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Nor WMFSBWM, Kwong SC, Fuzi AAM, Said NABM, Jamil AHA, Lee YY, Lee SC, Lim YAL, Chung I. Linking microRNA to metabolic reprogramming and gut microbiota in the pathogenesis of colorectal cancer (Review). Int J Mol Med 2025; 55:46. [PMID: 39820715 PMCID: PMC11759585 DOI: 10.3892/ijmm.2025.5487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 12/03/2024] [Indexed: 01/19/2025] Open
Abstract
Colorectal cancer (CRC), an emerging public health concern, is one of the leading causes of cancer morbidity and mortality worldwide. An increasing body of evidence shows that dysfunction in metabolic reprogramming is a crucial characteristic of CRC progression. Specifically, metabolic reprogramming abnormalities in glucose, glutamine and lipid metabolism provide the tumour with energy and nutrients to support its rapid cell proliferation and survival. More recently, microRNAs (miRNAs) appear to be involved in the pathogenesis of CRC, including regulatory roles in energy metabolism. In addition, it has been revealed that dysbiosis in CRC might play a key role in impairing the host metabolic reprogramming processes, and while the exact interactions remain unclear, the link may lie with miRNAs. Hence, the aims of the current review include first, to delineate the metabolic reprogramming abnormalities in CRC; second, to explain how miRNAs mediate the aberrant regulations of CRC metabolic pathways; third, linking miRNAs with metabolic abnormalities and dysbiosis in CRC and finally, to discuss the roles of miRNAs as potential biomarkers.
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Affiliation(s)
| | - Soke Chee Kwong
- Centre for Population Health (CePH), Department of Social and Preventive Medicine, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Afiqah Alyaa Md Fuzi
- Office of Deputy Vice Chancellor (Research and Innovation), Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Nur Akmarina Binti Mohd Said
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Amira Hajirah Abd Jamil
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains Malaysia, 16150 Kota Bharu, Malaysia
| | - Soo Ching Lee
- Department of Parasitology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Yvonne Ai-Lian Lim
- Department of Parasitology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Ivy Chung
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
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2
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Kuwabara S, Mizoguchi T, Ma J, Kanoh T, Ohta Y, Itoh M. Notch signaling pathway suppresses mRNA expression of hexokinase 2 under nutrient-poor conditions in U87-MG glioma cells. Genes Cells 2024. [PMID: 39462157 DOI: 10.1111/gtc.13176] [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: 05/15/2024] [Revised: 10/16/2024] [Accepted: 10/18/2024] [Indexed: 10/29/2024]
Abstract
Control of nutrient homeostasis plays a central role in cell proliferation/survival during embryonic development and tumor growth. Activation of the Notch signaling pathway, a major contributor to cell-cell interactions, is a potential mechanism for cell adaptation to nutrient-poor conditions. Our previous study also demonstrated that during embryogenesis when nutrients such as glutamine and growth factors are potentially maintained at lower levels, Notch signaling suppresses mRNA expression of hexokinase 2 (hk2), which is a glycolysis-associated gene, in the central nervous system. However, whether and how the genetic regulation of HK2 via Notch signaling contributes to cellular adaptability to nutrient-poor environments remains unknown. In this study, we performed gene expression analysis using a U87-MG human glioma cell line and revealed that under conditions where both glutamine and serum were absent, Notch signaling was activated and HK2 expression was downregulated by Notch signaling. We also found that Notch-mediated HK2 suppression was triggered in a Notch ligand-selective manner. Furthermore, HK2 was shown to inhibit cell proliferation of U87-MG gliomas, which might depend on Notch signaling activity. Together, our findings suggest the involvement of Notch-mediated HK2 suppression in an adaptive mechanism of U87-MG glioma cells to nutrient-poor conditions.
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Affiliation(s)
- Shuhei Kuwabara
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Takamasa Mizoguchi
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Jiawei Ma
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Tohgo Kanoh
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Yuki Ohta
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Motoyuki Itoh
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
- Research Institute of Disaster Medicine, Chiba University, Chiba, Japan
- Health and Disease Omics Center, Chiba University, Chiba, Japan
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3
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Ma RJ, Zhang M, Wu JS, Wang ZP, Wang GL, He N, Luo MJ, Tan JH. Role of miRNAs in glucose metabolism of mouse cumulus cells†. Biol Reprod 2024; 110:895-907. [PMID: 38267362 DOI: 10.1093/biolre/ioae013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 12/26/2023] [Accepted: 01/10/2024] [Indexed: 01/26/2024] Open
Abstract
It is known that the oocyte has a limited capacity to acquire and metabolize glucose, and it must rely on cumulus cells (CCs) to take up glucose and produce pyruvate for use to produce ATP through oxidative phosphorylation. We therefore propose that miRNAs might regulate glucose metabolism (GM) in CCs and might be used as markers for oocyte quality assessment. Here, mouse CC models with impaired glycolysis or pentose phosphate pathway (PPP) were established, and miRNAs targeting the key enzymes in glycolysis/PPP were predicted using the miRNA target prediction databases. Expression of the predicted miRNAs was compared between CCs with normal and impaired glycolysis/PPP to identify candidate miRNAs. Function of the candidate miRNAs was validated by transfecting CCs or cumulus-oocyte-complexes (COCs) with miRNA inhibitors and observing effects on glucose metabolites of CCs and on competence of oocytes. The results validated that miR-23b-3p, let-7b-5p, 34b-5p and 145a-5p inhibited glycolysis, and miR-24-3p, 3078-3p,183-5p and 7001-5p inhibited PPP of CCs. Our observation using a more physiologically relevant model (intact cultured COCs) further validated the four glycolysis-targeting miRNAs we identified. Furthermore, miR-let-7b-5p, 34b-5p and 145a-5p may also inhibit PPP, as they decreased the production of glucose-6-phosphate. In conclusion, miRNAs play critical roles in GM of CCs and may be used as markers for oocyte quality assessment. Summary sentence: We identified and validated eight new miRNAs that inhibit glycolysis and/or pentose phosphate pathways in cumulus cells (CCs) suggesting that miRNAs play critical roles in glucose metabolism of CCs and may be used for oocyte quality markers.
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Affiliation(s)
- Rui-Jie Ma
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Min Zhang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Jia-Shun Wu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Zhi-Peng Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Guo-Liang Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Nan He
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Ming-Jiu Luo
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
| | - Jing-He Tan
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City 271018, P. R. China
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4
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Xiong B, Huang Q, Zheng H, Lin S, Xu J. Recent advances microRNAs and metabolic reprogramming in colorectal cancer research. Front Oncol 2023; 13:1165862. [PMID: 37576895 PMCID: PMC10415904 DOI: 10.3389/fonc.2023.1165862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/07/2023] [Indexed: 08/15/2023] Open
Abstract
Colorectal cancer (CRC) is a cancer with the highest incidence and mortality. Alteration of gene expression is the main pathophysiological mechanism of CRC, which results in disturbed signaling pathways and cellular metabolic processes. MicroRNAs are involved in almost all pathophysiological processes and are correlative with colorectal cancer metabolism, proliferation, and chemotherapy resistance. Metabolic reprogramming, an important feature of cancer, is strongly correlative with the development and prognosis of cancers, including colorectal cancer. MicroRNAs can target enzymes involved in metabolic processes, thus playing a regulatory role in tumor metabolism. The disorder of the signaling pathway is another characteristic of tumor, which induces the occurrence and proliferation of tumors, and is closely correlative with the prognosis and chemotherapy resistance of tumor patients. MicroRNAs can target the components of the signaling pathways to regulate their transduction. Understanding the function of microRNAs in the occurrence and proliferation of CRC provides novel insights into the optimal treatment strategies, prognosis, and development of diagnosis in CRC. This article reviews the relationship between CRC and microRNA expression and hopes to provide new options for the diagnosis and treatment of CRC.
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Affiliation(s)
- Bin Xiong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Qiaoyi Huang
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Huida Zheng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Jianhua Xu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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Safi A, Saberiyan M, Sanaei MJ, Adelian S, Davarani Asl F, Zeinaly M, Shamsi M, Ahmadi R. The role of noncoding RNAs in metabolic reprogramming of cancer cells. Cell Mol Biol Lett 2023; 28:37. [PMID: 37161350 PMCID: PMC10169341 DOI: 10.1186/s11658-023-00447-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 04/11/2023] [Indexed: 05/11/2023] Open
Abstract
Metabolic reprogramming is a well-known feature of cancer that allows malignant cells to alter metabolic reactions and nutrient uptake, thereby promoting tumor growth and spread. It has been discovered that noncoding RNAs (ncRNAs), including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA), have a role in a variety of biological functions, control physiologic and developmental processes, and even influence disease. They have been recognized in numerous cancer types as tumor suppressors and oncogenic agents. The role of ncRNAs in the metabolic reprogramming of cancer cells has recently been noticed. We examine this subject, with an emphasis on the metabolism of glucose, lipids, and amino acids, and highlight the therapeutic use of targeting ncRNAs in cancer treatment.
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Affiliation(s)
- Amir Safi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammadreza Saberiyan
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Adelian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Fateme Davarani Asl
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mahsa Zeinaly
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Mahdi Shamsi
- Department of Cell and Molecular Biology, Najafabad Branch, Islamic Azad University, Najafabad, Iran
| | - Reza Ahmadi
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Rahmatiyeh Region, Shahrekord, Iran.
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Chamarthy S, Mekala JR. Functional importance of glucose transporters and chromatin epigenetic factors in Glioblastoma Multiforme (GBM): possible therapeutics. Metab Brain Dis 2023; 38:1441-1469. [PMID: 37093461 DOI: 10.1007/s11011-023-01207-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/22/2023] [Indexed: 04/25/2023]
Abstract
Glioblastoma Multiforme (GBM) is an aggressive brain cancer affecting glial cells and is chemo- and radio-resistant. Glucose is considered the most vital energy source for cancer cell proliferation. During metabolism, hexose molecules will be transported into the cells via transmembrane proteins known as glucose transporter (GLUT). Among them, GLUT-1 and GLUT-3 play pivotal roles in glucose transport in GBM. Knockdown studies have established the role of GLUT-1, and GLUT-3 mediated glucose transport in GBM cells, providing insight into GLUT-mediated cancer signaling and cancer aggressiveness. This review focussed on the vital role of GLUT-1 and GLUT-3 proteins, which regulate glucose transport. Recent studies have identified the role of GLUT inhibitors in effective cancer prevention. Several of them are in clinical trials. Understanding and functional approaches towards glucose-mediated cell metabolism and chromatin epigenetics will provide valuable insights into the mechanism of cancer aggressiveness, cancer stemness, and chemo-resistance in Glioblastoma Multiforme (GBM). This review summarizes the role of GLUT inhibitors, micro-RNAs, and long non-coding RNAs that aid in inhibiting glucose uptake by the GBM cells and other cancer cells leading to the identification of potential therapeutic, prognostic as well as diagnostic markers. Furthermore, the involvement of epigenetic factors, such as microRNAs, in regulating glycolytic genes was demonstrated.
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Affiliation(s)
- Sahiti Chamarthy
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (KLEF), Green Fields, Vaddeswaram, Guntur, Andhra Pradesh, 522302, India
| | - Janaki Ramaiah Mekala
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (KLEF), Green Fields, Vaddeswaram, Guntur, Andhra Pradesh, 522302, India.
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Alizadeh J, Kavoosi M, Singh N, Lorzadeh S, Ravandi A, Kidane B, Ahmed N, Mraiche F, Mowat MR, Ghavami S. Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer. Cancers (Basel) 2023; 15:2195. [PMID: 37190124 PMCID: PMC10136996 DOI: 10.3390/cancers15082195] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/21/2023] [Accepted: 03/28/2023] [Indexed: 05/17/2023] Open
Abstract
Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer.
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Affiliation(s)
- Javad Alizadeh
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Mahboubeh Kavoosi
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Navjit Singh
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Amir Ravandi
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Institute of Cardiovascular Sciences, Albrechtsen Research Centre, St. Boniface Hospital, Winnipeg, MB R2H 2A6, Canada;
| | - Biniam Kidane
- Section of Thoracic Surgery, Department of Surgery, Health Sciences Centre, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 6C5, Canada;
- CancerCare Manitoba Research Institute, Winnipeg, MB R3E 0V9, Canada; (N.A.)
| | - Naseer Ahmed
- CancerCare Manitoba Research Institute, Winnipeg, MB R3E 0V9, Canada; (N.A.)
- Department of Radiology, Section of Radiation Oncology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Fatima Mraiche
- College of Pharmacy, QU Health, Qatar University, Doha 2713, Qatar;
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Michael R. Mowat
- CancerCare Manitoba Research Institute, Winnipeg, MB R3E 0V9, Canada; (N.A.)
- Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
- Research Institute of Oncology and Hematology, Winnipeg, MB R3E 0V9, Canada
- Faculty of Medicine in Zabrze, Academia of Silesia, 41-800 Zabrze, Poland
- Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 3P5, Canada
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8
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Farooq Z, Ismail H, Bhat SA, Layden BT, Khan MW. Aiding Cancer's "Sweet Tooth": Role of Hexokinases in Metabolic Reprogramming. Life (Basel) 2023; 13:946. [PMID: 37109475 PMCID: PMC10141071 DOI: 10.3390/life13040946] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/24/2023] [Accepted: 03/31/2023] [Indexed: 04/08/2023] Open
Abstract
Hexokinases (HKs) convert hexose sugars to hexose-6-phosphate, thus trapping them inside cells to meet the synthetic and energetic demands. HKs participate in various standard and altered physiological processes, including cancer, primarily through the reprogramming of cellular metabolism. Four canonical HKs have been identified with different expression patterns across tissues. HKs 1-3 play a role in glucose utilization, whereas HK 4 (glucokinase, GCK) also acts as a glucose sensor. Recently, a novel fifth HK, hexokinase domain containing 1 (HKDC1), has been identified, which plays a role in whole-body glucose utilization and insulin sensitivity. Beyond the metabolic functions, HKDC1 is differentially expressed in many forms of human cancer. This review focuses on the role of HKs, particularly HKDC1, in metabolic reprogramming and cancer progression.
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Affiliation(s)
- Zeenat Farooq
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Hagar Ismail
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Sheraz Ahmad Bhat
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Brian T. Layden
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
- Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA
| | - Md. Wasim Khan
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
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Liu J, Wang H, Zeng D, Xiong J, Luo J, Chen X, Chen T, Xi Q, Sun J, Ren X, Zhang Y. The novel importance of miR-143 in obesity regulation. Int J Obes (Lond) 2023; 47:100-108. [PMID: 36528726 DOI: 10.1038/s41366-022-01245-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 11/25/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022]
Abstract
Obesity and substantially increased risk of metabolic diseases have become a global epidemic. microRNAs have attracted a great deal of attention as a potential therapeutic target for obesity. MiR-143 has been known to specifically promote adipocyte differentiation by downregulating extracellular signal-regulated kinase 5. Our latest study found that miR-143 knockout is against diet-induced obesity by promoting brown adipose tissue thermogenesis and inhibiting white adipose tissue adipogenesis. Moreover, LPS- or IL-6-induced inhibition of miR-143 expression in brown adipocytes promotes thermogenesis by targeting adenylate cyclase 9. In this review, we will summarize the expression and functions of miR-143 in different tissues, the influence of obesity on miR-143 in various tissues, the important role of adipose-derived miR-143 in the development of obesity, the role of miR-143 in immune cells and thermoregulation and discuss the potential significance and application prospects of miR-143 in obesity management.
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Affiliation(s)
- Jie Liu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Huan Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Dewei Zeng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Jiali Xiong
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Junyi Luo
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Xingping Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.,Jiangxi Province Key Laboratory of Animal Nutrition, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, China
| | - Ting Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Qianyun Xi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Jiajie Sun
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Xiaohui Ren
- Ocean College of Hebei Agricultural University, Qinhuangdao, 066003, China.
| | - Yongliang Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
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Alshahrani SH, Ibrahim YS, Jalil AT, Altoum AA, Achmad H, Zabibah RS, Gabr GA, Ramírez-Coronel AA, Alameri AA, Qasim QA, Karampoor S, Mirzaei R. Metabolic reprogramming by miRNAs in the tumor microenvironment: Focused on immunometabolism. Front Oncol 2022; 12:1042196. [PMID: 36483029 PMCID: PMC9723351 DOI: 10.3389/fonc.2022.1042196] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/24/2022] [Indexed: 01/15/2023] Open
Abstract
MicroRNAs (miRNAs) are emerging as a significant modulator of immunity, and their abnormal expression/activity has been linked to numerous human disorders, such as cancer. It is now known that miRNAs potentially modulate the production of several metabolic processes in tumor-associated immune cells and indirectly via different metabolic enzymes that affect tumor-associated signaling cascades. For instance, Let-7 has been identified as a crucial modulator for the long-lasting survival of CD8+ T cells (naive phenotypes) in cancer by altering their metabolism. Furthermore, in T cells, it has been found that enhancer of zeste homolog 2 (EZH2) expression is controlled via glycolytic metabolism through miRNAs in patients with ovarian cancer. On the other hand, immunometabolism has shown us that cellular metabolic reactions and processes not only generate ATP and biosynthetic intermediates but also modulate the immune system and inflammatory processes. Based on recent studies, new and encouraging approaches to cancer involving the modification of miRNAs in immune cell metabolism are currently being investigated, providing insight into promising targets for therapeutic strategies based on the pivotal role of immunometabolism in cancer. Throughout this overview, we explore and describe the significance of miRNAs in cancer and immune cell metabolism.
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Affiliation(s)
- Shadia Hamoud Alshahrani
- Medical Surgical Nursing Department, King Khalid University, Almahala, Khamis Mushate, Saudi Arabia
| | - Yousif Saleh Ibrahim
- Department of Medical Laboratory Techniques, Al-maarif University College, Ramadi, Al-Anbar, Iraq
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, Iraq
| | - Abdelgadir Alamin Altoum
- Department of Medical Laboratory Sciences, College of Health Sciences, Gulf Medical University, Ajman, United Arab Emirates
| | - Harun Achmad
- Department of Pediatric Dentistry, Faculty of Dentistry, Hasanuddin University, Makassar, Indonesia
| | - Rahman S. Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Gamal A. Gabr
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
- Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center, Giza, Egypt
| | - Andrés Alexis Ramírez-Coronel
- Health and Behavior Research Group (HBR), Catholic University of Cuenca, Cuenca, Ecuador
- Laboratory of Psychometry and Ethology, Catholic University of Cuenca, Cuenca, Ecuador
- Epidemiology and Biostatistics Research Group, Universidad CES, Medellin, Colombia
| | | | | | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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11
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MSC-Derived exosomes suppress colorectal cancer cell proliferation and metastasis via miR-100/mTOR/miR-143 pathway. Int J Pharm 2022; 627:122214. [PMID: 36152993 DOI: 10.1016/j.ijpharm.2022.122214] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/05/2022] [Accepted: 09/16/2022] [Indexed: 11/21/2022]
Abstract
Exosomes derived from mesenchymal stem cells (MSCs) are mostly responsible for the therapeutic effects of MSCs. To show the therapeutic effects of the human bone marrow MSC-derived exosomes (MSC-Exos) on colorectal cancer (CRC) and explore the molecular cross-talks between them, CRC cells were treated with the MSC-Exos. We found that MSC-Exos were enriched with miR-100 and miR-143, which effectively downregulated mTOR, Cyclin D1, K-RAS, HK2 while upregulated p-27 expression. All these effects were reversed by concurrent treatment with MSC-Exos and antagomiR-100, confirming that they were caused by exosomal transfer of miR-100 into recipient CRC cells. Moreover, exosomal miR-100 promoted endogenous miR-143 expression. The flow cytometry, MTT and trypan blue assays revealed that MSC-Exos could efficiently suppress proliferation and induce apoptosis of the CRC cells. Furthermore, wound healing, transwell migration and invasion assays confirmed their inhibitory effects on the migration and invasiveness of SW480 cells. We further confirmed these effects by analyzing the expression levels of epithelial to mesenchymal transition (EMT) factors and metastasis-related genes. Results showed that MSC-Exos significantly suppressed the expression of MMP2 and MMP9 (metastasis-related genes), SNAIL and TWIST (EMT-inducing transcription factors), Vimentin and N-cadherin (mesenchymal cell markers), whereas E-cadherin (epithelial cell marker) was remarkably up-regulated. Collectively, our data indicated that MSC-Exos could suppress proliferation, migration, invasion and metastasis while inducing the apoptosis of the CRC cells via miR-100/mTOR/miR-143 axis. Our findings highlight that MSC-Exo treatment as well as miR-100 restoration might be considered as potential therapeutic strategies for CRC.
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12
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Suriya Muthukumaran N, Velusamy P, Akino Mercy CS, Langford D, Natarajaseenivasan K, Shanmughapriya S. MicroRNAs as Regulators of Cancer Cell Energy Metabolism. J Pers Med 2022; 12:1329. [PMID: 36013278 PMCID: PMC9410355 DOI: 10.3390/jpm12081329] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/11/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
To adapt to the tumor environment or to escape chemotherapy, cancer cells rapidly reprogram their metabolism. The hallmark biochemical phenotype of cancer cells is the shift in metabolic reprogramming towards aerobic glycolysis. It was thought that this metabolic shift to glycolysis alone was sufficient for cancer cells to meet their heightened energy and metabolic demands for proliferation and survival. Recent studies, however, show that cancer cells rely on glutamine, lipid, and mitochondrial metabolism for energy. Oncogenes and scavenging pathways control many of these metabolic changes, and several metabolic and tumorigenic pathways are post-transcriptionally regulated by microRNA (miRNAs). Genes that are directly or indirectly responsible for energy production in cells are either negatively or positively regulated by miRNAs. Therefore, some miRNAs play an oncogenic role by regulating the metabolic shift that occurs in cancer cells. Additionally, miRNAs can regulate mitochondrial calcium stores and energy metabolism, thus promoting cancer cell survival, cell growth, and metastasis. In the electron transport chain (ETC), miRNAs enhance the activity of apoptosis-inducing factor (AIF) and cytochrome c, and these apoptosome proteins are directed towards the ETC rather than to the apoptotic pathway. This review will highlight how miRNAs regulate the enzymes, signaling pathways, and transcription factors of cancer cell metabolism and mitochondrial calcium import/export pathways. The review will also focus on the metabolic reprogramming of cancer cells to promote survival, proliferation, growth, and metastasis with an emphasis on the therapeutic potential of miRNAs for cancer treatment.
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Affiliation(s)
| | - Prema Velusamy
- Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Dauphin, PA 17033, USA
| | - Charles Solomon Akino Mercy
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
| | - Dianne Langford
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Kalimuthusamy Natarajaseenivasan
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Santhanam Shanmughapriya
- Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Dauphin, PA 17033, USA
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13
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Yan S, Wang S, Wang X, Dai W, Chu J, Cheng M, Guo Z, Xu D. Emerging role of non-coding RNAs in glucose metabolic reprogramming and chemoresistance in colorectal cancer. Front Oncol 2022; 12:954329. [PMID: 35978828 PMCID: PMC9376248 DOI: 10.3389/fonc.2022.954329] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/11/2022] [Indexed: 11/28/2022] Open
Abstract
Metabolic reprogramming plays a critical role in colorectal cancer (CRC). It contributes to CRC by shaping metabolic phenotypes and causing uncontrolled proliferation of CRC cells. Glucose metabolic reprogramming is common in carcinogenesis and cancer progression. Growing evidence has implicated the modifying effects of non-coding RNAs (ncRNAs) in glucose metabolic reprogramming and chemoresistance in CRC. In this review, we have summarized currently published studies investigating the role of ncRNAs in glucose metabolic alterations and chemoresistance in CRC. Elucidating the interplay between ncRNAs and glucose metabolic reprogramming provides insight into exploring novel biomarkers for the diagnosis and prognosis prediction of CRC.
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Affiliation(s)
- Shushan Yan
- Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Shufeng Wang
- Medical Experimental Training Center, Weifang Medical University, Weifang, China
| | - Xinyi Wang
- Clinical Medicine of Basic Medical School, Shandong First Medical University, Jinan, China
| | - Wenqing Dai
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Jinjin Chu
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Min Cheng
- Department of Physiology, Weifang Medical University, Weifang, China
| | - Zhiliang Guo
- Department of Spine Surgery, The 80th Group Army Hospital of Chinese People’s Liberation Army (PLA), Weifang, China
- *Correspondence: Zhiliang Guo, ; Donghua Xu,
| | - Donghua Xu
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang, China
- *Correspondence: Zhiliang Guo, ; Donghua Xu,
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14
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Chen C, Wang Z, Qin Y. Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy. Front Pharmacol 2022; 13:935536. [PMID: 35935878 PMCID: PMC9354823 DOI: 10.3389/fphar.2022.935536] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/29/2022] [Indexed: 12/26/2022] Open
Abstract
Cancer cells undergo metabolic adaptations to sustain their growth and proliferation under several stress conditions thereby displaying metabolic plasticity. Epigenetic modification is known to occur at the DNA, histone, and RNA level, which can alter chromatin state. For almost a century, our focus in cancer biology is dominated by oncogenic mutations. Until recently, the connection between metabolism and epigenetics in a reciprocal manner was spotlighted. Explicitly, several metabolites serve as substrates and co-factors of epigenetic enzymes to carry out post-translational modifications of DNA and histone. Genetic mutations in metabolic enzymes facilitate the production of oncometabolites that ultimately impact epigenetics. Numerous evidences also indicate epigenome is sensitive to cancer metabolism. Conversely, epigenetic dysfunction is certified to alter metabolic enzymes leading to tumorigenesis. Further, the bidirectional relationship between epigenetics and metabolism can impact directly and indirectly on immune microenvironment, which might create a new avenue for drug discovery. Here we summarize the effects of metabolism reprogramming on epigenetic modification, and vice versa; and the latest advances in targeting metabolism-epigenetic crosstalk. We also discuss the principles linking cancer metabolism, epigenetics and immunity, and seek optimal immunotherapy-based combinations.
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Chen X, Luo J, Yang L, Guo Y, Fan Y, Liu J, Sun J, Zhang Y, Jiang Q, Chen T, Xi Q. miR-143-Mediated Responses to Betaine Supplement Repress Lipogenesis and Hepatic Gluconeogenesis by Targeting MAT1a and MAPK11. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:7981-7992. [PMID: 35734958 DOI: 10.1021/acs.jafc.2c02940] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
The liver as the central organ is responsible for lipogenesis, gluconeogenesis and one-carbon metabolism. Methyl donors (e.g., betaine) modulate metabolic homeostasis and gene regulation through one-carbon metabolism. MiR-143 regulates DNA methylation by targeting DNMT3A, thereby suggesting that this miRNA participates in one-carbon metabolic pathways. However, the effect and mechanism that regulate glucose and lipid metabolism via the methyl group metabolism pathway remain elusive. In this study, we found that a betaine supplement and miR-143 KO significantly promoted lipolysis and glucose utilization and repressed lipogenesis and gluconeogenesis through enhancing energy consumption and thermogenesis, repressing GPNMB and targeting MAPK11, respectively. We further explored the relationship between miR-143 and a methyl donor (betaine) and the miR-143-mediated responses to the betaine supplement regulating the mechanism of the glucose and lipid metabolism. The results showed that betaine significantly down-regulated the expression of miR-143 that subsequently increased SAM levels in the liver by targeting MAT1a. In brief, the regulations of glucose and lipid metabolism are related to the miR-143-regulation of one-carbon units, and the relationship between betaine and miR-143 in the methionine cycle is a typical yin-yang type of regulation. Thus, betaine and miR-143 function together as key regulators and biomarkers for preventing and diagnosing metabolic diseases such as fatty liver disease, obesity, and diabetes.
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Affiliation(s)
- Xingping Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou, 510642 China
| | - Junyi Luo
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou, 510642 China
| | - Lekai Yang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou, 510642 China
| | - Yue Guo
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou, 510642 China
| | - Yaotian Fan
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou, 510642 China
| | - Jie Liu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou, 510642 China
| | - Jiajie Sun
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou, 510642 China
| | - Yongliang Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou, 510642 China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou, 510642 China
| | - Ting Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou, 510642 China
| | - Qianyun Xi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou, 510642 China
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16
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Follicular fluid-derived exosomal miR-143-3p/miR-155-5p regulate follicular dysplasia by modulating glycolysis in granulosa cells in polycystic ovary syndrome. Cell Commun Signal 2022; 20:61. [PMID: 35534864 PMCID: PMC9082924 DOI: 10.1186/s12964-022-00876-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/02/2022] [Indexed: 12/02/2022] Open
Abstract
Objective Polycystic ovary syndrome (PCOS) is characterized by follicular dysplasia. An insufficient glycolysis-derived energy supply of granulosa cells (GCs) is an important cause of follicular dysplasia in PCOS. Follicular fluid (FF) exosomal microRNAs (miRNAs) have been proven to regulate the function of GCs. In this study, exosomes extracted from clinical FF samples were used for transcriptome sequencing (RNA-seq) analysis, and a human ovarian granulocyte tumour cell line (KGN cells) was used for in vitro mechanistic studies. Methods and results In FF exosomal RNA-seq analysis, a decrease in glycolysis-related pathways was identified as an important feature of the PCOS group, and the differentially expressed miR-143-3p and miR-155-5p may be regulatory factors of glycolysis. By determining the effects of miR-143-3p and miR-155-5p on hexokinase (HK) 2, pyruvate kinase muscle isozyme M2 (PKM2), lactate dehydrogenase A (LDHA), pyruvate, lactate and apoptosis in KGN cells, we found that upregulated miR-143-3p expression in exosomes from the PCOS group inhibited glycolysis in KGN cells; knockdown of miR-143-3p significantly alleviated the decrease in glycolysis in KGN cells in PCOS. MiR-155-5p silencing attenuated glycolytic activation in KGN cells; overexpression of miR-155-5p significantly promoted glycolysis in KGN cells in PCOS. In this study, HK2 was found to be the mediator of miR-143-3p and miR-155-5p in FF-derived exosome-mediated regulation of glycolysis in KGN cells. Reduced glycolysis accelerated apoptosis of KGN cells, which mediated follicular dysplasia through ATP, lactate and apoptotic pathways. Conclusions In conclusion, these results indicate that miR-143-3p and miR-155-5p in FF-derived exosomes antagonistically regulate glycolytic-mediated follicular dysplasia of GCs in PCOS.
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17
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Li W, Lu Y, Ye C, Ouyang M. The Regulatory Network of MicroRNA in the Metabolism of Colorectal Cancer. J Cancer 2022; 12:7454-7464. [PMID: 35003365 PMCID: PMC8734415 DOI: 10.7150/jca.61618] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 10/24/2021] [Indexed: 01/26/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignant tumor in the world. During the progression of CRC, the entire metabolic network undergoes reprogramming, including marked changes in the regulation of glucose, lipid and amino acid metabolism. Although microRNAs (miRNAs) account for only 1% of the entire human genome, they play an important role in almost all physiological and pathological processes in the body. MiRNAs can react directly with key enzymes in the metabolic processes. MiRNAs also interact with other ncRNAs, as a member of non-coding RNA (ncRNA), to form their own regulatory network in various oncogenic pathways of CRC metabolism. The progression of colorectal cancer is closely related to the intestinal flora, where miRNAs act as important mediators. Understanding how miRNAs act in the regulatory network of CRC metabolism is helpful to elucidate the characteristics of tumor occurrence, proliferation, metastasis and drug resistance. This review summarizes the role of miRNAs in the metabolism of CRC and how miRNAs interact with key enzymes, ncRNA and intestinal flora to further discuss how miRNAs affect CRC and realize some new strategies for the early diagnosis and treatment of CRC.
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Affiliation(s)
- Wangji Li
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Yan Lu
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
| | - Changda Ye
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Manzhao Ouyang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
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18
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Adhikari S, Guha D, Mohan C, Mukherjee S, Tyler JK, Das C. Reprogramming Carbohydrate Metabolism in Cancer and Its Role in Regulating the Tumor Microenvironment. Subcell Biochem 2022; 100:3-65. [PMID: 36301490 PMCID: PMC10760510 DOI: 10.1007/978-3-031-07634-3_1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Altered metabolism has become an emerging feature of cancer cells impacting their proliferation and metastatic potential in myriad ways. Proliferating heterogeneous tumor cells are surrounded by other resident or infiltrating cells, along with extracellular matrix proteins, and other secretory factors constituting the tumor microenvironment. The diverse cell types of the tumor microenvironment exhibit different molecular signatures that are regulated at their genetic and epigenetic levels. The cancer cells elicit intricate crosstalks with these supporting cells, exchanging essential metabolites which support their anabolic processes and can promote their survival, proliferation, EMT, angiogenesis, metastasis and even therapeutic resistance. In this context, carbohydrate metabolism ensures constant energy supply being a central axis from which other metabolic and biosynthetic pathways including amino acid and lipid metabolism and pentose phosphate pathway are diverged. In contrast to normal cells, increased glycolytic flux is a distinguishing feature of the highly proliferative cancer cells, which supports them to adapt to a hypoxic environment and also protects them from oxidative stress. Such rewired metabolic properties are often a result of epigenetic alterations in the cancer cells, which are mediated by several factors including, DNA, histone and non-histone protein modifications and non-coding RNAs. Conversely, epigenetic landscapes of the cancer cells are also dictated by their diverse metabolomes. Altogether, this metabolic and epigenetic interplay has immense potential for the development of efficient anti-cancer therapeutic strategies. In this book chapter we emphasize upon the significance of reprogrammed carbohydrate metabolism in regulating the tumor microenvironment and cancer progression, with an aim to explore the different metabolic and epigenetic targets for better cancer treatment.
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Affiliation(s)
- Swagata Adhikari
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
- Homi Bhaba National Institute, Mumbai, India
| | - Deblina Guha
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
| | - Chitra Mohan
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Shravanti Mukherjee
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
| | - Jessica K Tyler
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Chandrima Das
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India.
- Homi Bhaba National Institute, Mumbai, India.
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Das D, Karthik N, Taneja R. Epigenetic Small-Molecule Modulators Targeting Metabolic Pathways in Cancer. Subcell Biochem 2022; 100:523-555. [PMID: 36301505 DOI: 10.1007/978-3-031-07634-3_16] [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] [Indexed: 06/16/2023]
Abstract
Metabolic deregulation is a key factor in cancer progression. Epigenetic changes and metabolic rewiring are intertwined in cancer. Deregulated epigenetic modifiers cause metabolic aberrations by targeting the expression of metabolic enzymes. Conversely, metabolites and cofactors affect the expression and activity of epigenetic regulators. Small molecules are promising therapeutic approaches to target the epigenetic-metabolomic crosstalk in cancer. Here, we focus on the interplay between metabolic rewiring and epigenetic landscape in the context of tumourigenesis and highlight recent advances in the use of small-molecule drug targets for therapy.
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Affiliation(s)
- Dipanwita Das
- Department of Physiology and Healthy Longevity Translational Research Program Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Nandini Karthik
- Department of Physiology and Healthy Longevity Translational Research Program Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Reshma Taneja
- Department of Physiology and Healthy Longevity Translational Research Program Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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20
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Gao SJ, Ren SN, Liu YT, Yan HW, Chen XB. Targeting EGFR sensitizes 5-Fu-resistant colon cancer cells through modification of the lncRNA-FGD5-AS1-miR-330-3p-Hexokinase 2 axis. MOLECULAR THERAPY-ONCOLYTICS 2021; 23:14-25. [PMID: 34589581 PMCID: PMC8455313 DOI: 10.1016/j.omto.2021.06.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/30/2021] [Indexed: 12/19/2022]
Abstract
5-Fluorouracil (5-Fu) is a widely applied anti-cancer agent against colorectal cancer (CRC), yet a number of CRC patients have developed resistance to 5-Fu-based chemotherapy. The epidermal growth factor receptor (EGFR) is recognized as an oncogene that promotes diverse cancer progresses. In addition, long noncoding RNAs (lncRNAs) are essential regulators of cancers. Here we report that EGFR and lncRNA-FGD5-AS1 promoted 5-Fu resistance of CRC. By establishing the 5-Fu-resistant CRC cell line, we detected that EGFR, FGD5-AS1, and glucose metabolism were significantly elevated in 5-Fu-resistant CRC cells. A microRNA-microarray analysis revealed that miR-330-3p functions as a downstream effector of FGD5-AS1. FGD5-AS1 directly sponged miR-330-3p to form a competing endogenous RNA (ceRNA) network, leading to inhibition of miR-330-3p expression. Furthermore, bioinformatics analysis revealed that Hexokinase 2 (HK2) was a potential target of miR-330-3p, which was validated by luciferase assay. Rescue experiments demonstrated that FGD5-AS1 promotes glycolysis through modulating the miR-330-3p-HK2 axis, leading to 5-Fu resistance of CRC cancer cells. Finally, in vitro and in vivo xenograft experiments consistently demonstrated that inhibition of EGFR by the specific inhibitor erlotinib effectively enhanced the anti-tumor toxicity of 5-Fu by targeting the EGFR-FGD5-AS1-miR-330-3p-HK2 pathway. In summary, this study demonstrates new mechanisms of the EGFR-modulated 5-Fu resistance through modulating the noncoding RNA network, contributing to development of new approaches against chemoresistant CRC.
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Affiliation(s)
- Su-Jie Gao
- Department of Anesthesia, China-Japan Union Hospital of Jilin University, Changchun, 130033 Jilin Province, China
| | - Sheng-Nan Ren
- Department of General Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033 Jilin Province, China
| | - Yi-Ting Liu
- Department of Radiology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 100871 Beijing, China
| | - Hong-Wei Yan
- Department of General Surgery, Chinese Medicine Hospital, Liuhe, 135300 Jilin Province, China
| | - Xue-Bo Chen
- Department of General Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033 Jilin Province, China
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21
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Interplay between Epigenetics and Cellular Metabolism in Colorectal Cancer. Biomolecules 2021; 11:biom11101406. [PMID: 34680038 PMCID: PMC8533383 DOI: 10.3390/biom11101406] [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: 08/16/2021] [Revised: 09/17/2021] [Accepted: 09/18/2021] [Indexed: 01/30/2023] Open
Abstract
Cellular metabolism alterations have been recognized as one of the most predominant hallmarks of colorectal cancers (CRCs). It is precisely regulated by many oncogenic signaling pathways in all kinds of regulatory levels, including transcriptional, post-transcriptional, translational and post-translational levels. Among these regulatory factors, epigenetics play an essential role in the modulation of cellular metabolism. On the one hand, epigenetics can regulate cellular metabolism via directly controlling the transcription of genes encoding metabolic enzymes of transporters. On the other hand, epigenetics can regulate major transcriptional factors and signaling pathways that control the transcription of genes encoding metabolic enzymes or transporters, or affecting the translation, activation, stabilization, or translocation of metabolic enzymes or transporters. Interestingly, epigenetics can also be controlled by cellular metabolism. Metabolites not only directly influence epigenetic processes, but also affect the activity of epigenetic enzymes. Actually, both cellular metabolism pathways and epigenetic processes are controlled by enzymes. They are highly intertwined and are essential for oncogenesis and tumor development of CRCs. Therefore, they are potential therapeutic targets for the treatment of CRCs. In recent years, both epigenetic and metabolism inhibitors are studied for clinical use to treat CRCs. In this review, we depict the interplay between epigenetics and cellular metabolism in CRCs and summarize the underlying molecular mechanisms and their potential applications for clinical therapy.
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22
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Abi Zamer B, Abumustafa W, Hamad M, Maghazachi AA, Muhammad JS. Genetic Mutations and Non-Coding RNA-Based Epigenetic Alterations Mediating the Warburg Effect in Colorectal Carcinogenesis. BIOLOGY 2021; 10:847. [PMID: 34571724 PMCID: PMC8472255 DOI: 10.3390/biology10090847] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/16/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) development is a gradual process defined by the accumulation of numerous genetic mutations and epigenetic alterations leading to the adenoma-carcinoma sequence. Despite significant advances in the diagnosis and treatment of CRC, it continues to be a leading cause of cancer-related deaths worldwide. Even in the presence of oxygen, CRC cells bypass oxidative phosphorylation to produce metabolites that enable them to proliferate and survive-a phenomenon known as the "Warburg effect". Understanding the complex glucose metabolism in CRC cells may support the development of new diagnostic and therapeutic approaches. Here we discuss the most recent findings on genetic mutations and epigenetic modulations that may positively or negatively regulate the Warburg effect in CRC cells. We focus on the non-coding RNA (ncRNA)-based epigenetics, and we present a perspective on the therapeutic relevance of critical molecules and ncRNAs mediating the Warburg effect in CRC cells. All the relevant studies were identified and assessed according to the genes and enzymes mediating the Warburg effect. The findings summarized in this review should provide a better understanding of the relevance of genetic mutations and the ncRNA-based epigenetic alterations to CRC pathogenesis to help overcome chemoresistance.
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Affiliation(s)
- Batoul Abi Zamer
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; (B.A.Z.); (W.A.)
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; (M.H.); (A.A.M.)
| | - Wafaa Abumustafa
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; (B.A.Z.); (W.A.)
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; (M.H.); (A.A.M.)
| | - Mawieh Hamad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; (M.H.); (A.A.M.)
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Azzam A. Maghazachi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; (M.H.); (A.A.M.)
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; (B.A.Z.); (W.A.)
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; (M.H.); (A.A.M.)
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23
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Chen B, Deng YN, Wang X, Xia Z, He Y, Zhang P, Syed SE, Li Q, Liang S. miR-26a enhances colorectal cancer cell growth by targeting RREB1 deacetylation to activate AKT-mediated glycolysis. Cancer Lett 2021; 521:1-13. [PMID: 34419497 DOI: 10.1016/j.canlet.2021.08.017] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 08/13/2021] [Accepted: 08/16/2021] [Indexed: 02/05/2023]
Abstract
We previously reported the inhibitory effects of microRNA-26a (miR-26a) on the conversion of pyruvate to acetyl coenzyme A in glucose metabolism by directly targeting pyruvate dehydrogenase protein X component in colorectal cancer (CRC) cells (Chen B et al., BMC Cancer 2014). Here, using microRNA in situ hybridization, we confirmed that miR-26a levels were elevated in 77 human CRC tissue samples and further investigated the key miR-26a-mediated metabolic regulation elements and signaling pathways in CRC cells through quantitative proteomic dissection combined with cancer cell biology and biochemical loss-of-function analysis. We found that AKT transcription signaling was a target pathway via miR-26a-mediated deacetylation modification of Ras-responsive element-binding protein 1 (RREB1) at the Lys-60 residue. miR-26a improved the deacetylation level of RREB1, thus contributing to RREB1 binding to the AKT1 promoter to activate AKT transcription and its related signaling pathway in glycolysis. Moreover, miR-26a promoted CRC tumorigenesis in CRC cells and subcutaneous xenograft mice. Thus, miR-26a is a key regulator of CRC tumorigenesis that mediates the deacetylation modification of RREB1 to enhance AKT1 transcription and downstream target gene expression in glycolysis for CRC growth.
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Affiliation(s)
- Bing Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, And Collaborative Innovation Center for Biotherapy, Chengdu, PR China.
| | - Ya-Nan Deng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, And Collaborative Innovation Center for Biotherapy, Chengdu, PR China.
| | - Xixi Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, And Collaborative Innovation Center for Biotherapy, Chengdu, PR China.
| | - Zijing Xia
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, And Collaborative Innovation Center for Biotherapy, Chengdu, PR China; Department of Rheumatology and Immunology, West China Hospital, West China Medical School, Sichuan University, Chengdu, PR China.
| | - Yu He
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, And Collaborative Innovation Center for Biotherapy, Chengdu, PR China.
| | - Peng Zhang
- Department of Urinary Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, PR China.
| | - Samina Ejaz Syed
- Department of Biochemistry and Biotechnology, Baghdad Campus, The Islamia University of Bahawalpur, Pakistan.
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, PR China.
| | - Shufang Liang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, And Collaborative Innovation Center for Biotherapy, Chengdu, PR China.
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Liu X, Chen D, Chen H, Wang W, Liu Y, Wang Y, Duan C, Ning Z, Guo X, Otkur W, Liu J, Qi H, Liu X, Lin A, Xia T, Liu H, Piao H. YB1 regulates miR-205/200b-ZEB1 axis by inhibiting microRNA maturation in hepatocellular carcinoma. Cancer Commun (Lond) 2021; 41:576-595. [PMID: 34110104 PMCID: PMC8286141 DOI: 10.1002/cac2.12164] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/15/2021] [Accepted: 05/05/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Y-box binding protein 1 (YB1 or YBX1) plays a critical role in tumorigenesis and cancer progression. However, whether YB1 affects malignant transformation by modulating non-coding RNAs remains largely unknown. This study aimed to investigate the relationship between YB1 and microRNAs and reveal the underlying mechanism by which YB1 impacts on tumor malignancy via miRNAs-mediated regulatory network. METHODS The biological functions of YB1 in hepatocellular carcinoma (HCC) cells were investigated by cell proliferation, wound healing, and transwell invasion assays. The miRNAs dysregulated by YB1 were screened by microarray analysis in HCC cell lines. The regulation of YB1 on miR-205 and miR-200b was determined by quantitative real-time PCR, dual-luciferase reporter assay, RNA immunoprecipitation, and pull-down assay. The relationships of YB1, DGCR8, Dicer, TUT4, and TUT1 were identified by pull-down and coimmunoprecipitation experiments. The cellular co-localization of YB1, DGCR8, and Dicer were detected by immunofluorescent staining. The in vivo effect of YB1 on tumor metastasis was determined by injecting MHCC97H cells transduced with YB1 shRNA or shControl via the tail vein in nude BALB/c mice. The expression levels of epithelial to mesenchymal transition markers were detected by immunoblotting and immunohistochemistry assays. RESULTS YB1 promoted HCC cell migration and tumor metastasis by regulating miR-205/200b-ZEB1 axis partially in a Snail-independent manner. YB1 suppressed miR-205 and miR-200b maturation by interacting with the microprocessors DGCR8 and Dicer as well as TUT4 and TUT1 via the conserved cold shock domain. Subsequently, the downregulation of miR-205 and miR-200b enhanced ZEB1 expression, thus leading to increased cell migration and invasion. Furthermore, statistical analyses on gene expression data from HCC and normal liver tissues showed that YB1 expression was positively associated with ZEB1 expression and remarkably correlated with clinical prognosis. CONCLUSION This study reveals a previously undescribed mechanism by which YB1 promotes cancer progression by regulating the miR-205/200b-ZEB1 axis in HCC cells. Furthermore, these results highlight that YB1 may play biological functions via miRNAs-mediated gene regulation, and it can serve as a potential therapeutic target in human cancers.
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Affiliation(s)
- Xiumei Liu
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
| | - Di Chen
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
| | - Huan Chen
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
| | - Wen Wang
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
| | - Yu Liu
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
- Department of Thoracic SurgeryLiaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangLiaoning110042P. R. China
| | - Yawei Wang
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
- Department of Thoracic SurgeryLiaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangLiaoning110042P. R. China
| | - Chao Duan
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
- Department of Thoracic SurgeryLiaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangLiaoning110042P. R. China
| | - Zhen Ning
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Dalian Medical UniversityDalian Medical UniversityDalianLiaoning116000P. R. China
| | - Xin Guo
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
- Department of Hepatobiliary SurgeryThe First Affiliated Hospital of Dalian Medical UniversityDalian Medical UniversityDalianLiaoning116000P. R. China
| | - Wuxiyar Otkur
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
| | - Jing Liu
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
| | - Huan Qi
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
| | - Xiaolong Liu
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
| | - Aifu Lin
- MOE Laboratory of Biosystem Homeostasis and ProtectionCollege of Life SciencesZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Tian Xia
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
| | - Hong‐xu Liu
- Department of Thoracic SurgeryLiaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangLiaoning110042P. R. China
| | - Hai‐long Piao
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalianLiaoning116023P. R. China
- Department of Biochemistry & Molecular BiologySchool of Life SciencesChina Medical UniversityShenyangLiaoning110122P. R. China
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Kim KW, Kim SW, Lim S, Yoo KJ, Hwang KC, Lee S. Neutralization of hexokinase 2-targeting miRNA attenuates the oxidative stress-induced cardiomyocyte apoptosis. Clin Hemorheol Microcirc 2021; 78:57-68. [PMID: 33523042 DOI: 10.3233/ch-200924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hexokinase 2 (HK2) is a metabolic sensor that couples glycolysis and oxidative phosphorylation of mitochondria by binding to the outer mitochondrial membrane (OMM), and it also has been implicated in induction of apoptotic process by regulating the integrity of OMM. When HK2 detaches from the mitochondria, it triggers permeability increase of the OMM and subsequently facilitates the cytosolic release of cytochrome c, a major apoptosis-inducing factor. According to previous studies, a harsh microenvironment created by ischemic heart disease such as low tissue oxygen and nutrients, and increased reactive oxygen species (ROS) can cause cardiomyocyte apoptosis. Under these conditions, the expression of HK2 in heart significantly decrease and such down-regulation of HK2 was correlated to the increased apoptosis of cardiomyocytes. Therefore, prevention of HK2 down-regulation may salvage cardiomyocytes from apoptosis. MicroRNAs are short, non-coding RNAs that either inhibit transcription of target mRNAs or degrade the targeted mRNAs via complementary binding to the 3'UTR (untranslated region) of the targeted mRNAs. Since miRNAs are known to be involved in virtually every biological processes, it is reasonable to assume that the expression of HK2 is also regulated by miRNAs. Currently, to my best knowledge, there is no previous study examined the miRNA-mediated regulation of HK2 in cardiomyocytes. Thus, in the present study, miRNA-mediated modulation of HK2 during ROS (H2O2)-induced cardiomyocyte apoptosis was investigated. First, the expression of HK2 in cardiomyocytes exposed to H2O2 was evaluated. H2O2 (500 μM) induced cardiomyocyte apoptosis and it also decreased the mitochondrial expression of HK2. Based on miRNA-target prediction databases and empirical data, miR-181a was identified as a HK2-targeting miRNA. To further examine the effect of negative regulation of the selected HK2-targeting miRNA on cardiomyocyte apoptosis, anti-miR-181a, which neutralizes endogenous miR-181a, was utilized. Delivery of anti-miR-181a significantly abrogated the H2O2-induced suppression of HK2 expression and subsequent disruption of mitochondrial membrane potential, improving the survival of cardiomyocytes exposed to H2O2. These findings suggest that miR-181a-mediated down-regulation of HK2 contributes to the apoptosis of cardiomyocytes exposed to ROS. Neutralizing miR-181a can be a viable and effective means to prevent cardiomyocyte from apoptosis in ischemic heart disease.
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Affiliation(s)
- Kwan Wook Kim
- Department of Medicine, The Graduate School, Yonsei University, Seoul, South Korea.,Department of Thoracic and Cardiovascular Surgery, CHA Bundang Medical Center, CHA University, Pangyo, South Korea
| | - Sang Woo Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, South Korea
| | - Soyeon Lim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, South Korea
| | - Kyung-Jong Yoo
- Division of Cardiovascular Surgery, Department of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, South Korea
| | - Seahyoung Lee
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, South Korea
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26
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Brockmueller A, Sameri S, Liskova A, Zhai K, Varghese E, Samuel SM, Büsselberg D, Kubatka P, Shakibaei M. Resveratrol's Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism. Cancers (Basel) 2021; 13:cancers13020188. [PMID: 33430318 PMCID: PMC7825813 DOI: 10.3390/cancers13020188] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/02/2021] [Accepted: 01/04/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The prevention and treatment of cancer is an ongoing medical challenge. In the context of personalized medicine, the well-studied polyphenol resveratrol could complement classical tumor therapy. It may affect key processes such as inflammation, angiogenesis, proliferation, metastasis, glucose metabolism, and apoptosis in various cancers because resveratrol acts as a multi-targeting agent by modulating multiple signal transduction pathways. This review article focuses on resveratrol’s ability to modify tumor glucose metabolism and its associated therapeutic capacity. Resveratrol reduces glucose uptake and glycolysis by affecting Glut1, PFK1, HIF-1α, ROS, PDH, and the CamKKB/AMPK pathway. It also inhibits cell growth, invasion, and proliferation by targeting NF-kB, Sirt1, Sirt3, LDH, PI-3K, mTOR, PKM2, R5P, G6PD, TKT, talin, and PGAM. In addition, resveratrol induces apoptosis by targeting integrin, p53, LDH, and FAK. In conclusion, resveratrol has many potentials to intervene in tumor processes if bioavailability can be increased and this natural compound can be used selectively. Abstract Tumor cells develop several metabolic reprogramming strategies, such as increased glucose uptake and utilization via aerobic glycolysis and fermentation of glucose to lactate; these lead to a low pH environment in which the cancer cells thrive and evade apoptosis. These characteristics of tumor cells are known as the Warburg effect. Adaptive metabolic alterations in cancer cells can be attributed to mutations in key metabolic enzymes and transcription factors. The features of the Warburg phenotype may serve as promising markers for the early detection and treatment of tumors. Besides, the glycolytic process of tumors is reversible and could represent a therapeutic target. So-called mono-target therapies are often unsafe and ineffective, and have a high prevalence of recurrence. Their success is hindered by the ability of tumor cells to simultaneously develop multiple chemoresistance pathways. Therefore, agents that modify several cellular targets, such as energy restriction to target tumor cells specifically, have therapeutic potential. Resveratrol, a natural active polyphenol found in grapes and red wine and used in many traditional medicines, is known for its ability to target multiple components of signaling pathways in tumors, leading to the suppression of cell proliferation, activation of apoptosis, and regression in tumor growth. Here, we describe current knowledge on the various mechanisms by which resveratrol modulates glucose metabolism, its potential as an imitator of caloric restriction, and its therapeutic capacity in tumors.
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Affiliation(s)
- Aranka Brockmueller
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany;
| | - Saba Sameri
- Department of Molecular Medicine and Genetics, Hamadan University of Medical Sciences, 6517838678 Hamadan, Iran;
| | - Alena Liskova
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia;
| | - Kevin Zhai
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (K.Z.); (E.V.); (S.M.S.); (D.B.)
| | - Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (K.Z.); (E.V.); (S.M.S.); (D.B.)
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (K.Z.); (E.V.); (S.M.S.); (D.B.)
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (K.Z.); (E.V.); (S.M.S.); (D.B.)
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia;
| | - Mehdi Shakibaei
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany;
- Correspondence: ; Tel.: +49-892-1807-2624; Fax: +49-892-1807-2625
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27
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Taefehshokr S, Taefehshokr N, Hemmat N, Hajazimian S, Isazadeh A, Dadebighlu P, Baradaran B. The pivotal role of MicroRNAs in glucose metabolism in cancer. Pathol Res Pract 2020; 217:153314. [PMID: 33341548 DOI: 10.1016/j.prp.2020.153314] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/17/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023]
Abstract
Cancer cells are able to undergo aerobic glycolysis and metabolize glucose to lactate instead of oxidative phosphorylation, which is known as Warburg effect. Accumulating evidence has revealed that microRNAs regulate cancer cell metabolism, which manifest a higher rate of glucose metabolism. Various signaling pathways along with glycolytic enzymes are responsible for the emergence of glycolytic dependence. MicroRNAs are a class of non-coding RNAs that are not translated into proteins but regulate target gene expression or in other words function pre-translationally and post-transcriptionally. MicroRNAs have been shown to be involved in various biological processes, including glucose metabolism via targeting major transcription factors, enzymes, oncogenes or tumor suppressors alongside the oncogenic signaling pathways. In this review, we describe the regulatory role of microRNAs of cancer cell glucose metabolism, including in the glucose uptake, glycolysis, tricarboxylic acid cycle and several signaling pathways and further suggest that microRNA-based therapeutics can be used to inhibit the process of glucose metabolism reprogramming in cancer cells and thus suppressing cancer progression.
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Affiliation(s)
- Sina Taefehshokr
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nima Taefehshokr
- Department of Microbiology and Immunology, Center for Human Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Hajazimian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Isazadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pourya Dadebighlu
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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28
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Sun L, Wang P, Zhang Z, Zhang K, Xu Z, Li S, Mao J. MicroRNA-615 functions as a tumor suppressor in osteosarcoma through the suppression of HK2. Oncol Lett 2020; 20:226. [PMID: 32968448 PMCID: PMC7500052 DOI: 10.3892/ol.2020.12089] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 08/12/2020] [Indexed: 12/16/2022] Open
Abstract
At present, the regulatory mechanisms of various microRNAs (miRNAs/miRs) have been elucidated in human cancers including osteosarcoma (OS). This study mainly focused on the role of miR-615 in OS, which has not yet been reported. Ninety-two OS tissues and normal samples were used in this study. Human osteoblast hFOB1.19 cells and OS cell line HOS were utilized to detect the expression of miR-615. The expression of miR-615 and gene expression were assessed by RT-qPCR and western blot analysis. Transwell, MTT and luciferase reporter assays were used to investigate the regulatory mechanism of miR-615 in OS. The results revealed that miR-615 expression was reduced in OS tissues and cells, and was associated with poor clinical outcomes and prognosis in OS patients. In addition, overexpression of miR-615 restrained cell viability and metastasis in OS. Furthermore, hexokinase 2 (HK2) was confirmed as a direct target of miR-615. Upregulation of HK2 was detected in OS tissues. The upregulation of HK2 weakened the tumor-suppressive effect of miR-615 in OS. Moreover, miR-615 blocked epithelial-mesenchymal transition (EMT) and inactivated the PI3K/AKT pathway in OS. To conclude, miR-615 acts as a tumor suppressor in OS, thus miR-615 can be used as a target for OS treatment.
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Affiliation(s)
- Limin Sun
- Department of Orthopedics, Shandong Provincial Third Hospital, Jinan, Shandong 250031, P.R. China
| | - Peng Wang
- Department of Orthopedics, Shandong Provincial Third Hospital, Jinan, Shandong 250031, P.R. China
| | - Zhiqiang Zhang
- Department of Orthopedics, Shandong Provincial Third Hospital, Jinan, Shandong 250031, P.R. China
| | - Kai Zhang
- Department of Orthopedics, Shandong Provincial Third Hospital, Jinan, Shandong 250031, P.R. China
| | - Zheng Xu
- Department of Orthopedics, Shandong Provincial Third Hospital, Jinan, Shandong 250031, P.R. China
| | - Siyuan Li
- Department of Orthopedics, Shandong Provincial Third Hospital, Jinan, Shandong 250031, P.R. China
| | - Junsheng Mao
- Department of Orthopedic Surgery, Taishan Hospital of Shandong Province, Tai'an, Shandong 271000, P.R. China
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29
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Saw PE, Xu X, Chen J, Song EW. Non-coding RNAs: the new central dogma of cancer biology. SCIENCE CHINA-LIFE SCIENCES 2020; 64:22-50. [PMID: 32930921 DOI: 10.1007/s11427-020-1700-9] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023]
Abstract
The central dogma of molecular biology states that the functions of RNA revolve around protein translation. Until the last decade, most researches were geared towards characterization of RNAs as intermediaries in protein translation, namely, messenger RNAs (mRNAs) as temporary copies of genetic information, ribosomal RNAs (rRNAs) as a main component of ribosome, or translators of codon sequence (tRNAs). The statistical reality, however, is that these processes account for less than 2% of the genome, and insufficiently explain the functionality of 98% of transcribed RNAs. Recent discoveries have unveiled thousands of unique non-coding RNAs (ncRNAs) and shifted the perception of them from being "junk" transcriptional products to "yet to be elucidated"-and potentially monumentally important-RNAs. Most ncRNAs are now known as key regulators in various networks in which they could lead to specific cellular responses and fates. In major cancers, ncRNAs have been identified as both oncogenic drivers and tumor suppressors, indicating a complex regulatory network among these ncRNAs. Herein, we provide a comprehensive review of the various ncRNAs and their functional roles in cancer, and the pre-clinical and clinical development of ncRNA-based therapeutics. A deeper understanding of ncRNAs could facilitate better design of personalized therapeutics.
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Affiliation(s)
- Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Jianing Chen
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Er-Wei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China. .,Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
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30
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Samec M, Liskova A, Koklesova L, Samuel SM, Zhai K, Buhrmann C, Varghese E, Abotaleb M, Qaradakhi T, Zulli A, Kello M, Mojzis J, Zubor P, Kwon TK, Shakibaei M, Büsselberg D, Sarria GR, Golubnitschaja O, Kubatka P. Flavonoids against the Warburg phenotype-concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism. EPMA J 2020; 11:377-398. [PMID: 32843908 PMCID: PMC7429635 DOI: 10.1007/s13167-020-00217-y] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 06/30/2020] [Indexed: 01/10/2023]
Abstract
The Warburg effect is characterised by increased glucose uptake and lactate secretion in cancer cells resulting from metabolic transformation in tumour tissue. The corresponding molecular pathways switch from oxidative phosphorylation to aerobic glycolysis, due to changes in glucose degradation mechanisms known as the 'Warburg reprogramming' of cancer cells. Key glycolytic enzymes, glucose transporters and transcription factors involved in the Warburg transformation are frequently dysregulated during carcinogenesis considered as promising diagnostic and prognostic markers as well as treatment targets. Flavonoids are molecules with pleiotropic activities. The metabolism-regulating anticancer effects of flavonoids are broadly demonstrated in preclinical studies. Flavonoids modulate key pathways involved in the Warburg phenotype including but not limited to PKM2, HK2, GLUT1 and HIF-1. The corresponding molecular mechanisms and clinical relevance of 'anti-Warburg' effects of flavonoids are discussed in this review article. The most prominent examples are provided for the potential application of targeted 'anti-Warburg' measures in cancer management. Individualised profiling and patient stratification are presented as powerful tools for implementing targeted 'anti-Warburg' measures in the context of predictive, preventive and personalised medicine.
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Affiliation(s)
- Marek Samec
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Alena Liskova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Kevin Zhai
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Constanze Buhrmann
- Musculoskeletal Research Group and Tumour Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, 80336 Munich, Germany
| | - Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Mariam Abotaleb
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Tawar Qaradakhi
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3011 Australia
| | - Anthony Zulli
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3011 Australia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, P. J. Šafarik University, 040 11 Košice, Slovakia
| | - Jan Mojzis
- Department of Pharmacology, Faculty of Medicine, P. J. Šafarik University, 040 11 Košice, Slovakia
| | - Pavol Zubor
- Department of Gynecologic Oncology, Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway
- OBGY Health & Care, Ltd., 01001 Zilina, Slovak Republic
| | - Taeg Kyu Kwon
- Department of Immunology and School of Medicine, Keimyung University, Dalseo-Gu, Daegu, 426 01 South Korea
| | - Mehdi Shakibaei
- Musculoskeletal Research Group and Tumour Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, 80336 Munich, Germany
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Gustavo R. Sarria
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Olga Golubnitschaja
- Predictive, Preventive Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
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Wai Hon K, Zainal Abidin SA, Othman I, Naidu R. Insights into the Role of microRNAs in Colorectal Cancer (CRC) Metabolism. Cancers (Basel) 2020; 12:cancers12092462. [PMID: 32878019 PMCID: PMC7565715 DOI: 10.3390/cancers12092462] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers, with a high mortality rate globally. The pathophysiology of CRC is mainly initiated by alteration in gene expression, leading to dysregulation in multiple signalling pathways and cellular processes. Metabolic reprogramming is one of the important cancer hallmarks in CRC, which involves the adaptive changes in tumour cell metabolism to sustain the high energy requirements for rapid cell proliferation. There are several mechanisms in the metabolic reprogramming of cancer cells, such as aerobic glycolysis, oxidative phosphorylation, lactate and fatty acids metabolism. MicroRNAs (miRNAs) are a class of non-coding RNAs that are responsible for post-transcriptional regulation of gene expression. Differential expression of miRNAs has been shown to play an important role in different aspects of tumorigenesis, such as proliferation, apoptosis, and drug resistance, as well as metabolic reprogramming. Increasing evidence also reports that miRNAs could function as potential regulators of metabolic reprogramming in CRC cells. This review provides an insight into the role of different miRNAs in regulating the metabolism of CRC cells as well as to discuss the potential role of miRNAs as biomarkers or therapeutic targets in CRC tumour metabolism.
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Pidíkova P, Reis R, Herichova I. miRNA Clusters with Down-Regulated Expression in Human Colorectal Cancer and Their Regulation. Int J Mol Sci 2020; 21:E4633. [PMID: 32610706 PMCID: PMC7369991 DOI: 10.3390/ijms21134633] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/24/2020] [Accepted: 06/27/2020] [Indexed: 02/07/2023] Open
Abstract
Regulation of microRNA (miRNA) expression has been extensively studied with respect to colorectal cancer (CRC), since CRC is one of the leading causes of cancer mortality worldwide. Transcriptional control of miRNAs creating clusters can be, to some extent, estimated from cluster position on a chromosome. Levels of miRNAs are also controlled by miRNAs "sponging" by long non-coding RNAs (ncRNAs). Both types of miRNA regulation strongly influence their function. We focused on clusters of miRNAs found to be down-regulated in CRC, containing miR-1, let-7, miR-15, miR-16, miR-99, miR-100, miR-125, miR-133, miR-143, miR-145, miR-192, miR-194, miR-195, miR-206, miR-215, miR-302, miR-367 and miR-497 and analysed their genome position, regulation and functions. Only evidence provided with the use of CRC in vivo and/or in vitro models was taken into consideration. Comprehensive research revealed that down-regulated miRNA clusters in CRC are mostly located in a gene intron and, in a majority of cases, miRNA clusters possess cluster-specific transcriptional regulation. For all selected clusters, regulation mediated by long ncRNA was experimentally demonstrated in CRC, at least in one cluster member. Oncostatic functions were predominantly linked with the reviewed miRNAs, and their high expression was usually associated with better survival. These findings implicate the potential of down-regulated clusters in CRC to become promising multi-targets for therapeutic manipulation.
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Affiliation(s)
- Paulína Pidíkova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia;
| | - Richard Reis
- First Surgery Department, University Hospital, Comenius University in Bratislava, 811 07 Bratislava, Slovakia;
| | - Iveta Herichova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia;
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Turdo A, Porcelli G, D’Accardo C, Di Franco S, Verona F, Forte S, Giuffrida D, Memeo L, Todaro M, Stassi G. Metabolic Escape Routes of Cancer Stem Cells and Therapeutic Opportunities. Cancers (Basel) 2020; 12:E1436. [PMID: 32486505 PMCID: PMC7352619 DOI: 10.3390/cancers12061436] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/27/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
Although improvement in early diagnosis and treatment ameliorated life expectancy of cancer patients, metastatic disease still lacks effective therapeutic approaches. Resistance to anticancer therapies stems from the refractoriness of a subpopulation of cancer cells-termed cancer stem cells (CSCs)-which is endowed with tumor initiation and metastasis formation potential. CSCs are heterogeneous and diverge by phenotypic, functional and metabolic perspectives. Intrinsic as well as extrinsic stimuli dictated by the tumor microenvironment (TME)have critical roles in determining cell metabolic reprogramming from glycolytic toward an oxidative phenotype and vice versa, allowing cancer cells to thrive in adverse milieus. Crosstalk between cancer cells and the surrounding microenvironment occurs through the interchange of metabolites, miRNAs and exosomes that drive cancer cells metabolic adaptation. Herein, we identify the metabolic nodes of CSCs and discuss the latest advances in targeting metabolic demands of both CSCs and stromal cells with the scope of improving current therapies and preventing cancer progression.
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Affiliation(s)
- Alice Turdo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (A.T.); (C.D.); (M.T.)
| | - Gaetana Porcelli
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
| | - Caterina D’Accardo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (A.T.); (C.D.); (M.T.)
| | - Simone Di Franco
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
| | - Francesco Verona
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
| | - Stefano Forte
- Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), 95029 Catania, Italy; (S.F.); (D.G.); (L.M.)
| | - Dario Giuffrida
- Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), 95029 Catania, Italy; (S.F.); (D.G.); (L.M.)
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), 95029 Catania, Italy; (S.F.); (D.G.); (L.M.)
| | - Matilde Todaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (A.T.); (C.D.); (M.T.)
| | - Giorgio Stassi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
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Bekric D, Neureiter D, Ritter M, Jakab M, Gaisberger M, Pichler M, Kiesslich T, Mayr C. Long Non-Coding RNAs in Biliary Tract Cancer-An Up-to-Date Review. J Clin Med 2020; 9:jcm9041200. [PMID: 32331331 PMCID: PMC7231154 DOI: 10.3390/jcm9041200] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/31/2020] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
The term long non-coding RNA (lncRNA) describes non protein-coding transcripts with a length greater than 200 base pairs. The ongoing discovery, characterization and functional categorization of lncRNAs has led to a better understanding of the involvement of lncRNAs in diverse biological and pathological processes including cancer. Aberrant expression of specific lncRNA species was demonstrated in various cancer types and associated with unfavorable clinical characteristics. Recent studies suggest that lncRNAs are also involved in the development and progression of biliary tract cancer, a rare disease with high mortality and limited therapeutic options. In this review, we summarize current findings regarding the manifold roles of lncRNAs in biliary tract cancer and give an overview of the clinical and molecular consequences of aberrant lncRNA expression as well as of underlying regulatory functions of selected lncRNA species in the context of biliary tract cancer.
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Affiliation(s)
- Dino Bekric
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria;
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
| | - Markus Ritter
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Paracelsus Medical University, 5020 Salzburg, Austria
- Gastein Research Institute, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Martin Jakab
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
| | - Martin Gaisberger
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Paracelsus Medical University, 5020 Salzburg, Austria
- Gastein Research Institute, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Martin Pichler
- Research Unit of Non-Coding RNAs and Genome Editing, Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria;
| | - Tobias Kiesslich
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
| | - Christian Mayr
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
- Correspondence:
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Li WC, Huang CH, Hsieh YT, Chen TY, Cheng LH, Chen CY, Liu CJ, Chen HM, Huang CL, Lo JF, Chang KW. Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis. Front Oncol 2020; 10:176. [PMID: 32195170 PMCID: PMC7063098 DOI: 10.3389/fonc.2020.00176] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 01/31/2020] [Indexed: 12/15/2022] Open
Abstract
To support great demand of cell growth, cancer cells preferentially obtain energy and biomacromolecules by glycolysis over mitochondrial oxidative phosphorylation (OxPhos). Among all glycolytic enzymes, hexokinase (HK), a rate-limiting enzyme at the first step of glycolysis to catalyze cellular glucose into glucose-6-phosphate, is herein emphasized. Four HK isoforms, HK1-HK4, were discovered in nature. It was shown that HK2 expression is enriched in many tumor cells and correlated with poorer survival rates in most neoplastic cells. HK2-mediated regulations for cell malignancy and mechanistic cues in regulating head and neck tumorigenesis, however, are not fully elucidated. Cellular malignancy index, such as cell growth, cellular motility, and treatment sensitivity, and molecular alterations were determined in HK2-deficient head and neck squamous cell carcinoma (HNSCC) cells. By using various cancer databases, HK2, but not HK1, positively correlates with HNSCC progression in a stage-dependent manner. A high HK2 expression was detected in head and neck cancerous tissues compared with their normal counterparts, both in mouse and human subjects. Loss of HK2 in HNSCC cells resulted in reduced cell (in vitro) and tumor (in vivo) growth, as well as decreased epithelial-mesenchymal transition–mediated cell movement; in contrast, HK2-deficient HNSCC cells exhibited greater sensitivity to chemotherapeutic drugs cisplatin and 5-fluorouracil but are more resistant to photodynamic therapy, indicating that HK2 expression could selectively define treatment sensitivity in HNSCC cells. At the molecular level, it was found that HK2 alteration drove metabolic reprogramming toward OxPhos and modulated oncogenic Akt and mutant TP53-mediated signals in HNSCC cells. In summary, the present study showed that HK2 suppression could lessen HNSCC oncogenicity and modulate therapeutic sensitivity, thereby being an ideal therapeutic target for HNSCCs.
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Affiliation(s)
- Wan-Chun Li
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Chien-Hsiang Huang
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
| | - Yi-Ta Hsieh
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
| | - Tsai-Ying Chen
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
| | - Li-Hao Cheng
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
| | - Chang-Yi Chen
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
| | - Chung-Ji Liu
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Department of Oral and Maxillofacial Surgery, MacKay Memorial Hospital, Taipei, Taiwan.,Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Hsin-Ming Chen
- School of Dentistry and Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan
| | - Chien-Ling Huang
- Department of Health Technology and Informatics (HTI), The Hong Kong Polytechnic University (PolyU), Kowloon, Hong Kong
| | - Jeng-Fang Lo
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan.,Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Kuo-Wei Chang
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan.,Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan
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Garcia SN, Guedes RC, Marques MM. Unlocking the Potential of HK2 in Cancer Metabolism and Therapeutics. Curr Med Chem 2020; 26:7285-7322. [PMID: 30543165 DOI: 10.2174/0929867326666181213092652] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 10/26/2018] [Accepted: 11/06/2018] [Indexed: 12/24/2022]
Abstract
Glycolysis is a tightly regulated process in which several enzymes, such as Hexokinases (HKs), play crucial roles. Cancer cells are characterized by specific expression levels of several isoenzymes in different metabolic pathways and these features offer possibilities for therapeutic interventions. Overexpression of HKs (mostly of the HK2 isoform) have been consistently reported in numerous types of cancer. Moreover, deletion of HK2 has been shown to decrease cancer cell proliferation without explicit side effects in animal models, which suggests that targeting HK2 is a viable strategy for cancer therapy. HK2 inhibition causes a substantial decrease of glycolysis that affects multiple pathways of central metabolism and also destabilizes the mitochondrial outer membrane, ultimately enhancing cell death. Although glycolysis inhibition has met limited success, partly due to low selectivity for specific isoforms and excessive side effects of the reported HK inhibitors, there is ample ground for progress. The current review is focused on HK2 inhibition, envisaging the development of potent and selective anticancer agents. The information on function, expression, and activity of HKs is presented, along with their structures, known inhibitors, and reported effects of HK2 ablation/inhibition. The structural features of the different isozymes are discussed, aiming to stimulate a more rational approach to the design of selective HK2 inhibitors with appropriate drug-like properties. Particular attention is dedicated to a structural and sequence comparison of the structurally similar HK1 and HK2 isoforms, aiming to unveil differences that could be explored therapeutically. Finally, several additional catalytic- and non-catalytic roles on different pathways and diseases, recently attributed to HK2, are reviewed and their implications briefly discussed.
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Affiliation(s)
- Sara N Garcia
- Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal.,iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
| | - Rita C Guedes
- iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
| | - M Matilde Marques
- Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
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Pedroza-Torres A, Romero-Córdoba SL, Justo-Garrido M, Salido-Guadarrama I, Rodríguez-Bautista R, Montaño S, Muñiz-Mendoza R, Arriaga-Canon C, Fragoso-Ontiveros V, Álvarez-Gómez RM, Hernández G, Herrera LA. MicroRNAs in Tumor Cell Metabolism: Roles and Therapeutic Opportunities. Front Oncol 2019; 9:1404. [PMID: 31921661 PMCID: PMC6917641 DOI: 10.3389/fonc.2019.01404] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 11/27/2019] [Indexed: 12/16/2022] Open
Abstract
Dysregulated metabolism is a common feature of cancer cells and is considered a hallmark of cancer. Altered tumor-metabolism confers an adaptive advantage to cancer cells to fulfill the high energetic requirements for the maintenance of high proliferation rates, similarly, reprogramming metabolism confers the ability to grow at low oxygen concentrations and to use alternative carbon sources. These phenomena result from the dysregulated expression of diverse genes, including those encoding microRNAs (miRNAs) which are involved in several metabolic and tumorigenic pathways through its post-transcriptional-regulatory activity. Further, the identification of key actionable altered miRNA has allowed to propose novel targeted therapies to modulated tumor-metabolism. In this review, we discussed the different roles of miRNAs in cancer cell metabolism and novel miRNA-based strategies designed to target the metabolic machinery in human cancer.
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Affiliation(s)
- Abraham Pedroza-Torres
- Cátedra CONACyT-Clínica de Cáncer Hereditario, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Sandra L Romero-Córdoba
- Departamento de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - Montserrat Justo-Garrido
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas - Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Iván Salido-Guadarrama
- Biología Computacional, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas", Mexico City, Mexico
| | - Rubén Rodríguez-Bautista
- Unidad de Oncología Torácica y Laboratorio de Medicina Personalizada, Instituto Nacional de Cancerologia, Mexico City, Mexico
| | - Sarita Montaño
- Laboratorio de Bioinformática, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Sinaloa (FCQB-UAS), Culiacán, Mexico
| | - Rodolfo Muñiz-Mendoza
- Clínica de Cáncer Hereditario, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Cristian Arriaga-Canon
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas - Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | | | | | - Greco Hernández
- Laboratorio de Traducción y Cáncer, Unidad de Investigaciones Biomedicas en Cáncer, Instituto Nacional de Cancerolgía, Mexico City, Mexico
| | - Luis A Herrera
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas - Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
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Pinweha P, Phillips CA, Gregory PA, Li X, Chuayboonya P, Mongkolsiri P, Goodall GJ, Jitrapakdee S. MicroRNA-143-3p targets pyruvate carboxylase expression and controls proliferation and migration of MDA-MB-231 cells. Arch Biochem Biophys 2019; 677:108169. [DOI: 10.1016/j.abb.2019.108169] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/31/2019] [Accepted: 11/02/2019] [Indexed: 01/06/2023]
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Mesgarzadeh AH, Aali M, Farhadi F, Noorolyai S, Baghbani E, Mohammadnejad F, Baradaran B. Transfection of microRNA-143 mimic could inhibit migration of HN-5 cells through down-regulating of metastatic genes. Gene 2019; 716:144033. [DOI: 10.1016/j.gene.2019.144033] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/30/2019] [Accepted: 07/31/2019] [Indexed: 11/17/2022]
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40
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Ullmann P, Nurmik M, Begaj R, Haan S, Letellier E. Hypoxia- and MicroRNA-Induced Metabolic Reprogramming of Tumor-Initiating Cells. Cells 2019; 8:E528. [PMID: 31159361 PMCID: PMC6627778 DOI: 10.3390/cells8060528] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/28/2019] [Accepted: 05/28/2019] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC), the second most common cause of cancer mortality in the Western world, is a highly heterogeneous disease that is driven by a rare subpopulation of tumorigenic cells, known as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Over the past few years, a plethora of different approaches, aimed at identifying and eradicating these self-renewing TICs, have been described. A focus on the metabolic and bioenergetic differences between TICs and less aggressive differentiated cancer cells has thereby emerged as a promising strategy to specifically target the tumorigenic cell compartment. Extrinsic factors, such as nutrient availability or tumor hypoxia, are known to influence the metabolic state of TICs. In this review, we aim to summarize the current knowledge on environmental stress factors and how they affect the metabolism of TICs, with a special focus on microRNA (miRNA)- and hypoxia-induced effects on colon TICs.
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Affiliation(s)
- Pit Ullmann
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
| | - Martin Nurmik
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
| | - Rubens Begaj
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
| | - Serge Haan
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
| | - Elisabeth Letellier
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg.
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Nisha KJ, Janam P, Harshakumar K. Identification of a novel salivary biomarker miR-143-3p for periodontal diagnosis: A proof of concept study. J Periodontol 2019; 90:1149-1159. [PMID: 31021403 DOI: 10.1002/jper.18-0729] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 03/22/2019] [Accepted: 03/22/2019] [Indexed: 01/06/2023]
Abstract
BACKGROUND Though the use of salivary miRNAs as potential biomarkers has been reported in few diseases/conditions such as rheumatoid arthritis and oral cancer, there are no reported studies on their utility in periodontal diagnostics. Thus, the aim of the present study was to profile salivary miRNAs and identify the most suitable salivary miRNA biomarker in chronic periodontitis. METHODS In this study, we have explored the potential application of next generation sequencing (NGS) technology for profiling miRNAs in two unstimulated saliva samples collected by passive drool method from a patient diagnosed with generalized chronic periodontitis and a healthy control. Subsequently, the validation of most highly expressed known miRNA in periodontitis was performed in saliva samples collected from an independent set of 16 chronic periodontitis patients and 16 periodontally healthy controls using quantitative real-time PCR (qRT-PCR). Target gene prediction and pathway mapping were performed using bioinformatic tools. RESULTS NGS analysis identified 40 upregulated and 40 downregulated known miRNAs in chronic periodontitis compared to healthy controls, of which miR-143-3p was the most highly expressed miRNA in periodontitis (Read count - 227630; fold change - 5.82). Validation using qRT-PCR showed significant upregulation of miR-143-3p expression in the test group compared with controls (P < 0.05). K-RAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene) gene was predicted as the target gene for miR-143-3p in humans. KEGG (Kyoto Encyclopedia of genes and genomes) pathway mapping revealed the involvement of K-RAS in mitogen-activated protein kinases (MAPK) pathway. CONCLUSIONS The application of NGS for miRNA expression profiling can be considered a valuable tool in detection of novel biomarkers in periodontal diagnostics. Also, the results of the study points to the potential utility of miR143-3p as a novel salivary biomarker for chronic periodontitis.
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Affiliation(s)
- K J Nisha
- Department of Periodontics, Vydehi Institute of Dental Sciences and Research Centre, Bangalore, Karnataka, India
| | - Presanthila Janam
- Department of Periodontics, PMS College of Dental Science and Research, Thiruvananthapuram, Kerala, India
| | - K Harshakumar
- Department of Prosthodontics, Government Dental College, Thiruvananthapuram, Kerala, India
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Bound polyphenol from foxtail millet bran exhibits an antiproliferative activity in HT-29 cells by reprogramming miR-149-mediated aerobic glycolysis. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.03.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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B7-H3 promotes aerobic glycolysis and chemoresistance in colorectal cancer cells by regulating HK2. Cell Death Dis 2019; 10:308. [PMID: 30952834 PMCID: PMC6450969 DOI: 10.1038/s41419-019-1549-6] [Citation(s) in RCA: 170] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 03/22/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023]
Abstract
Accumulating evidence suggests that aerobic glycolysis is important for colorectal cancer (CRC) development. However, the underlying mechanisms have yet to be elucidated. B7-H3, an immunoregulatory protein, is broadly overexpressed by multiple tumor types and plays a vital role in tumor progression. In this study, we found that overexpression of B7-H3 effectively increased the rate of glucose consumption and lactate production, whereas knockdown of B7-H3 had the opposite effect. Furthermore, we showed that B7-H3 increased glucose consumption and lactate production by promoting hexokinase 2 (HK2) expression in CRC cells, and we also found that HK2 was a key mediator of B7-H3-induced CRC chemoresistance. Depletion of HK2 expression or treating cells with HK2 inhibitors could reverse the B7-H3-induced increase in aerobic glycolysis and B7-H3-endowed chemoresistance of cancer cells. Moreover, we verified a positive correlation between the expression of B7-H3 and HK2 in tumor tissues of CRC patients. Collectively, our findings suggest that B7-H3 may be a novel regulator of glucose metabolism and chemoresistance via controlling HK2 expression in CRC cells, a result that could help develop B7-H3 as a promising therapeutic target for CRC treatment.
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Chen J, Yu Y, Li H, Hu Q, Chen X, He Y, Xue C, Ren F, Ren Z, Li J, Liu L, Duan Z, Cui G, Sun R. Long non-coding RNA PVT1 promotes tumor progression by regulating the miR-143/HK2 axis in gallbladder cancer. Mol Cancer 2019; 18:33. [PMID: 30825877 PMCID: PMC6397746 DOI: 10.1186/s12943-019-0947-9] [Citation(s) in RCA: 284] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 01/23/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The long non-coding RNA PVT1 (lncRNA PVT1) has been reported to act as an oncogenic regulator of several cancers. However, its expression and function in gallbladder cancer (GBC) remain largely unknown. METHODS In situ hybridization (ISH) and quantitative real-time PCR (qPCR) were performed to detect the expression of PVT1 and miR-143 in GBC tissues and cell lines. Immunohistochemistry (IHC) assays were performed to assess the expression of the hexokinase 2 (HK2) protein. The relationships among PVT1, miR-143 and HK2 were evaluated using dual-luciferase reporter, RNA immunoprecipitation (RIP) and biotin pull-down assays. The biological functions of PVT1, miR-143 and HK2 in GBC cells were explored with cell counting kit 8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU), colony formation, transwell, wound healing and glucose metabolism assays in vitro. For in vivo experiments, a xenograft model was used to investigate the effects of PVT1 and HK2 on GBC. RESULTS PVT1 was upregulated in GBC tissues and cells and was positively associated with malignancies and worse overall survival. PVT1 knockdown inhibited cell proliferation, migration, and invasion in vitro and restrained tumor growth in vivo. Further studies demonstrated that PVT1 positively regulated HK2 expression via its competing endogenous RNA (ceRNA) activity on miR-143. Additionally, HK2 expression and function were positively correlated with PVT1. Furthermore, we observed that the PVT1/miR-143/HK2 axis promoted cell proliferation and metastasis by regulating aerobic glucose metabolism in GBC cells. CONCLUSIONS The results of our study reveal a potential ceRNA regulatory pathway in which PVT1 modulates HK2 expression by competitively binding to endogenous miR-143 in GBC cells, which may provide new insights into novel molecular therapeutic targets for GBC.
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Affiliation(s)
- Jianan Chen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Yan Yu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Hua Li
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Qiuyue Hu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Xiaolong Chen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Yuting He
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Chen Xue
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Fang Ren
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Zhigang Ren
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Juan Li
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Liwen Liu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Zhenfeng Duan
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095 USA
| | - Guangying Cui
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Ranran Sun
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- National Engineering Laboratory for Internet Medical System and Application, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
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Lyu X, Wang J, Guo X, Wu G, Jiao Y, Faleti OD, Liu P, Liu T, Long Y, Chong T, Yang X, Huang J, He M, Tsang CM, Tsao SW, Wang Q, Jiang Q, Li X. EBV-miR-BART1-5P activates AMPK/mTOR/HIF1 pathway via a PTEN independent manner to promote glycolysis and angiogenesis in nasopharyngeal carcinoma. PLoS Pathog 2018; 14:e1007484. [PMID: 30557400 PMCID: PMC6312352 DOI: 10.1371/journal.ppat.1007484] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 12/31/2018] [Accepted: 11/23/2018] [Indexed: 12/17/2022] Open
Abstract
Abnormal metabolism and uncontrolled angiogenesis are two important characteristics of malignant tumors. The occurrence of both events involves many key molecular changes including miRNA. However, EBV encoded miRNAs are rarely mentioned as capable of regulating tumor metabolism and tumor angiogenesis. Here, we reported that one of the key miRNAs encoded by EBV, EBV-miR-Bart1-5P, can significantly promote nasopharyngeal carcinoma (NPC) cell glycolysis and induces angiogenesis in vitro and in vivo. Mechanistically, EBV-miR-Bart1-5P directly targets the α1 catalytic subunit of AMP-activated protein kinase (AMPKα1) and consequently regulates the AMPK/mTOR/HIF1 pathway which impelled NPC cell anomalous aerobic glycolysis and angiogenesis, ultimately leads to uncontrolled growth of NPC. Our findings provide new insights into metabolism and angiogenesis of NPC and new opportunities for the development of targeted NPC therapy in the future. The Epstein-Barr virus (EBV), the first reported human tumor virus found to encode miRNAs, which closely related to malignant progression of tumors. In our study, we have observed that EBV-miR-BART1-5P, an EBV-BARTs encoded miRNA, promotes glycolysis and induces angiogenesis in NPC. Interestingly, we showed that overexpression of EBV-miR -BART1-5P and restored PTEN at the same time, did not completely reverse the phenotypes of glycolysis, angiogenesis and proliferation, suggesting that EBV-miR-BART1-5P can mediate glycolysis and induction angiogenesis by a PTEN-independent manner. Further mechanism exploration demonstrated that EBV-miR-BART1-5P has important roles in cancer cell glucose metabolism and angiogenesis by inhibiting AMPKα1 and PTEN, which provides a molecular basis for the regulation of AMPK/mTOR/HIF1 and PTEN/FAK, Shc, AKT pathways, respectively.
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Affiliation(s)
- Xiaoming Lyu
- Department of laboratory medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, P.R. China
- * E-mail: (XL); (QJ); (XL)
| | - Jianguo Wang
- Department of laboratory medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Xia Guo
- Shenzhen Key Laboratory of Viral Oncology, the Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Gongfa Wu
- Department of Pathology, Zengcheng District People’s Hospital of Guangzhou City, Guangzhou, P.R. China
| | - Yang Jiao
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | | | - Pengfei Liu
- Department of laboratory medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Tielian Liu
- Department of laboratory medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Yufei Long
- Shenzhen Key Laboratory of Viral Oncology, the Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Tuotuo Chong
- Shenzhen Key Laboratory of Viral Oncology, the Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Xu Yang
- Shenzhen Key Laboratory of Viral Oncology, the Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jing Huang
- Department of laboratory medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Mingliang He
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Chi Man Tsang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Sai Wah Tsao
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Qian Wang
- Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Qiang Jiang
- Shenzhen Key Laboratory of Viral Oncology, the Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China
- Department of Oncology, Henan Provincial People’s Hospital, Zhengzhou, P.R. China
- * E-mail: (XL); (QJ); (XL)
| | - Xin Li
- Shenzhen Key Laboratory of Viral Oncology, the Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China
- * E-mail: (XL); (QJ); (XL)
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Targeting MicroRNA-143 Leads to Inhibition of Glioblastoma Tumor Progression. Cancers (Basel) 2018; 10:cancers10100382. [PMID: 30322013 PMCID: PMC6210372 DOI: 10.3390/cancers10100382] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 10/03/2018] [Accepted: 10/08/2018] [Indexed: 12/11/2022] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive of all brain tumors, with a median survival of only 14 months after initial diagnosis. Novel therapeutic approaches are an unmet need for GBM treatment. MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level. Several dysregulated miRNAs have been identified in all cancer types including GBM. In this study, we aimed to uncover the role of miR-143 in GBM cell lines, patient samples, and mouse models. Quantitative real-time RT-PCR of RNA extracted from formalin-fixed paraffin-embedded (FFPE) samples showed that the relative expression of miR-143 was higher in GBM patients compared to control individuals. Transient transfection of GBM cells with a miR-143 oligonucleotide inhibitor (miR-143-inh) resulted in reduced cell proliferation, increased apoptosis, and cell cycle arrest. SLC30A8, a glucose metabolism-related protein, was identified as a direct target of miR-143 in GBM cells. Moreover, multiple injections of GBM tumor-bearing mice with a miR-143-inh-liposomal formulation significantly reduced tumor growth compared to control mice. The reduced in vitro cell growth and in vivo tumor growth following miRNA-143 inhibition suggests that miR-143 is a potential therapeutic target for GBM therapy.
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Zhao W, Li W, Dai W, Huang N, Qiu J. LINK-A promotes cell proliferation through the regulation of aerobic glycolysis in non-small-cell lung cancer. Onco Targets Ther 2018; 11:6071-6080. [PMID: 30275711 PMCID: PMC6158004 DOI: 10.2147/ott.s171216] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Non-small-cell lung cancer (NSCLC) is the one of the most common malignancies worldwide, and occurs at a higher frequency in male individuals. Little is known about the role of the long intergenic noncoding RNA for kinase activation (LINK-A) in NSCLC, so in the present study we assessed its potential role on cell proliferation in NSCLC. METHODS Expression levels of LINK-A in NSCLC tissues and cell lines were detected by quantitative reverse-transcription polymerase chain reaction. LINK-A was knocked down and overexpressed separately in A549 cells and NCI-H1299 cells. The effect of LINK-A expression on cell proliferation was determined by MTT assay. The correlation between LINK-A and hexokinase II (HKII) expression was investigated by Western blot and HKII Activity Assay. Glucose consumption and lactate production assay were used to investigate the aerobic glycolysis in NSCLC cells. The effect of LINK-A in vivo was determined by xenograft assay. RESULTS LINK-A expression levels were increased in NSCLC tissues compared with normal tissues. Moreover, LINK-A expression was positively correlated with NSCLC clinicopathological characteristics and survival rate, while knockdown of LINK-A reduced NSCLC cell proliferation. LINK-A expression was also positively correlated with HKII, and NSCLC cells with low LINK-A expression were found to have significantly reduced HKII protein expression, accompanied by a reduction in enzyme activity levels. Both in vitro and in vivo experiments showed that LINK-A expression affected glucose consumption and lactate production through regulation of HKII expression. CONCLUSION These data suggest that the functions of LINK-A in NSCLC might play a key role in tumor progression and that LINK-A could be a promising predictive biomarker and potential therapeutic target for NSCLC.
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Affiliation(s)
- Wei Zhao
- Department of Clinical Biochemistry, School of Laboratory Medicine, Chengdu Medical College, Chengdu, People's Republic of China,
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, People's Republic of China,
| | - Wancheng Li
- Department of Respiratory Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, People's Republic of China
| | - Wenjing Dai
- Department of Respiratory Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, People's Republic of China
| | - Na Huang
- Department of Respiratory Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, People's Republic of China
| | - Jing Qiu
- Department of Respiratory Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, People's Republic of China
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Zhou M, Chen X, Wu J, He X, Ren R. MicroRNA-143 regulates cell migration and invasion by targeting GOLM1 in cervical cancer. Oncol Lett 2018; 16:6393-6400. [PMID: 30405775 PMCID: PMC6202488 DOI: 10.3892/ol.2018.9441] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 09/03/2018] [Indexed: 12/20/2022] Open
Abstract
Accumulated research has revealed that the abnormal expression of microRNAs play a crucial role in tumorigenesis, potentially serving as therapeutic biomarkers in multiple tumors including cervical cancer. However, the expression level, biological role and the underlying mechanism of miRNA-143 in cervical cancer remain unclear. In the current study, we analyzed the miRNA-143 and golgi membrane protein 1 (GOLM1) expression in cervical cancer tissues and cells to explore their effects on cervical cancer occurrence and metastasis. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect the miRNA-143 expression in cervical cancer tissues and cells. Following transfection, cell Transwell assays, western blot analysis and luciferase reporter assays were carried out in human cervical cancer cells. Results demonstrated that the miRNA-143 expression was dramatically decreased in both cervical cancer tissue samples and cells in contrast with the control group. We also found that the miRNA-143 expression negatively correlated with the GOLM1 expression in cervical cancer tissues and miRNA-143 inhibited cell invasion and migration via targeting GOLM1 in cervical cancer.
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Affiliation(s)
- Meiying Zhou
- Department of Gynecology, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Xiaohong Chen
- Department of Gynecology, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Jian Wu
- Department of Burn, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Xiaoyan He
- Department of Gynecology, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Rui Ren
- Department of Gynecology, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
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Iqbal MA, Arora S, Prakasam G, Calin GA, Syed MA. MicroRNA in lung cancer: role, mechanisms, pathways and therapeutic relevance. Mol Aspects Med 2018; 70:3-20. [PMID: 30102929 DOI: 10.1016/j.mam.2018.07.003] [Citation(s) in RCA: 306] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 07/28/2018] [Accepted: 07/30/2018] [Indexed: 12/29/2022]
Abstract
Lung cancer is the cardinal cause of cancer-related deaths with restricted recourse of therapy throughout the world. Clinical success of therapies is not very promising due to - late diagnosis, limited therapeutic tools, relapse and the development of drug resistance. Recently, small ∼20-24 nucleotides molecules called microRNAs (miRNAs) have come into the limelight as they play outstanding role in the process of tumorigenesis by regulating cell cycle, metastasis, angiogenesis, metabolism and apoptosis. miRNAs essentially regulate gene expression via post-transcriptional regulation of mRNA. Nevertheless, few studies have conceded the role of miRNAs in activation of gene expression. A large body of data generated by numerous studies is suggestive of their tumor-suppressing, oncogenic, diagnostic and prognostic biomarker roles in lung cancer. They have also been implicated in regulating cancer cell metabolism and resistance or sensitivity towards chemotherapy and radiotherapy. Further, miRNAs have also been convoluted in regulation of immune checkpoints - Programmed death 1 (PD-1) and its ligand (PD-L1). These molecules play a significant role in tumor immune escape leading to the generation of a microenvironment favouring tumor growth and progression. Therefore, it is imperative to explore the expression of miRNA and understand its relevance in lung cancer and development of anti-cancer strategies (anti - miRs, miR mimics and micro RNA sponges). In view of the above, the role of miRNA in lung cancer has been dissected and the associated mechanisms and pathways are discussed in this review.
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Affiliation(s)
- Mohammad Askandar Iqbal
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi-110025, India.
| | - Shweta Arora
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi-110025, India.
| | - Gopinath Prakasam
- School of Life Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
| | - George A Calin
- Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX-77030, USA.
| | - Mansoor Ali Syed
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi-110025, India.
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Kasomva K, Sen A, Paulraj MG, Sailo S, Raphael V, Puro KU, Assumi SR, Ignacimuthu S. Roles of microRNA in prostate cancer cell metabolism. Int J Biochem Cell Biol 2018; 102:109-116. [PMID: 30010013 DOI: 10.1016/j.biocel.2018.07.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 07/02/2018] [Accepted: 07/11/2018] [Indexed: 02/08/2023]
Abstract
MicroRNAs are non-coding RNA which functions as regulators of genes expression. MicroRNAs have shown their biological functions in cell proliferation, cell cycle, cell metabolism, apoptosis, invasion and metastasis. Cancer cells have the ability to grow in the absence of growth factors by increased metabolic activity. MicroRNAs regulate cell metabolic processes by targeting the key enzymes or transporters and change the metabolic activities by interfering with oncogenes/tumor suppressors, hypoxia, signalling pathways and cell adhesion. This review mainly explains the roles of microRNAs in prostate cancer cell metabolism, such as glucose uptake, glycolysis and lactate secretion, lipid metabolism and interaction with signalling pathways. The relation of microRNAs with hypoxia and cell adhesion in cell metabolism is also highlighted. Therefore, miRNAs help in regulating the metabolism of survived tumor cells, understanding such miRNA-mediated interaction could lead to new avenues in therapeutic application to treat PCa.
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Affiliation(s)
- Khanmi Kasomva
- Biotechnology & Molecular Biology Unit, Entomology Research Institute, Loyola College, Chennai, 600 034, India; Division of Animal health, ICAR Research Complex for NEH Region, Umiam, 793 103, Meghalaya, India; Department of Urology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, 793 018, Meghalaya, India
| | - Arnab Sen
- Division of Animal health, ICAR Research Complex for NEH Region, Umiam, 793 103, Meghalaya, India
| | - Michael Gabriel Paulraj
- Biotechnology & Molecular Biology Unit, Entomology Research Institute, Loyola College, Chennai, 600 034, India
| | - Stephen Sailo
- Department of Urology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, 793 018, Meghalaya, India
| | - Vandana Raphael
- Department of Pathology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, 793 018, Meghalaya, India
| | - Kekungu-U Puro
- Division of Animal health, ICAR Research Complex for NEH Region, Umiam, 793 103, Meghalaya, India
| | | | - Savarimuthu Ignacimuthu
- Biotechnology & Molecular Biology Unit, Entomology Research Institute, Loyola College, Chennai, 600 034, India; International Scientific Partnership Program, King Saud University, Saudi Arabia.
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