Z, Zheng H, Lv J, Jiang Y, Hou Y, Lou B, Zhou H, Zhang Y, Guo K. MiR-140 inhibits classical swine fever virus replication by targeting Rab25 in swine umbilical vein endothelial cells. Virulence 2021; 11:260-269. [PMID: 32114898 PMCID: PMC7051144 DOI: 10.1080/21505594.2020.1735051] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Classical swine fever virus (CSFV) is one of the most important viral pathogens leading worldwide threats to pig industry. MicroRNAs (miRNAs) play important roles in regulating virus replication, but whether miRNAs affect CSFV infection is still poorly understood. In previous study, we identified four miRNAs that were down-regulated by CSFV in swine umbilical vein endothelial cells (SUVEC). In this study, miR-140, one of the most potently down-regulated genes was investigated. We found that the miRNA expression was significantly inhibited by CSFV infection. Subsequent studies revealed that miR-140 mimics significantly inhibited CSFV replication, while the inhibition of endogenous miR-140 enhanced CSFV replication. By using bioinformatics prediction, luciferase reporter system, real-time fluorescence quantitative PCR (RT-qPCR) and Western blot assays, we further demonstrated that miR-140 bind to the 3' UTR of Rab25 mRNA to regulate its expression. We also analyzed the expression pattern of Rab25 in SUVECs after CSFV infection. The results showed that CSFV infection induced Rab25 expression. Finally, Rab25 was found to promote CSFV replication. In conclusion, this study demonstrated that CSFV inhibits miR-140 expression and miR-140 inhibits replication by binding to host factor Rab25.
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Affiliation(s)
- Panpan Xu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi China
| | - Shuangkai Jia
- Medical College of QingHai University, Xining, Qinghai, China
| | - Kai Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi China
| | - Zhixin Fan
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi China
| | - Hongqing Zheng
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi China
| | - Jiangman Lv
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi China
| | - Yanfen Jiang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi China
| | - Yufeng Hou
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi China
| | - Bihao Lou
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi China
| | - Hongchao Zhou
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi China
| | - Yanming Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi China
| | - Kangkang Guo
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi China
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Li D, Liu Z, Ning G. [Expression of CDC25A in non-small cell lung cancer and its relationship with let-7 gene]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:1622-1627. [PMID: 33243735 DOI: 10.12122/j.issn.1673-4254.2020.11.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To investigate the expression of CDC25A in non- small cell lung cancer (NSCLC) tissues and explore its correlation with the clinicpathological features of the patients and the expressions of let-7a1 and let-7c. METHODS We collected surgical specimens of pathologically confirmed NSCLC tissues and paired adjacent lung tissues from 44 patients and tissues of benign lung lesions from 9 patients. The expressions of CDC25A protein and mRNA in the tissues were detected by immunohistochemistry and fluorescence quantitative RT-PCR, respectively; the expressions of let-7a1 and let-7c mRNA were detected using tail-adding fluorescence quantitative RT-PCR. RESULTS The positivity rate of CDC25A protein expression was significantly higher in NSCLC tissues than in the adjacent tissues and benign pulmonary lesions (P < 0.05). CDC25A protein expression in NSCLC was not correlated with the patients' age, gender, pathological type, degree of tumor differentiation, or clinical stages (P > 0.05), and was significantly correlated with smoking and lymph node metastasis (P < 0.05). CDC25A mRNA expression was also significantly higher in NSCLC tissues than in the adjacent tissues and benign pulmonary lesions (F=6.33, P < 0.05), and was similar between the latter two tissues (P > 0.05). Pearson correlation analysis showed that CDC25A expression had a significant negative correlation with let-7c expression in both NSCLC tissues (r=-0.42) and adjacent lung tissues (r=-0.40) but was not correlated with let-7a1 expression. CONCLUSIONS The expression level of CDC25A is significantly increased in NSCLC with a negative correlation with Let-7c expression, which identifies CDC25A as a possible downstream target gene of Let-7c.
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Affiliation(s)
- Dianming Li
- Department of Respiratory and Critical Medicine, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China
| | - Zhaofei Liu
- Department of Respiratory Medicine, Linquan County People's Hospital, Linquan 236400, China
| | - Guolan Ning
- Department of Respiratory and Critical Care Medicine, Fuyang Second People's Hospital, Fuyang 236000, China
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Arora A, Olshen AB, Seshan VE, Shen R. Pan-cancer identification of clinically relevant genomic subtypes using outcome-weighted integrative clustering. Genome Med 2020; 12:110. [PMID: 33272320 PMCID: PMC7716509 DOI: 10.1186/s13073-020-00804-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 11/10/2020] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Comprehensive molecular profiling has revealed somatic variations in cancer at genomic, epigenomic, transcriptomic, and proteomic levels. The accumulating data has shown clearly that molecular phenotypes of cancer are complex and influenced by a multitude of factors. Conventional unsupervised clustering applied to a large patient population is inevitably driven by the dominant variation from major factors such as cell-of-origin or histology. Translation of these data into clinical relevance requires more effective extraction of information directly associated with patient outcome. METHODS Drawing from ideas in supervised text classification, we developed survClust, an outcome-weighted clustering algorithm for integrative molecular stratification focusing on patient survival. survClust was performed on 18 cancer types across multiple data modalities including somatic mutation, DNA copy number, DNA methylation, and mRNA, miRNA, and protein expression from the Cancer Genome Atlas study to identify novel prognostic subtypes. RESULTS Our analysis identified the prognostic role of high tumor mutation burden with concurrently high CD8 T cell immune marker expression and the aggressive clinical behavior associated with CDKN2A deletion across cancer types. Visualization of somatic alterations, at a genome-wide scale (total mutation burden, mutational signature, fraction genome altered) and at the individual gene level, using circomap further revealed indolent versus aggressive subgroups in a pan-cancer setting. CONCLUSIONS Our analysis has revealed prognostic molecular subtypes not previously identified by unsupervised clustering. The algorithm and tools we developed have direct utility toward patient stratification based on tumor genomics to inform clinical decision-making. The survClust software tool is available at https://github.com/arorarshi/survClust .
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Affiliation(s)
- Arshi Arora
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Adam B Olshen
- Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA
| | - Venkatraman E Seshan
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ronglai Shen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Marzano F, Caratozzolo MF, Consiglio A, Licciulli F, Liuni S, Sbisà E, D'Elia D, Tullo A, Catalano D. Plant miRNAs Reduce Cancer Cell Proliferation by Targeting MALAT1 and NEAT1: A Beneficial Cross-Kingdom Interaction. Front Genet 2020; 11:552490. [PMID: 33193626 PMCID: PMC7531330 DOI: 10.3389/fgene.2020.552490] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 08/20/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are ubiquitous regulators of gene expression, evolutionarily conserved in plants and mammals. In recent years, although a growing number of papers debate the role of plant miRNAs on human gene expression, the molecular mechanisms through which this effect is achieved are still not completely elucidated. Some evidence suggest that this interaction might be sequence specific, and in this work, we investigated this possibility by transcriptomic and bioinformatics approaches. Plant and human miRNA sequences from primary databases were collected and compared for their similarities (global or local alignments). Out of 2,588 human miRNAs, 1,606 showed a perfect match of their seed sequence with the 5′ end of 3,172 plant miRNAs. Further selections were applied based on the role of the human target genes or of the miRNA in cell cycle regulation (as an oncogene, tumor suppressor, or a biomarker for prognosis, or diagnosis in cancer). Based on these criteria, 20 human miRNAs were selected as potential functional analogous of 7 plant miRNAs, which were in turn transfected in different cell lines to evaluate their effect on cell proliferation. A significant decrease was observed in colorectal carcinoma HCT116 cell line. RNA-Seq demonstrated that 446 genes were differentially expressed 72 h after transfection. Noteworthy, we demonstrated that the plant mtr-miR-5754 and gma-miR4995 directly target the tumor-associated long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and nuclear paraspeckle assembly transcript 1 (NEAT1) in a sequence-specific manner. In conclusion, according to other recent discoveries, our study strengthens and expands the hypothesis that plant miRNAs can have a regulatory effect in mammals by targeting both protein-coding and non-coding RNA, thus suggesting new biotechnological applications.
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Affiliation(s)
- Flaviana Marzano
- Department of Biomedical Sciences, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Bari, Italy
| | - Mariano Francesco Caratozzolo
- Department of Biomedical Sciences, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Bari, Italy
| | - Arianna Consiglio
- Department of Biomedical Sciences, Institute for Biomedical Technologies, Bari, Italy
| | - Flavio Licciulli
- Department of Biomedical Sciences, Institute for Biomedical Technologies, Bari, Italy
| | - Sabino Liuni
- Department of Biomedical Sciences, Institute for Biomedical Technologies, Bari, Italy
| | - Elisabetta Sbisà
- Department of Biomedical Sciences, Institute for Biomedical Technologies, Bari, Italy
| | - Domenica D'Elia
- Department of Biomedical Sciences, Institute for Biomedical Technologies, Bari, Italy
| | - Apollonia Tullo
- Department of Biomedical Sciences, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Bari, Italy
| | - Domenico Catalano
- Department of Biomedical Sciences, Institute for Biomedical Technologies, Bari, Italy
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Zhang X, Chen Y, Yang M, Shang J, Xu Y, Zhang L, Wu X, Ding Y, Liu Y, Chu M, Yin Z. MiR-21-5p actions at the Smad7 gene during pig ovarian granulosa cell apoptosis. Anim Reprod Sci 2020; 223:106645. [PMID: 33217624 DOI: 10.1016/j.anireprosci.2020.106645] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 12/26/2022]
Abstract
MicroRNAs (miRNAs) are endogenous non-coding RNAs in eukaryotic cells that modulate apoptosis of ovarian granulosa cells (GCs), which is an important cause of mammalian follicular atresia. In the present study, associations were evaluated between miR-21-5p and the extent of Smad7 protein production in regulation of ovarian granulosa cell (pGC) apoptosis. There was detection of miR-21-5p and Smad7 primarily in the cytoplasm and nucleus of pGCs, respectively. When there was an enhanced abundance of miR-21-5p and decreased abundance of Smad7 there were similar effects in pGCs, including inducing proliferation, inhibiting apoptosis, increasing the number of cells in S and G2/M phases, increasing serum estradiol, and decreasing serum progesterone concentrations. Furthermore, the Smad7 mRNA transcript was identified as a target for miR-21-5p actions, with enhanced abundances of miR-21-5p being associated with a lesser abundance of Smad7 mRNA transcript and protein in pGCs. Overall, results from the present study indicate that miR-21-5p has actions on the Smad7 mRNA transcript during the process of ovarian granulosa cell apoptosis in pigs.
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Affiliation(s)
- Xiaodong Zhang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China; Key Laboratory of Local Animal Genetic Resources Conservation and Bio-Breeding of Anhui Province, Hefei, 230036, PR China
| | - Yige Chen
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China; Key Laboratory of Local Animal Genetic Resources Conservation and Bio-Breeding of Anhui Province, Hefei, 230036, PR China
| | - Min Yang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China; Key Laboratory of Local Animal Genetic Resources Conservation and Bio-Breeding of Anhui Province, Hefei, 230036, PR China
| | - Jinnan Shang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China; Key Laboratory of Local Animal Genetic Resources Conservation and Bio-Breeding of Anhui Province, Hefei, 230036, PR China
| | - Yiliang Xu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China; Key Laboratory of Local Animal Genetic Resources Conservation and Bio-Breeding of Anhui Province, Hefei, 230036, PR China
| | - Liang Zhang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China; Key Laboratory of Local Animal Genetic Resources Conservation and Bio-Breeding of Anhui Province, Hefei, 230036, PR China
| | - Xudong Wu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China; Key Laboratory of Local Animal Genetic Resources Conservation and Bio-Breeding of Anhui Province, Hefei, 230036, PR China
| | - Yueyun Ding
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China; Key Laboratory of Local Animal Genetic Resources Conservation and Bio-Breeding of Anhui Province, Hefei, 230036, PR China
| | - Yuanyuan Liu
- The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, PR China
| | - Mingxing Chu
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, PR China
| | - Zongjun Yin
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China; Key Laboratory of Local Animal Genetic Resources Conservation and Bio-Breeding of Anhui Province, Hefei, 230036, PR China.
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Wang H, Radomska HS, Phelps MA. Replication Study: Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. eLife 2020; 9:56651. [PMID: 33073769 DOI: 10.7554/elife.56651] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 09/18/2020] [Indexed: 12/19/2022] Open
Abstract
As part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Phelps et al., 2016) that described how we intended to replicate selected experiments from the paper 'Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs' (Tay et al., 2011). Here, we report the results. We found depletion of putative PTEN competing endogenous mRNAs (ceRNAs) in DU145 cells did not impact PTEN 3'UTR regulation using a reporter, while the original study reported decreased activity when SERINC1, VAPA, and CNOT6L were depleted (Figure 3C; Tay et al., 2011). Using the same reporter, we found decreased activity when ceRNA 3'UTRs were overexpressed, while the original study reported increased activity (Figure 3D; Tay et al., 2011). In HCT116 cells, ceRNA depletion resulted in decreased PTEN protein levels, a result similar to the findings reported in the original study (Figure 3G,H; Tay et al., 2011); however, while the original study reported an attenuated ceRNA effect in microRNA deficient (DicerEx5) HCT116 cells, we observed increased PTEN protein levels. Further, we found depletion of the ceRNAs VAPA or CNOT6L did not statistically impact DU145, wild-type HCT116, or DicerEx5 HCT116 cell proliferation. The original study reported increased DU145 and wild-type HCT116 cell proliferation when these ceRNAs were depleted, which was attenuated in the DicerEx5 HCT116 cells (Figure 5B; Tay et al., 2011). Differences between the original study and this replication attempt, such as variance between biological repeats, are factors that might have influenced the results. Finally, we report meta-analyses for each result.
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Affiliation(s)
- Hongyan Wang
- Pharmacoanalytic Shared Resource (PhASR), Comprehensive Cancer Center, The Ohio State University, Columbus, United States
| | - Hanna S Radomska
- Pharmacoanalytic Shared Resource (PhASR), Comprehensive Cancer Center, The Ohio State University, Columbus, United States
| | - Mitch A Phelps
- Pharmacoanalytic Shared Resource (PhASR), Comprehensive Cancer Center, The Ohio State University, Columbus, United States
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- Science Exchange, Palo Alto, United States.,Center for Open Science, Charlottesville, United States
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Dai Y, Chen Z, Zhao W, Cai G, Wang Z, Wang X, Hu H, Zhang Y. miR-29a-5p Regulates the Proliferation, Invasion, and Migration of Gliomas by Targeting DHRS4. Front Oncol 2020; 10:1772. [PMID: 33014873 PMCID: PMC7511594 DOI: 10.3389/fonc.2020.01772] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/07/2020] [Indexed: 02/06/2023] Open
Abstract
Gliomas are the most common malignant primary brain tumors in adults and exhibit a spectrum of aberrantly aggressive phenotypes. MicroRNAs (miRNAs) play a regulatory role in various cancers, including gliomas; however, their specific roles and mechanisms have not been fully investigated. Studies have indicated that miR-29a is a tumor-suppressive miRNA, but the data are limited. In this study, we investigated the role of miR-29a-5p in glioma and further explored its underlying mechanisms. On the basis of bioinformatics, dehydrogenase/reductase 4 (DHRS4) was considered a potential target of miR-29a-5p and was also found to be highly expressed in gliomas in our experiments. Moreover, with a luciferase reporter assay, DHRS4 was found to be a target gene of miR-29a-5p and to be correlated with glioma proliferation, invasion, and migration in our in vivo and in vitro experiments. Simultaneously, we observed that the knockdown of DHRS4 rescued the downregulation of glioma proliferation, invasion, and migration caused by treatment with a mir-29a-5p inhibitor. The present findings demonstrate that miR-29a-5p suppresses cell proliferation, invasion, and migration by targeting DHRS4, and DHRS4 may be a potential new oncogene and prognostic factor in gliomas.
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Affiliation(s)
- Yong Dai
- Department of Neurosurgery, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Zhenhua Chen
- Department of Neurosurgery, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Wei Zhao
- Department of Neurosurgery, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Gang Cai
- Department of Neurosurgery, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Zhifeng Wang
- Department of Neurosurgery, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Xuejiang Wang
- Department of Neurosurgery, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Hongkang Hu
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yi Zhang
- Department of Neurosurgery, Second Affiliated Hospital of Nantong University, Nantong, China
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Wang D, Wang T, Gill A, Hilliard T, Chen F, Karamyshev AL, Zhang F. Uncovering the cellular capacity for intensive and specific feedback self-control of the argonautes and MicroRNA targeting activity. Nucleic Acids Res 2020; 48:4681-4697. [PMID: 32297952 PMCID: PMC7229836 DOI: 10.1093/nar/gkaa209] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 03/13/2020] [Accepted: 03/24/2020] [Indexed: 11/13/2022] Open
Abstract
The miRNA pathway has three segments—biogenesis, targeting and downstream regulatory effectors. We aimed to better understand their cellular control by exploring the miRNA-mRNA-targeting relationships. We first used human evolutionarily conserved sites. Strikingly, AGOs 1–3 are all among the top 14 mRNAs with the highest miRNA site counts, along with ANKRD52, the phosphatase regulatory subunit of the recently identified AGO phosphorylation cycle; and the AGO phosphorylation cycle mRNAs share much more than expected miRNA sites. The mRNAs for TNRC6, which acts with AGOs to channel miRNA-mediated regulatory actions onto specific mRNAs, are also heavily miRNA-targeted. In contrast, upstream miRNA biogenesis mRNAs are not, and neither are downstream regulatory effectors. In short, binding site enrichment in miRNA targeting machinery mRNAs, but neither upstream biogenesis nor downstream effector mRNAs, was observed, endowing a cellular capacity for intensive and specific feedback control of the targeting activity. The pattern was confirmed with experimentally determined miRNA-mRNA target relationships. Moreover, genetic experiments demonstrated cellular utilization of this capacity. Thus, we uncovered a capacity for intensive, and specific, feedback-regulation of miRNA targeting activity directly by miRNAs themselves, i.e. segment-specific feedback auto-regulation of miRNA pathway, complementing miRNAs pairing with transcription factors to form hybrid feedback-loop.
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Affiliation(s)
- Degeng Wang
- Department of Environmental Toxicology, Lubbock, TX 79409, USA.,The Institute of Environmental and Human Health (TIEHH), Lubbock, TX 79409, USA
| | - Tingzeng Wang
- Department of Environmental Toxicology, Lubbock, TX 79409, USA.,The Institute of Environmental and Human Health (TIEHH), Lubbock, TX 79409, USA
| | - Audrey Gill
- Department of Mathematics and Statistics, Texas Tech University, Lubbock, TX 79409, USA
| | - Terrell Hilliard
- Department of Environmental Toxicology, Lubbock, TX 79409, USA.,The Institute of Environmental and Human Health (TIEHH), Lubbock, TX 79409, USA
| | - Fengqian Chen
- Department of Environmental Toxicology, Lubbock, TX 79409, USA.,The Institute of Environmental and Human Health (TIEHH), Lubbock, TX 79409, USA
| | - Andrey L Karamyshev
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock TX 79430, USA
| | - Fangyuan Zhang
- Department of Mathematics and Statistics, Texas Tech University, Lubbock, TX 79409, USA
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