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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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Cui X, Lei X, Huang T, Mao X, Shen Z, Yang X, Peng W, Yu J, Zhang S, Huo P. Follicular fluid-derived extracellular vesicles miR-34a-5p regulates granulosa cell glycolysis in polycystic ovary syndrome by targeting LDHA. J Ovarian Res 2024; 17:223. [PMID: 39538292 PMCID: PMC11562512 DOI: 10.1186/s13048-024-01542-w] [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: 07/27/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is highly prevalent in women of reproductive age worldwide, exhibits highly heterogeneous clinical presentation and biochemical parameters, and has no cure. This study aimed to investigate the role of miR-34a-5p in PCOS, its effect on glycolysis in granulosa cells (GCs), and its potential contribution to follicular dysregulation. METHODS Herein, Follicular follicular fluid (FF) samples were collected from six patients with PCOS and six healthy controls undergoing in vitro fertilization-embryo transfer. The isolated extracellular vesicles were characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Additionally, miRNA sequencing was performed to identify differentially expressed microRNAs, and their functions were analyzed through transcriptomics. The In vitro effects of miR-34a-5p on glycolysis, cell proliferation, and apoptosis were assessed in human ovarian granulosa tumour cell line (KGN cells). Targets of miR-34a-5p were identified by dual-luciferase reporter assays, and quantitative real-time polymerase chain reaction and western blotting were performed to determine gene and protein expression. RESULTS The level of miR-34a-5p in FF-derived extracellular vesicles derived from patients with PCOS was significantly higher than that of the control group. Transcriptomic analysis highlighted miR-34a-5p as a key regulator of glycolysis and apoptosis. Furthermore, in vitro analysis showed that miR-34a-5p targeted lactate dehydrogenase A (LDHA), inhibited glycolysis, reduced energy supply to GCs, and promoted apoptosis of KGN cells. Conversely, miR-34a-5p inhibition restored glycolysis function and cell viability. CONCLUSION The findings of this study show that miR-34a-5p mediates GC apoptosis in PCOS by targeting LDHA and inhibiting glycolysis, suggesting its crucial role in PCOS pathophysiology, and offering potential therapeutic targets for improving follicular development and fertility outcomes in patients with PCOS. Further research is needed to explore the clinical implications of miR-34a-5p and its use as a biomarker for early diagnosis and prognosis of PCOS.
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Affiliation(s)
- Xueying Cui
- Department of Reproductive Medical Center, The Affiliated Hospital of Guilin Medical University, Guilin, 541004, Guangxi, China
| | - Xiaocan Lei
- Clinical Anatomy and Reproductive Medicine Application Institute, Department of Histology and Embryology, University of South China, Hengyang, 421001, Hunan, China
| | - Tao Huang
- The Second Affiliated Hospital of Guilin Medical University, Guilin, 541100, Guangxi, China
| | - Xueyan Mao
- Clinical Anatomy and Reproductive Medicine Application Institute, Department of Histology and Embryology, University of South China, Hengyang, 421001, Hunan, China
| | - Zhiwei Shen
- Clinical Anatomy and Reproductive Medicine Application Institute, Department of Histology and Embryology, University of South China, Hengyang, 421001, Hunan, China
| | - Xiuli Yang
- Department of Reproductive Medical Center, The Affiliated Hospital of Guilin Medical University, Guilin, 541004, Guangxi, China
| | - Wanting Peng
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin, 541004, Guangxi, China
| | - Jingjing Yu
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin, 541004, Guangxi, China
| | - Shun Zhang
- Department of Reproductive Medical Center, The Affiliated Hospital of Guilin Medical University, Guilin, 541004, Guangxi, China.
| | - Peng Huo
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin, 541004, Guangxi, China.
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Mu M, Lu Y, Tu K, Tu L, Guo C, Li Z, Zhang X, Chen Y, Liu X, Xu Q, Huang D, Li X. FAM188B promotes the growth, metastasis, and invasion of hepatocellular carcinoma by targeting the hnRNPA1/PKM2 axis. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119773. [PMID: 38844182 DOI: 10.1016/j.bbamcr.2024.119773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 05/27/2024] [Accepted: 05/29/2024] [Indexed: 06/10/2024]
Abstract
Hepatocellular carcinoma (HCC), the leading cause of cancer-related deaths worldwide, is characterised by rapid growth and marked invasiveness. Accumulating evidence suggests that deubiquitinases play a pivotal role in HCC growth and metastasis. However, the expression of the deubiquitinase FAM188B and its biological functions in HCC remain unknown. The aim of our study was to investigate the potential role of FAM188B in HCC. The expression of FAM188B was significantly upregulated in liver cancer cells compared to normal liver cells, both at the transcriptional and translational levels. Similarly, FAM188B expression was higher in liver cancer tissues than in normal liver tissues. Bioinformatic analysis revealed that high FAM188B expression was associated with poor prognosis in patients with HCC. We further demonstrated that FAM188B knockdown inhibited cell proliferation, epithelial-mesenchymal transition, migration and invasion both in vitro and in vivo. Mechanistically, FAM188B knockdown significantly inhibited the hnRNPA1/PKM2 pathway in HCC cells. FAM188B may inhibit ubiquitin-mediated degradation of hnRNPA1 through deubiquitination. Notably, we observed that the inhibitory effects of FAM188B knockdown on HCC cell proliferation, migration and invasion were reversed when hnRNPA1 expression was restored. In conclusion, FAM188B promotes HCC progression by enhancing the deubiquitination of hnRNPA1 and subsequently activating the hnRNPA1/PKM2 pathway. Therefore, targeting FAM188B is a potential strategy for HCC therapy.
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Affiliation(s)
- Mingshan Mu
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou 310053, Zhejiang, China
| | - Yisong Lu
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou 310053, Zhejiang, China
| | - Kangsheng Tu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China
| | - Linglan Tu
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou 310053, Zhejiang, China
| | - Chaoqin Guo
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou 310053, Zhejiang, China
| | - Zilin Li
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou 310053, Zhejiang, China
| | - Xu Zhang
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou 310053, Zhejiang, China
| | - Yihong Chen
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou 310053, Zhejiang, China
| | - Xin Liu
- Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, Zhejiang, China
| | - Qiuran Xu
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou 310053, Zhejiang, China; Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, Zhejiang, China.
| | - Dongsheng Huang
- Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, Zhejiang, China.
| | - Xiaoyan Li
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou 310053, Zhejiang, China; Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, Zhejiang, China.
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4
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Li F, Li W. Readers of RNA Modification in Cancer and Their Anticancer Inhibitors. Biomolecules 2024; 14:881. [PMID: 39062595 PMCID: PMC11275166 DOI: 10.3390/biom14070881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/19/2024] [Accepted: 07/21/2024] [Indexed: 07/28/2024] Open
Abstract
Cancer treatment has always been a challenge for humanity. The inadequacies of current technologies underscore the limitations of our efforts against this disease. Nevertheless, the advent of targeted therapy has introduced a promising avenue, furnishing us with more efficacious tools. Consequently, researchers have turned their attention toward epigenetics, offering a novel perspective in this realm. The investigation of epigenetics has brought RNA readers to the forefront, as they play pivotal roles in recognizing and regulating RNA functions. Recently, the development of inhibitors targeting these RNA readers has emerged as a focal point in research and holds promise for further strides in targeted therapy. In this review, we comprehensively summarize various types of inhibitors targeting RNA readers, including non-coding RNA (ncRNA) inhibitors, small-molecule inhibitors, and other potential inhibitors. We systematically elucidate their mechanisms in suppressing cancer progression by inhibiting readers, aiming to present inhibitors of readers at the current stage and provide more insights into the development of anticancer drugs.
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Affiliation(s)
| | - Wenjin Li
- Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China;
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5
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Li Y, Zhang S, Li Y, Liu J, Li Q, Zang W, Pan Y. The Regulatory Network of hnRNPs Underlying Regulating PKM Alternative Splicing in Tumor Progression. Biomolecules 2024; 14:566. [PMID: 38785973 PMCID: PMC11117501 DOI: 10.3390/biom14050566] [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: 03/30/2024] [Revised: 04/26/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
One of the hallmarks of cancer is metabolic reprogramming in tumor cells, and aerobic glycolysis is the primary mechanism by which glucose is quickly transformed into lactate. As one of the primary rate-limiting enzymes, pyruvate kinase (PK) M is engaged in the last phase of aerobic glycolysis. Alternative splicing is a crucial mechanism for protein diversity, and it promotes PKM precursor mRNA splicing to produce PKM2 dominance, resulting in low PKM1 expression. Specific splicing isoforms are produced in various tissues or illness situations, and the post-translational modifications are linked to numerous disorders, including cancers. hnRNPs are one of the main components of the splicing factor families. However, there have been no comprehensive studies on hnRNPs regulating PKM alternative splicing. Therefore, this review focuses on the regulatory network of hnRNPs on PKM pre-mRNA alternative splicing in tumors and clinical drug research. We elucidate the role of alternative splicing in tumor progression, prognosis, and the potential mechanism of abnormal RNA splicing. We also summarize the drug targets retarding tumorous splicing events, which may be critical to improving the specificity and effectiveness of current therapeutic interventions.
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Affiliation(s)
- Yuchao Li
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang 110002, China; (Y.L.); (S.Z.); (J.L.); (Q.L.); (W.Z.)
| | - Shuwei Zhang
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang 110002, China; (Y.L.); (S.Z.); (J.L.); (Q.L.); (W.Z.)
| | - Yuexian Li
- Department of Radiation Oncology Gastrointestinal and Urinary and Musculoskeletal Cancer, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang 110042, China;
| | - Junchao Liu
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang 110002, China; (Y.L.); (S.Z.); (J.L.); (Q.L.); (W.Z.)
| | - Qian Li
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang 110002, China; (Y.L.); (S.Z.); (J.L.); (Q.L.); (W.Z.)
| | - Wenli Zang
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang 110002, China; (Y.L.); (S.Z.); (J.L.); (Q.L.); (W.Z.)
| | - Yaping Pan
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang 110002, China; (Y.L.); (S.Z.); (J.L.); (Q.L.); (W.Z.)
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Upadhyay S, Khan S, Hassan MI. Exploring the diverse role of pyruvate kinase M2 in cancer: Navigating beyond glycolysis and the Warburg effect. Biochim Biophys Acta Rev Cancer 2024; 1879:189089. [PMID: 38458358 DOI: 10.1016/j.bbcan.2024.189089] [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: 12/20/2023] [Revised: 02/25/2024] [Accepted: 03/03/2024] [Indexed: 03/10/2024]
Abstract
Pyruvate Kinase M2, a key enzyme in glycolysis, has garnered significant attention in cancer research due to its pivotal role in the metabolic reprogramming of cancer cells. Originally identified for its association with the Warburg effect, PKM2 has emerged as a multifaceted player in cancer biology. The functioning of PKM2 is intricately regulated at multiple levels, including controlling the gene expression via various transcription factors and non-coding RNAs, as well as adding post-translational modifications that confer distinct functions to the protein. Here, we explore the diverse functions of PKM2, encompassing newly emerging roles in non-glycolytic metabolic regulation, immunomodulation, inflammation, DNA repair and mRNA processing, beyond its canonical role in glycolysis. The ever-expanding list of its functions has recently grown to include roles in subcellular compartments such as the mitochondria and extracellular milieu as well, all of which make PKM2 an attractive drug target in the pursuit of therapeutics for cancer.
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Affiliation(s)
- Saurabh Upadhyay
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
| | - Shumayila Khan
- International Health Division, Indian Council of Medical Research, Ansari Nagar, New Delhi 110029, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.
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7
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Varlı M, Bhosle SR, Kim E, Yang Y, Taş İ, Zhou R, Pulat S, Gamage CDB, Park SY, Ha HH, Kim H. Usnic Acid Targets 14-3-3 Proteins and Suppresses Cancer Progression by Blocking Substrate Interaction. JACS AU 2024; 4:1521-1537. [PMID: 38665668 PMCID: PMC11040559 DOI: 10.1021/jacsau.3c00774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 03/07/2024] [Accepted: 03/19/2024] [Indexed: 04/28/2024]
Abstract
The anticancer therapeutic effects of usnic acid (UA), a lichen secondary metabolite, have been demonstrated in vitro and in vivo. However, the mechanism underlying the anticancer effect of UA remains to be clarified. In this study, the target protein of UA was identified using a UA-linker-Affi-Gel molecule, which showed that UA binds to the 14-3-3 protein. UA binds to 14-3-3, causing the degradation of proteasomal and autophagosomal proteins. The interaction of UA with 14-3-3 isoforms modulated cell invasion, cell cycle progression, aerobic glycolysis, mitochondrial biogenesis, and the Akt/mTOR, JNK, STAT3, NF-κB, and AP-1 signaling pathways in colorectal cancer. A peptide inhibitor of 14-3-3 blocked or regressed the activity of UA and inhibited its effects. The results suggest that UA binds to 14-3-3 isoforms and suppresses cancer progression by affecting 14-3-3 targets and phosphorylated proteins.
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Affiliation(s)
- Mücahit Varlı
- College
of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Suresh R. Bhosle
- College
of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Eunae Kim
- College
of Pharmacy, Chosun University, 146 Chosundae-gil, Gwangju 61452, Republic of Korea
| | - Yi Yang
- College
of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - İsa Taş
- College
of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Rui Zhou
- College
of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Sultan Pulat
- College
of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Chathurika D. B. Gamage
- College
of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - So-Yeon Park
- College
of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Hyung-Ho Ha
- College
of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
| | - Hangun Kim
- College
of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam 57922, Republic of Korea
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8
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Thirunavukkarasu S, Banerjee S, Tantray I, Ojha R. Non-coding RNA and reprogrammed mitochondrial metabolism in genitourinary cancer. Front Genet 2024; 15:1364389. [PMID: 38544804 PMCID: PMC10965626 DOI: 10.3389/fgene.2024.1364389] [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: 01/02/2024] [Accepted: 03/04/2024] [Indexed: 11/11/2024] Open
Abstract
Non-coding ribonucleic acids (ncRNAs) have been recently shown to contribute to tumorigenesis by mediating changes in metabolism. ncRNAs act as key molecules in metabolic pathways regulation. The dysregulation of ncRNAs during cancer progression contributes to altered metabolic phenotypes leading to reprogrammed metabolism. Since ncRNAs affect different tumor processes by regulating mitochondrial dynamics and metabolism, in the future ncRNAs can be exploited in disease detection, diagnosis, treatment, and resistance. The purpose of this review is to highlight the role of ncRNAs in mitochondrial metabolic reprogramming and to relate their therapeutic potential in the management of genitourinary cancer.
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Affiliation(s)
- Sandiya Thirunavukkarasu
- Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Shouryarudra Banerjee
- Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ishaq Tantray
- InventX Scientia, Kashmir, India
- Department of Pathology, School of Medicine, Stanford University, Stanford, CA, United States
| | - Rani Ojha
- Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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Kashefi S, Mohammadi-Yeganeh S, Ghorbani-Bidkorpeh F, Shabani M, Koochaki A, Safarzadeh M, Hoseini MHM. Anti-cancer Effects of a Chitosan Based Nanoformulation Expressing miR-340 on 4T1 Breast Cancer Cells. J Pharm Sci 2024; 113:445-454. [PMID: 37806438 DOI: 10.1016/j.xphs.2023.10.006] [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: 04/08/2023] [Revised: 10/02/2023] [Accepted: 10/02/2023] [Indexed: 10/10/2023]
Abstract
MicroRNAs (miRNAs) have a crucial role in the regulation of gene expression in tumor development, invasion, and metastasis. Herein, miRNA-340 (miR-340) has been shown to play tumor suppressor activity in breast cancer (BC). However, the clinical applications of miRNAs request the development of safe and effective delivery systems capable of protecting nucleic acids from degradation. In this study, biodegradable chitosan nanoparticles incorporating miR-340 plasmid DNA (pDNA) (miR-340 CNPs) were synthesized and characterized. Then, the anti-tumor effects of miR-340 CNPs were investigated using 4T1 BCE cells. The spherical nanoparticles (NPs) with an appropriate mean diameter of around 266 ± 9.3 nm and zeta potential of +17 ± 1.8 mV were successfully prepared. The NPs showed good stability, high entrapment efficiency and a reasonable release behavior, meanwhile their high resistance against enzymatic degradation was verified. Furthermore, NPs demonstrated appropriate transfection efficiency and could induce apoptosis, so had toxicity in 4T1 BCE cells. Also, CD47 expression on the surface of cancer cells was significantly reduced after treatment with miR-340 CNPs. The results showed that miR-340 CNPs augmented the expression of P-27 in BC cells. Furthermore, miR-340 CNPs caused down-regulation of BRP-39 (breast regression protein-39) increasingly suggested as a prognostic biomarker for neoplastic diseases like BC. In conclusion, our data show that miR-340 CNPs can be considered as a promising new platform for BC gene therapy.
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Affiliation(s)
- Sarvenaz Kashefi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samira Mohammadi-Yeganeh
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ghorbani-Bidkorpeh
- Department of Pharmaceutics and Pharmaceutical Nanotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Shabani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ameneh Koochaki
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Mostafa Haji Molla Hoseini
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Mondal D, Shinde S, Paul S, Thakur S, Velu GSK, Tiwari AK, Dixit V, Amit A, Vishvakarma NK, Shukla D. Diagnostic significance of dysregulated miRNAs in T-cell malignancies and their metabolic roles. Front Oncol 2023; 13:1230273. [PMID: 37637043 PMCID: PMC10448964 DOI: 10.3389/fonc.2023.1230273] [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: 05/28/2023] [Accepted: 07/17/2023] [Indexed: 08/29/2023] Open
Abstract
T-cell malignancy is a broad term used for a diverse group of disease subtypes representing dysfunctional malignant T cells transformed at various stages of their clonal evolution. Despite having similar clinical manifestations, these disease groups have different disease progressions and diagnostic parameters. The effective diagnosis and prognosis of such a diverse disease group demands testing of molecular entities that capture footprints of the disease physiology in its entirety. MicroRNAs (miRNAs) are a group of noncoding RNA molecules that regulate the expression of genes and, while doing so, leave behind specific miRNA signatures corresponding to cellular expression status in an altered stage of a disease. Using miRNAs as a diagnostic tool is justified, as they can effectively distinguish expressional diversity between various tumors and within subtypes of T-cell malignancies. As global attention for cancer diagnosis shifts toward liquid biopsy, diagnosis using miRNAs is more relevant in blood cancers than in solid tumors. We also lay forward the diagnostic significance of miRNAs that are indicative of subtype, progression, severity, therapy response, and relapse. This review discusses the potential use and the role of miRNAs, miRNA signatures, or classifiers in the diagnosis of major groups of T-cell malignancies like T-cell acute lymphoblastic lymphoma (T-ALL), peripheral T-cell lymphoma (PTCL), extranodal NK/T-cell lymphoma (ENKTCL), and cutaneous T-cell lymphoma (CTCL). The review also briefly discusses major diagnostic miRNAs having prominent metabolic roles in these malignancies to highlight their importance among other dysregulated miRNAs.
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Affiliation(s)
- Deepankar Mondal
- Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
| | - Sapnita Shinde
- Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
| | - Souvik Paul
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
| | - Suresh Thakur
- Centre for Excellence in Genomics, Trivitron Healthcare Pvt. Ltd., Chennai, India
| | - GSK Velu
- Centre for Excellence in Genomics, Trivitron Healthcare Pvt. Ltd., Chennai, India
| | - Atul Kumar Tiwari
- Department of Zoology, Dr. Bhawan Singh Porte Government College, Pendra, Chhattisgarh, India
| | - Vineeta Dixit
- Department of Botany, Sri Satguru Jagjit Singh Namdhari College, Gharwa, Jharkhand, India
| | - Ajay Amit
- Department of Forensic Sciences, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
| | | | - Dhananjay Shukla
- Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
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Varlı M, Kim SJ, Noh MG, Kim YG, Ha HH, Kim KK, Kim H. KITENIN promotes aerobic glycolysis through PKM2 induction by upregulating the c-Myc/hnRNPs axis in colorectal cancer. Cell Biosci 2023; 13:146. [PMID: 37553596 PMCID: PMC10410973 DOI: 10.1186/s13578-023-01089-1] [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: 03/02/2023] [Accepted: 07/19/2023] [Indexed: 08/10/2023] Open
Abstract
PURPOSE The oncoprotein KAI1 C-terminal interacting tetraspanin (KITENIN; vang-like 1) promotes cell metastasis, invasion, and angiogenesis, resulting in shorter survival times in cancer patients. Here, we aimed to determine the effects of KITENIN on the energy metabolism of human colorectal cancer cells. EXPERIMENTAL DESIGN The effects of KITENIN on energy metabolism were evaluated using in vitro assays. The GEPIA web tool was used to extrapolate the clinical relevance of KITENIN in cancer cell metabolism. The bioavailability and effect of the disintegrator of KITENIN complex compounds were evaluated by LC-MS, in vivo animal assay. RESULTS KITENIN markedly upregulated the glycolytic proton efflux rate and aerobic glycolysis by increasing the expression of GLUT1, HK2, PKM2, and LDHA. β-catenin, CD44, CyclinD1 and HIF-1A, including c-Myc, were upregulated by KITENIN expression. In addition, KITENIN promoted nuclear PKM2 and PKM2-induced transactivation, which in turn, increased the expression of downstream mediators. This was found to be mediated through an effect of c-Myc on the transcription of hnRNP isoforms and a switch to the M2 isoform of pyruvate kinase, which increased aerobic glycolysis. The disintegration of KITENIN complex by silencing the KITENIN or MYO1D downregulated aerobic glycolysis. The disintegrator of KITENIN complex compound DKC1125 and its optimized form, DKC-C14S, exhibited the inhibition activity of KITENIN-mediated aerobic glycolysis in vitro and in vivo. CONCLUSIONS The oncoprotein KITENIN induces PKM2-mediated aerobic glycolysis by upregulating the c-Myc/hnRNPs axis.
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Affiliation(s)
- Mücahit Varlı
- College of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam, 57922, Republic of Korea
| | - Sung Jin Kim
- College of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam, 57922, Republic of Korea
- Department of Pharmacology, Chonnam National University Medical School, 160 Baekseoro, Dong-gu, Gwangju, 61469, Republic of Korea
| | - Myung-Giun Noh
- Department of Pathology, Chonnam National University Medical School, 160 Baekseoro, Dong-gu, Gwanju, 61469, Republic of Korea
| | - Yoon Gyoon Kim
- College of Pharmacy, Dankook University, 119 Dandaero, Dongnam-gu, 31116, Cheonan-si, Republic of Korea
| | - Hyung-Ho Ha
- College of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam, 57922, Republic of Korea
| | - Kyung Keun Kim
- Department of Pharmacology, Chonnam National University Medical School, 160 Baekseoro, Dong-gu, Gwangju, 61469, Republic of Korea
| | - Hangun Kim
- College of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam, 57922, Republic of Korea.
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12
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Patel D, Thankachan S, Fawaz P P A, Venkatesh T, Prasada Kabekkodu S, Suresh PS. Deciphering the role of MitomiRs in cancer: A comprehensive review. Mitochondrion 2023; 70:118-130. [PMID: 37120081 DOI: 10.1016/j.mito.2023.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 04/01/2023] [Accepted: 04/23/2023] [Indexed: 05/01/2023]
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that regulate many metabolic and signal transduction pathways. The role of miRNAs, usually found in the cytoplasm, in regulating gene expression and cancer progression has been extensively studied in the last few decades. However, very recently, miRNAs were found to localize in the mitochondria. MiRNAs that specifically localize in the mitochondria and the cytoplasmic miRNAs associated with mitochondria that directly or indirectly modulate specific mitochondrial functions are termed as "mitomiRs". Although it is not clear about the origin of mitomiRs that are situated within mitochondria (nuclear or mitochondrial origin), it is evident that they have specific functions in modulating gene expression and regulating important mitochondrial metabolic pathways. Through this review, we aim to delineate the mechanisms by which mitomiRs alter mitochondrial metabolic pathways and influence the initiation and progression of cancer. We further discuss the functions of particular mitomiRs, which have been widely studied in the context of mitochondrial metabolism and oncogenic signaling pathways. Based on the current knowledge, we can conclude that mitomiRs contribute significantly to mitochondrial function and metabolic regulation, and that dysregulation of mitomiRs can aid the proliferation of cancer cells. Therefore, the less explored area of mitomiRs' biology can be an important topic of research investigation in the future for targeting cancer cells.
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Affiliation(s)
- Dimple Patel
- School of Biotechnology, National Institute of Technology, Calicut-673601, Kerala, India
| | - Sanu Thankachan
- School of Biotechnology, National Institute of Technology, Calicut-673601, Kerala, India
| | - Abu Fawaz P P
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipa1-576104, Karnataka, India
| | - Thejaswini Venkatesh
- Dept of Biochemistry and Molecular Biology, Central University of Kerala, Kasargod, Kerala, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipa1-576104, Karnataka, India
| | - Padmanaban S Suresh
- School of Biotechnology, National Institute of Technology, Calicut-673601, Kerala, India.
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13
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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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14
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Siculella L, Giannotti L, Di Chiara Stanca B, Spedicato F, Calcagnile M, Quarta S, Massaro M, Damiano F. A comprehensive understanding of hnRNP A1 role in cancer: new perspectives on binding with noncoding RNA. Cancer Gene Ther 2023; 30:394-403. [PMID: 36460805 DOI: 10.1038/s41417-022-00571-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/23/2022] [Accepted: 11/23/2022] [Indexed: 12/03/2022]
Abstract
The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is the most abundant and ubiquitously expressed member of the heterogeneous nuclear ribonucleoproteins family (hnRNPs). hnRNP A1 is an RNA-binding protein associated with complexes active in diverse biological processes such as RNA splicing, transactivation of gene expression, and modulation of protein translation. It is overexpressed in several cancers, where it actively promotes the expression and translation of several key proteins and regulators associated with tumorigenesis and cancer progression. Interesting recent studies have focused on the RNA-binding property of hnRNP A1 and revealed previously under-explored functions of hnRNP A1 in the processing of miRNAs, and loading non-coding RNAs into exosomes. Here, we will report the recent advancements in our knowledge of the role of hnRNP A1 in the biological processes underlying cancer proliferation and growth, with a particular focus on metabolic reprogramming.
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Affiliation(s)
- Luisa Siculella
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Laura Giannotti
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Benedetta Di Chiara Stanca
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Francesco Spedicato
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Matteo Calcagnile
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Stefano Quarta
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Marika Massaro
- Institute of Clinical Physiology (IFC), National Research Council (CNR), Lecce, Italy
| | - Fabrizio Damiano
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.
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15
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Breault NM, Wu D, Dasgupta A, Chen KH, Archer SL. Acquired disorders of mitochondrial metabolism and dynamics in pulmonary arterial hypertension. Front Cell Dev Biol 2023; 11:1105565. [PMID: 36819102 PMCID: PMC9933518 DOI: 10.3389/fcell.2023.1105565] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 01/09/2023] [Indexed: 02/05/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is an orphan disease of the cardiopulmonary unit that reflects an obstructive pulmonary vasculopathy and presents with hypertrophy, inflammation, fibrosis, and ultimately failure of the right ventricle (RVF). Despite treatment using pulmonary hypertension (PH)-targeted therapies, persistent functional impairment reduces the quality of life for people with PAH and death from RVF occurs in approximately 40% of patients within 5 years of diagnosis. PH-targeted therapeutics are primarily vasodilators and none, alone or in combination, are curative. This highlights a need to therapeutically explore molecular targets in other pathways that are involved in the pathogenesis of PAH. Several candidate pathways in PAH involve acquired mitochondrial dysfunction. These mitochondrial disorders include: 1) a shift in metabolism related to increased expression of pyruvate dehydrogenase kinase and pyruvate kinase, which together increase uncoupled glycolysis (Warburg metabolism); 2) disruption of oxygen-sensing related to increased expression of hypoxia-inducible factor 1α, resulting in a state of pseudohypoxia; 3) altered mitochondrial calcium homeostasis related to impaired function of the mitochondrial calcium uniporter complex, which elevates cytosolic calcium and reduces intramitochondrial calcium; and 4) abnormal mitochondrial dynamics related to increased expression of dynamin-related protein 1 and its binding partners, such as mitochondrial dynamics proteins of 49 kDa and 51 kDa, and depressed expression of mitofusin 2, resulting in increased mitotic fission. These acquired mitochondrial abnormalities increase proliferation and impair apoptosis in most pulmonary vascular cells (including endothelial cells, smooth muscle cells and fibroblasts). In the RV, Warburg metabolism and induction of glutaminolysis impairs bioenergetics and promotes hypokinesis, hypertrophy, and fibrosis. This review will explore our current knowledge of the causes and consequences of disordered mitochondrial function in PAH.
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Affiliation(s)
- Nolan M. Breault
- Department of Medicine, Queen’s University, Kingston, ON, Canada
| | - Danchen Wu
- Department of Medicine, Queen’s University, Kingston, ON, Canada,*Correspondence: Danchen Wu, ; Stephen L. Archer,
| | - Asish Dasgupta
- Department of Medicine, Queen’s University, Kingston, ON, Canada
| | - Kuang-Hueih Chen
- Department of Medicine, Queen’s University, Kingston, ON, Canada
| | - Stephen L. Archer
- Department of Medicine, Queen’s University, Kingston, ON, Canada,Queen’s Cardiopulmonary Unit (QCPU), Translational Institute of Medicine (TIME), Department of Medicine, Queen’s University, Kingston, ON, Canada,*Correspondence: Danchen Wu, ; Stephen L. Archer,
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16
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Teo AYT, Lim VY, Yang VS. MicroRNAs in the Pathogenesis, Prognostication and Prediction of Treatment Resistance in Soft Tissue Sarcomas. Cancers (Basel) 2023; 15:cancers15030577. [PMID: 36765536 PMCID: PMC9913386 DOI: 10.3390/cancers15030577] [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: 11/24/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 01/19/2023] Open
Abstract
Soft tissue sarcomas are highly aggressive malignant neoplasms of mesenchymal origin, accounting for less than 1% of adult cancers, but comprising over 20% of paediatric solid tumours. In locally advanced, unresectable, or metastatic disease, outcomes from even the first line of systemic treatment are invariably poor. MicroRNAs (miRNAs), which are short non-coding RNA molecules, target and modulate multiple dysregulated target genes and/or signalling pathways within cancer cells. Accordingly, miRNAs demonstrate great promise for their utility in diagnosing, prognosticating and improving treatment for soft tissue sarcomas. This review aims to provide an updated discussion on the known roles of specific miRNAs in the pathogenesis of sarcomas, and their potential use in prognosticating outcomes and prediction of therapeutic resistance.
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Affiliation(s)
- Andrea York Tiang Teo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Vivian Yujing Lim
- Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore
| | - Valerie Shiwen Yang
- Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore
- Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore
- Correspondence:
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17
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Feng J, Zhou J, Lin Y, Huang W. hnRNP A1 in RNA metabolism regulation and as a potential therapeutic target. Front Pharmacol 2022; 13:986409. [PMID: 36339596 PMCID: PMC9634572 DOI: 10.3389/fphar.2022.986409] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 10/10/2022] [Indexed: 11/22/2022] Open
Abstract
Abnormal RNA metabolism, regulated by various RNA binding proteins, can have functional consequences for multiple diseases. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is an important RNA binding protein, that regulates various RNA metabolic processes, including transcription, alternative splicing of pre-mRNA, translation, miRNA processing and mRNA stability. As a potent splicing factor, hnRNP A1 can regulate multiple splicing events, including itself, collaborating with other cooperative or antagonistical splicing factors by binding to splicing sites and regulatory elements in exons or introns. hnRNP A1 can modulate gene transcription by directly interacting with promoters or indirectly impacting Pol II activities. Moreover, by interacting with the internal ribosome entry site (IRES) or 3′-UTR of mRNAs, hnRNP A1 can affect mRNA translation. hnRNP A1 can alter the stability of mRNAs by binding to specific locations of 3′-UTR, miRNAs biogenesis and Nonsense-mediated mRNA decay (NMD) pathway. In this review, we conclude the selective sites where hnRNP A1 binds to RNA and DNA, and the co-regulatory factors that interact with hnRNP A1. Given the dysregulation of hnRNP A1 in diverse diseases, especially in cancers and neurodegeneration diseases, targeting hnRNP A1 for therapeutic treatment is extremely promising. Therefore, this review also provides the small-molecule drugs, biomedicines and novel strategies targeting hnRNP A1 for therapeutic purposes.
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18
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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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19
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Islas JF, Quiroz-Reyes AG, Delgado-Gonzalez P, Franco-Villarreal H, Delgado-Gallegos JL, Garza-Treviño EN, Gonzalez-Villarreal CA. Cancer Stem Cells in Tumor Microenvironment of Adenocarcinoma of the Stomach, Colon, and Rectum. Cancers (Basel) 2022; 14:3948. [PMID: 36010940 PMCID: PMC9405851 DOI: 10.3390/cancers14163948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/29/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022] Open
Abstract
Gastrointestinal adenocarcinomas are one of the world's deadliest cancers. Cancer stem cells and the tissue microenvironment are highly regulated by cell and molecular mechanisms. Cancer stem cells are essential for maintenance and progression and are associated with resistance to conventional treatments. This article reviews the current knowledge of the role of the microenvironment during the primary establishment of gastrointestinal adenocarcinomas in the stomach, colon, and rectum and its relationship with cancer stem cells. We also describe novel developments in cancer therapeutics, such as targeted therapy, and discuss the advantages and disadvantages of different treatments for improving gastrointestinal cancer prognosis.
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Affiliation(s)
- Jose Francisco Islas
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | - Adriana G. Quiroz-Reyes
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | - Paulina Delgado-Gonzalez
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | | | - Juan Luis Delgado-Gallegos
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | - Elsa N. Garza-Treviño
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
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20
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Erturk E, Enes Onur O, Akgun O, Tuna G, Yildiz Y, Ari F. Mitochondrial miRNAs (MitomiRs): Their potential roles in breast and other cancers. Mitochondrion 2022; 66:74-81. [PMID: 35963496 DOI: 10.1016/j.mito.2022.08.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/19/2022] [Accepted: 08/02/2022] [Indexed: 11/15/2022]
Abstract
Breast cancer is the most common cancer in women worldwide. MicroRNAs (miRNAs) are non-coding RNAs that are involved in the post-transcriptional regulation of gene expression. Although miRNAs mainly act in the cytoplasm, they can be found in the mitochondrial compartment of the cell. These miRNAs called "MitomiR", they can change mitochondrial functions by regulating proteins at the mitochondrial level and cause cancer. In this review, we have aimed to explain miRNA biogenesis, transport pathways to mitochondria, and summarize mitomiRs that have been shown to play an important role in mitochondrial function, especially in the initiation and progression of breast cancer.
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Affiliation(s)
- Elif Erturk
- Bursa Uludag University, Vocational School of Health Services, 16059, Bursa, Turkey
| | - Omer Enes Onur
- Bursa Uludag University, Department of Biology, Science and Art Faculty, 16059, Bursa, Turkey
| | - Oguzhan Akgun
- Bursa Uludag University, Department of Biology, Science and Art Faculty, 16059, Bursa, Turkey
| | - Gonca Tuna
- Bursa Uludag University, Department of Biology, Science and Art Faculty, 16059, Bursa, Turkey
| | - Yaren Yildiz
- Bursa Uludag University, Department of Biology, Science and Art Faculty, 16059, Bursa, Turkey
| | - Ferda Ari
- Bursa Uludag University, Department of Biology, Science and Art Faculty, 16059, Bursa, Turkey.
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21
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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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22
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Pyruvate kinase M1 regulates butyrate metabolism in cancerous colonocytes. Sci Rep 2022; 12:8771. [PMID: 35610475 PMCID: PMC9130307 DOI: 10.1038/s41598-022-12827-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 05/05/2022] [Indexed: 11/08/2022] Open
Abstract
Colorectal cancer (CRC) cells shift metabolism toward aerobic glycolysis and away from using oxidative substrates such as butyrate. Pyruvate kinase M1/2 (PKM) is an enzyme that catalyzes the last step in glycolysis, which converts phosphoenolpyruvate to pyruvate. M1 and M2 are alternatively spliced isoforms of the Pkm gene. The PKM1 isoform promotes oxidative metabolism, whereas PKM2 enhances aerobic glycolysis. We hypothesize that the PKM isoforms are involved in the shift away from butyrate oxidation towards glycolysis in CRC cells. Here, we find that PKM2 is increased and PKM1 is decreased in human colorectal carcinomas as compared to non-cancerous tissue. To test whether PKM1/2 alter colonocyte metabolism, we created a knockdown of PKM2 and PKM1 in CRC cells to analyze how butyrate oxidation and glycolysis would be impacted. We report that butyrate oxidation in CRC cells is regulated by PKM1 levels, not PKM2. Decreased butyrate oxidation observed through knockdown of PKM1 and PKM2 is rescued through re-addition of PKM1. Diminished PKM1 lowered mitochondrial basal respiration and decreased mitochondrial spare capacity. We demonstrate that PKM1 suppresses glycolysis and inhibits hypoxia-inducible factor-1 alpha. These data suggest that reduced PKM1 is, in part, responsible for increased glycolysis and diminished butyrate oxidation in CRC cells.
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23
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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: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [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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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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Rencelj A, Gvozdenovic N, Cemazar M. MitomiRs: their roles in mitochondria and importance in cancer cell metabolism. Radiol Oncol 2021; 55:379-392. [PMID: 34821131 PMCID: PMC8647792 DOI: 10.2478/raon-2021-0042] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 09/28/2021] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are short non-coding RNAs that play important roles in almost all biological pathways. They regulate post-transcriptional gene expression by binding to the 3'untranslated region (3'UTR) of messenger RNAs (mRNAs). MitomiRs are miRNAs of nuclear or mitochondrial origin that are localized in mitochondria and have a crucial role in regulation of mitochondrial function and metabolism. In eukaryotes, mitochondria are the major sites of oxidative metabolism of sugars, lipids, amino acids, and other bio-macromolecules. They are also the main sites of adenosine triphosphate (ATP) production. CONCLUSIONS In the review, we discuss the role of mitomiRs in mitochondria and introduce currently well studied mitomiRs, their target genes and functions. We also discuss their role in cancer initiation and progression through the regulation of mRNA expression in mitochondria. MitomiRs directly target key molecules such as transporters or enzymes in cell metabolism and regulate several oncogenic signaling pathways. They also play an important role in the Warburg effect, which is vital for cancer cells to maintain their proliferative potential. In addition, we discuss how they indirectly upregulate hexokinase 2 (HK2), an enzyme involved in glucose phosphorylation, and thus may affect energy metabolism in breast cancer cells. In tumor tissues such as breast cancer and head and neck tumors, the expression of one of the mitomiRs (miR-210) correlates with hypoxia gene signatures, suggesting a direct link between mitomiR expression and hypoxia in cancer. The miR-17/92 cluster has been shown to act as a key factor in metabolic reprogramming of tumors by regulating glycolytic and mitochondrial metabolism. This cluster is deregulated in B-cell lymphomas, B-cell chronic lymphocytic leukemia, acute myeloid leukemia, and T-cell lymphomas, and is particularly overexpressed in several other cancers. Based on the current knowledge, we can conclude that there is a large number of miRNAs present in mitochondria, termed mitomiR, and that they are important regulators of mitochondrial function. Therefore, mitomiRs are important players in the metabolism of cancer cells, which need to be further investigated in order to develop a potential new therapies for cancer.
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Affiliation(s)
- Andrej Rencelj
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nada Gvozdenovic
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia
| | - Maja Cemazar
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia
- Faculty of Health Sciences, University of Primorska, Izola, Slovenia
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Schorr AL, Mangone M. miRNA-Based Regulation of Alternative RNA Splicing in Metazoans. Int J Mol Sci 2021; 22:ijms222111618. [PMID: 34769047 PMCID: PMC8584187 DOI: 10.3390/ijms222111618] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 12/15/2022] Open
Abstract
Alternative RNA splicing is an important regulatory process used by genes to increase their diversity. This process is mainly executed by specific classes of RNA binding proteins that act in a dosage-dependent manner to include or exclude selected exons in the final transcripts. While these processes are tightly regulated in cells and tissues, little is known on how the dosage of these factors is achieved and maintained. Several recent studies have suggested that alternative RNA splicing may be in part modulated by microRNAs (miRNAs), which are short, non-coding RNAs (~22 nt in length) that inhibit translation of specific mRNA transcripts. As evidenced in tissues and in diseases, such as cancer and neurological disorders, the dysregulation of miRNA pathways disrupts downstream alternative RNA splicing events by altering the dosage of splicing factors involved in RNA splicing. This attractive model suggests that miRNAs can not only influence the dosage of gene expression at the post-transcriptional level but also indirectly interfere in pre-mRNA splicing at the co-transcriptional level. The purpose of this review is to compile and analyze recent studies on miRNAs modulating alternative RNA splicing factors, and how these events contribute to transcript rearrangements in tissue development and disease.
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Affiliation(s)
- Anna L. Schorr
- Molecular and Cellular Biology Graduate Program, School of Life Sciences, 427 East Tyler Mall, Tempe, AZ 85287, USA;
| | - Marco Mangone
- Virginia G. Piper Center for Personalized Diagnostics, The Biodesign Institute at Arizona State University, 1001 S McAllister Ave., Tempe, AZ 85287, USA
- Correspondence: ; Tel.: +1-480-965-7957
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27
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Kalushkova A, Nylund P, Párraga AA, Lennartsson A, Jernberg-Wiklund H. One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies. EPIGENOMES 2021; 5:epigenomes5040022. [PMID: 34968247 PMCID: PMC8715477 DOI: 10.3390/epigenomes5040022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/17/2021] [Accepted: 09/26/2021] [Indexed: 02/01/2023] Open
Abstract
Aberrant DNA methylation, dysregulation of chromatin-modifying enzymes, and microRNAs (miRNAs) play a crucial role in haematological malignancies. These epimutations, with an impact on chromatin accessibility and transcriptional output, are often associated with genomic instability and the emergence of drug resistance, disease progression, and poor survival. In order to exert their functions, epigenetic enzymes utilize cellular metabolites as co-factors and are highly dependent on their availability. By affecting the expression of metabolic enzymes, epigenetic modifiers may aid the generation of metabolite signatures that could be utilized as targets and biomarkers in cancer. This interdependency remains often neglected and poorly represented in studies, despite well-established methods to study the cellular metabolome. This review critically summarizes the current knowledge in the field to provide an integral picture of the interplay between epigenomic alterations and the cellular metabolome in haematological malignancies. Our recent findings defining a distinct metabolic signature upon response to enhancer of zeste homolog 2 (EZH2) inhibition in multiple myeloma (MM) highlight how a shift of preferred metabolic pathways may potentiate novel treatments. The suggested link between the epigenome and the metabolome in haematopoietic tumours holds promise for the use of metabolic signatures as possible biomarkers of response to treatment.
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Affiliation(s)
- Antonia Kalushkova
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden; (P.N.); (A.A.P.); (H.J.-W.)
- Correspondence:
| | - Patrick Nylund
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden; (P.N.); (A.A.P.); (H.J.-W.)
| | - Alba Atienza Párraga
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden; (P.N.); (A.A.P.); (H.J.-W.)
| | - Andreas Lennartsson
- Department of Biosciences and Nutrition, NEO, Karolinska Institutet, 14157 Huddinge, Sweden;
| | - Helena Jernberg-Wiklund
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden; (P.N.); (A.A.P.); (H.J.-W.)
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Bahreini F, Jabbari P, Gossing W, Aziziyan F, Frohme M, Rezaei N. The role of noncoding RNAs in pituitary adenoma. Epigenomics 2021; 13:1421-1437. [PMID: 34558980 DOI: 10.2217/epi-2021-0165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Pituitary adenomas (PAs) are common cranial tumors that affect the quality of life in patients. Early detection of PA is beneficial for avoiding clinical complications of this disease and increasing the quality of life. Noncoding RNAs, including long noncoding RNA, miRNA and circRNA, regulate protein expression, mostly by inhibiting the translation process. Studies have shown that dysregulation of noncoding RNAs is associated with PA. Hence understanding the expression pattern of noncoding RNAs can be considered a promising method for developing biomarkers. This article reviews data on the expression pattern of dysregulated noncoding RNAs involved in PA. Possible molecular mechanisms by which the dysregulated noncoding RNA could possibly induce PA are also described.
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Affiliation(s)
- Farbod Bahreini
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.,Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Parnian Jabbari
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Genetics, Genomics & Bioinformatics, University of California, Riverside, CA, USA
| | - Wilhelm Gossing
- Division Molecular Biotechnology & Functional Genomics, Technical University of Applied Sciences Wildau, Hochschulring 1, 15745, Wildau, Germany
| | - Fatemeh Aziziyan
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Marcus Frohme
- Division Molecular Biotechnology & Functional Genomics, Technical University of Applied Sciences Wildau, Hochschulring 1, 15745, Wildau, Germany
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Li L, Ma Y, Maerkeya K, Reyanguly D, Han L. LncRNA OIP5-AS1 Regulates the Warburg Effect Through miR-124-5p/IDH2/HIF-1α Pathway in Cervical Cancer. Front Cell Dev Biol 2021; 9:655018. [PMID: 34513821 PMCID: PMC8427313 DOI: 10.3389/fcell.2021.655018] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 03/18/2021] [Indexed: 12/13/2022] Open
Abstract
Hypoxia reprogrammed glucose metabolism affects the Warburg effect of tumor cells, but the mechanism is still unclear. Long-chain non-coding RNA (lncRNA) has been found by many studies to be involved in the Warburg effect of tumor cells under hypoxic condition. Herein, we find that lncRNA OIP5-AS1 is up-regulated in cervical cancer tissues and predicts poor 5-years overall survival in cervical cancer patients, and it promotes cell proliferation of cervical cancer cells in vitro and in vivo. Moreover, OIP5-AS1 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis which is IDH2 or hypoxia inducible factor-1α (HIF-1α) dependent. In cervical cancer cells, OIP5-AS1 promotes IDH2 expression by inhibiting miR-124-5p, and IDH2 promotes the Warburg effect of cervical under hypoxic condition through regulating HIF-1α expression. In conclusion, hypoxia induced OIP5-AS1 promotes the Warburg effect through miR-124-5p/IDH2/HIF-1α pathway in cervical cancer.
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Affiliation(s)
- Li Li
- Department of Gynecology, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Yan Ma
- Department of Gynecology, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Kamalibaike Maerkeya
- Department of Gynecology, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Davuti Reyanguly
- Department of Gynecology, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Lili Han
- Department of Gynecology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
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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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Serpe C, Monaco L, Relucenti M, Iovino L, Familiari P, Scavizzi F, Raspa M, Familiari G, Civiero L, D’Agnano I, Limatola C, Catalano M. Microglia-Derived Small Extracellular Vesicles Reduce Glioma Growth by Modifying Tumor Cell Metabolism and Enhancing Glutamate Clearance through miR-124. Cells 2021; 10:2066. [PMID: 34440835 PMCID: PMC8393731 DOI: 10.3390/cells10082066] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/26/2021] [Accepted: 08/06/2021] [Indexed: 12/12/2022] Open
Abstract
Brain homeostasis needs continuous exchange of intercellular information among neurons, glial cells, and immune cells, namely microglial cells. Extracellular vesicles (EVs) are active players of this process. All the cells of the body, including the brain, release at least two subtypes of EVs, the medium/large EVs (m/lEVs) and small EVs (sEVs). sEVs released by microglia play an important role in brain patrolling in physio-pathological processes. One of the most common and malignant forms of brain cancer is glioblastoma. Altered intercellular communications constitute a base for the onset and the development of the disease. In this work, we used microglia-derived sEVs to assay their effects in vitro on murine glioma cells and in vivo in a glioma model on C57BL6/N mice. Our findings indicated that sEVs carry messages to cancer cells that modify glioma cell metabolism, reducing lactate, nitric oxide (NO), and glutamate (Glu) release. sEVs affect Glu homeostasis, increasing the expression of Glu transporter Glt-1 on astrocytes. We demonstrated that these effects are mediated by miR-124 contained in microglia-released sEVs. The in vivo benefit of microglia-derived sEVs results in a significantly reduced tumor mass and an increased survival of glioma-bearing mice, depending on miR-124.
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Affiliation(s)
- Carmela Serpe
- Department of Physiology and Pharmacology, Sapienza University, 00185 Rome, Italy; (C.S.); (L.M.)
| | - Lucia Monaco
- Department of Physiology and Pharmacology, Sapienza University, 00185 Rome, Italy; (C.S.); (L.M.)
| | - Michela Relucenti
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University, 00185 Rome, Italy; (M.R.); (G.F.)
| | - Ludovica Iovino
- Department of Biology, University of Padova, 35131 Padova, Italy; (L.I.); (L.C.)
| | - Pietro Familiari
- Department of Human Neurosciences, Division of Neurosurgery, Sapienza University, 00185 Rome, Italy;
| | - Ferdinando Scavizzi
- Institute of Biochemistry and Cell Biology (IBBC), CNR, 00015 Monterotond, Italy; (F.S.); (M.R.)
| | - Marcello Raspa
- Institute of Biochemistry and Cell Biology (IBBC), CNR, 00015 Monterotond, Italy; (F.S.); (M.R.)
| | - Giuseppe Familiari
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University, 00185 Rome, Italy; (M.R.); (G.F.)
| | - Laura Civiero
- Department of Biology, University of Padova, 35131 Padova, Italy; (L.I.); (L.C.)
- IRCCS San Camillo Hospital, 30126 Venice, Italy
| | - Igea D’Agnano
- Institute of Biomedical Technologies, CNR, 20054 Segrate, Italy;
| | - Cristina Limatola
- Department of Physiology and Pharmacology, Laboratory Affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy
- IRCCS Neuromed, 86077 Pozzilli, Italy
| | - Myriam Catalano
- Department of Physiology and Pharmacology, Sapienza University, 00185 Rome, Italy; (C.S.); (L.M.)
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Lee YB, Min JK, Kim JG, Cap KC, Islam R, Hossain AJ, Dogsom O, Hamza A, Mahmud S, Choi DR, Kim YS, Koh YH, Kim HA, Chung WS, Suh SW, Park JB. Multiple functions of pyruvate kinase M2 in various cell types. J Cell Physiol 2021; 237:128-148. [PMID: 34311499 DOI: 10.1002/jcp.30536] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/28/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023]
Abstract
Glucose metabolism is a mechanism by which energy is produced in form of adenosine triphosphate (ATP) by mitochondria and precursor metabolites are supplied to enable the ultimate enrichment of mature metabolites in the cell. Recently, glycolytic enzymes have been shown to have unconventional but important functions. Among these enzymes, pyruvate kinase M2 (PKM2) plays several roles including having conventional metabolic enzyme activity, and also being a transcriptional regulator and a protein kinase. Compared with the closely related PKM1, PKM2 is highly expressed in cancer cells and embryos, whereas PKM1 is dominant in mature, differentiated cells. Posttranslational modifications such as phosphorylation and acetylation of PKM2 change its cellular functions. In particular, PKM2 can translocate to the nucleus, where it regulates the transcription of many target genes. It is notable that PKM2 also acts as a protein kinase to phosphorylate several substrate proteins. Besides cancer cells and embryonic cells, astrocytes also highly express PKM2, which is crucial for lactate production via expression of lactate dehydrogenase A (LDHA), while mature neurons predominantly express PKM1. The lactate produced in cancer cells promotes tumor progress and that in astrocytes can be supplied to neurons and may act as a major source for neuronal ATP energy production. Thereby, we propose that PKM2 along with its different posttranslational modifications has specific purposes for a variety of cell types, performing unique functions.
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Affiliation(s)
- Yoon-Beom Lee
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Jung K Min
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Jae-Gyu Kim
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea.,Institute of Cell Differentiation and Aging, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Kim Cuong Cap
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea.,eLmed Inc. #3419, Hallym University, Chuncheon, Kangwon-do, Republic of Korea.,Institute of Research and Development, Duy Tan University, Danang, Vietnam
| | - Rokibul Islam
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea.,Department of Biotechnology and Genetic Engineering, Faculty of Biological Science, Islamic University, Kushtia, Bangladesh
| | - Abu J Hossain
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Oyungerel Dogsom
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea.,Department of Biology, School of Bio-Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Amir Hamza
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Shohel Mahmud
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea.,National Institute of Biotechnology, Ganakbari, Savar, Dhaka, Bangladesh
| | - Dae R Choi
- Department of Internal Medicine, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Yong-Sun Kim
- Ilsong Institute of Life Science, Hallym University, Seoul, Republic of Korea
| | - Young-Ho Koh
- Ilsong Institute of Life Science, Hallym University, Seoul, Republic of Korea
| | - Hyun-A Kim
- Department of Internal Medicine, Hallym Sacred Heart Hospital, College of Medicine, Hallym University, Ahnyang, Republic of Korea
| | - Won-Suk Chung
- Department of Biological Science, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Sang W Suh
- Department of Physiology, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Jae-Bong Park
- Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea.,Institute of Cell Differentiation and Aging, College of Medicine, Hallym University, Chuncheon, Republic of Korea.,eLmed Inc. #3419, Hallym University, Chuncheon, Kangwon-do, Republic of Korea
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Sellitto A, Pecoraro G, Giurato G, Nassa G, Rizzo F, Saggese P, Martinez CA, Scafoglio C, Tarallo R. Regulation of Metabolic Reprogramming by Long Non-Coding RNAs in Cancer. Cancers (Basel) 2021; 13:cancers13143485. [PMID: 34298698 PMCID: PMC8308086 DOI: 10.3390/cancers13143485] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 01/10/2023] Open
Abstract
Metabolic reprogramming is a well described hallmark of cancer. Oncogenic stimuli and the microenvironment shape the metabolic phenotype of cancer cells, causing pathological modifications of carbohydrate, amino acid and lipid metabolism that support the uncontrolled growth and proliferation of cancer cells. Conversely, metabolic alterations in cancer can drive changes in genetic programs affecting cell proliferation and differentiation. In recent years, the role of non-coding RNAs in metabolic reprogramming in cancer has been extensively studied. Here, we review this topic, with a focus on glucose, glutamine, and lipid metabolism and point to some evidence that metabolic alterations occurring in cancer can drive changes in non-coding RNA expression, thus adding an additional level of complexity in the relationship between metabolism and genetic programs in cancer cells.
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Affiliation(s)
- Assunta Sellitto
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
| | - Giovanni Pecoraro
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
| | - Pasquale Saggese
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.S.); (C.A.M.); (C.S.)
| | - Cesar A. Martinez
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.S.); (C.A.M.); (C.S.)
| | - Claudio Scafoglio
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.S.); (C.A.M.); (C.S.)
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
- Correspondence: ; Tel.: +39-089-965067
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Wu D, Dasgupta A, Read AD, Bentley RET, Motamed M, Chen KH, Al-Qazazi R, Mewburn JD, Dunham-Snary KJ, Alizadeh E, Tian L, Archer SL. Oxygen sensing, mitochondrial biology and experimental therapeutics for pulmonary hypertension and cancer. Free Radic Biol Med 2021; 170:150-178. [PMID: 33450375 PMCID: PMC8217091 DOI: 10.1016/j.freeradbiomed.2020.12.452] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023]
Abstract
The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling molecule, hydrogen peroxide (H2O2), by superoxide dismutase (SOD2). H2O2 exits the mitochondria and regulates ion channels and enzymes, altering plasma membrane potential, intracellular Ca2+ and Ca2+-sensitization and controlling acute, adaptive, responses to hypoxia that involve changes in ventilation, vascular tone and neurotransmitter release. Subversion of this O2-sensing pathway creates a pseudohypoxic state that promotes disease progression in pulmonary arterial hypertension (PAH) and cancer. Pseudohypoxia is a state in which biochemical changes, normally associated with hypoxia, occur despite normal pO2. Epigenetic silencing of SOD2 by DNA methylation alters H2O2 production, activating hypoxia-inducible factor 1α, thereby disrupting mitochondrial metabolism and dynamics, accelerating cell proliferation and inhibiting apoptosis. Other epigenetic mechanisms, including dysregulation of microRNAs (miR), increase pyruvate dehydrogenase kinase and pyruvate kinase muscle isoform 2 expression in both diseases, favoring uncoupled aerobic glycolysis. This Warburg metabolic shift also accelerates cell proliferation and impairs apoptosis. Disordered mitochondrial dynamics, usually increased mitotic fission and impaired fusion, promotes disease progression in PAH and cancer. Epigenetic upregulation of dynamin-related protein 1 (Drp1) and its binding partners, MiD49 and MiD51, contributes to the pathogenesis of PAH and cancer. Finally, dysregulation of intramitochondrial Ca2+, resulting from impaired mitochondrial calcium uniporter complex (MCUC) function, links abnormal mitochondrial metabolism and dynamics. MiR-mediated decreases in MCUC function reduce intramitochondrial Ca2+, promoting Warburg metabolism, whilst increasing cytosolic Ca2+, promoting fission. Epigenetically disordered mitochondrial O2-sensing, metabolism, dynamics, and Ca2+ homeostasis offer new therapeutic targets for PAH and cancer. Promoting glucose oxidation, restoring the fission/fusion balance, and restoring mitochondrial calcium regulation are promising experimental therapeutic strategies.
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Affiliation(s)
- Danchen Wu
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Asish Dasgupta
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Austin D Read
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Rachel E T Bentley
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Mehras Motamed
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kuang-Hueih Chen
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Ruaa Al-Qazazi
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Jeffrey D Mewburn
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kimberly J Dunham-Snary
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Elahe Alizadeh
- Queen's Cardiopulmonary Unit (QCPU), Department of Medicine, Queen's University, 116 Barrie Street, Kingston, ON, K7L 3J9, Canada
| | - Lian Tian
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK
| | - Stephen L Archer
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada.
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Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22126434. [PMID: 34208601 PMCID: PMC8234711 DOI: 10.3390/ijms22126434] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.
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Gao C, Xu YJ, Qi L, Bao YF, Zhang L, Zheng L. CircRNA VIM silence synergizes with sevoflurane to inhibit immune escape and multiple oncogenic activities of esophageal cancer by simultaneously regulating miR-124/PD-L1 axis. Cell Biol Toxicol 2021; 38:825-845. [PMID: 34018092 DOI: 10.1007/s10565-021-09613-0] [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: 08/17/2020] [Accepted: 04/27/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Circular RNA of vimentin (circ-VIM) is a predictor for poor prognosis of acute myeloid leukemia, but we had little information on its function in esophageal cancer (EC). Here we examined the effects of circ-VIM together with sevoflurane on immune escape and multiple oncogenic activities of EC. METHODS Bioinformatic tools, luciferase assay, and RNA immunoprecipitation were used to examine regulations between circ-VIM, miR-124-3p (miR-124), and PD-L1. CCK-8, wound healing, and Transwell assays were used to measure cell proliferation, migration, and invasion, respectively. The impacts of EC cells on cytotoxicity, proliferation, and apoptosis of CD8+ T cells were examined using LDH assay, CFSE staining, and Annexin V/PI staining, respectively. The in vivo tumorigenesis and lung metastases were assessed using xenograft model and tail vein injection of EC cells. RESULTS Significant upregulation of circ-VIM and PD-L1 and downregulation of miR-124 were detected in EC tissues or cells. Circ-VIM sponged miR-124 and released its suppression on the downstream target PD-L1. Sevoflurane, independent of circ-VIM, also upregulated miR-124 to lower PD-L1 expression. By modulating miR-124/PD-L1 axis, silencing circ-VIM and applying sevoflurane both inhibited immune escape and multiple oncogenic activities of EC in vitro, and suppressed xenograft growth and lung metastases in vivo. The inactivation of Ras/ERK signaling pathway was involved in suppression of malignant phenotypes by silencing circ-VIM and sevoflurane treatment. CONCLUSIONS Silencing circ-VIM and applying sevoflurane, by separately regulating miR-124/PD-L1 axis, presented synergistic effects in inhibiting immune escape and multiple malignant phenotypes of EC cells.
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Affiliation(s)
- Cao Gao
- Departments of Anesthesiology, The Third Affiliated Hospital of Soochow University, Changzhou, 213000, Jiangsu Province, People's Republic of China
| | - Yan-Jie Xu
- Departments of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213000, Jiangsu Province, People's Republic of China
| | - Lei Qi
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University, Changzhou, 213000, Jiangsu Province, People's Republic of China
| | - Ya-Fei Bao
- Department of Thoracic Surgery, The Third Affiliated Hospital of Soochow University, No. 185, Juqian Road, Changzhou, 213000, Jiangsu Province, People's Republic of China
| | - Lei Zhang
- Department of Thoracic Surgery, The Third Affiliated Hospital of Soochow University, No. 185, Juqian Road, Changzhou, 213000, Jiangsu Province, People's Republic of China
| | - Liang Zheng
- Department of Thoracic Surgery, The Third Affiliated Hospital of Soochow University, No. 185, Juqian Road, Changzhou, 213000, Jiangsu Province, People's Republic of China.
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Bocchetti M, Ferraro MG, Ricciardiello F, Ottaiano A, Luce A, Cossu AM, Scrima M, Leung WY, Abate M, Stiuso P, Caraglia M, Zappavigna S, Yau TO. The Role of microRNAs in Development of Colitis-Associated Colorectal Cancer. Int J Mol Sci 2021; 22:3967. [PMID: 33921348 PMCID: PMC8068787 DOI: 10.3390/ijms22083967] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/01/2021] [Accepted: 04/08/2021] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is the third most deadly cancer worldwide, and inflammatory bowel disease (IBD) is one of the critical factors in CRC carcinogenesis. IBD is responsible for an unphysiological and sustained chronic inflammation environment favoring the transformation. MicroRNAs (miRNAs) belong to a class of highly conserved short single-stranded segments (18-25 nucleotides) non-coding RNA and have been extensively discussed in both CRC and IBD. However, the role of miRNAs in the development of colitis-associated CRC (CAC) is less clear. The aim of this review is to summarize the major upregulated (miR-18a, miR-19a, miR-21, miR-31, miR-155 and miR-214) and downregulated (miR-124, miR-193a-3p and miR-139-5p) miRNAs in CAC, and their roles in genes' expression modulation in chronic colonic-inflammation-induced carcinogenesis, including programmed cell-death pathways. These miRNAs dysregulation could be applied for early CAC diagnosis, to predict therapy efficacy and for precision treatment.
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Affiliation(s)
- Marco Bocchetti
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Maria Grazia Ferraro
- Department of Pharmacy, School of Medicine and Surgery, University of Naples “Federico II”, via D. Montesano 49, 80131 Naples, Italy;
| | | | - Alessandro Ottaiano
- SSD-Innovative Therapies for Abdominal Metastases, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy;
| | - Amalia Luce
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
| | - Alessia Maria Cossu
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Marianna Scrima
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Wing-Yan Leung
- Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China;
| | - Marianna Abate
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
| | - Paola Stiuso
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
- Biogem Scarl, Molecular Oncology and Precision Medicine Laboratory, via Camporeale, 83031 Ariano Irpino, Italy;
| | - Silvia Zappavigna
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.B.); (A.L.); (A.M.C.); (M.A.); (P.S.); (M.C.)
| | - Tung On Yau
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
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Ren K, Yu Y, Wang X, Liu H, Zhao J. MiR-340-3p-HUS1 axis suppresses proliferation and migration in lung adenocarcinoma cells. Life Sci 2021; 274:119330. [PMID: 33711383 DOI: 10.1016/j.lfs.2021.119330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/03/2021] [Accepted: 03/05/2021] [Indexed: 02/08/2023]
Abstract
AIMS The functions and molecular mechanisms of miR-340-3p in lung adenocarcinoma (LUAD) progression remain unclear. On the other hand, the role of HUS1 in LUAD progression should be further explored. MAIN METHODS Data from cancer database were subjected to bioinformatics analysis. Quantitative real-time PCR and western blot were performed to detect gene expression. Colony formation and MTT assay were performed to examine cell growth in vitro. Wound healing assays and transwell assays were performed to examine cell migration. KEY FINDINGS Here, our results showed that miR-340-3p was lower expressed in LUAD tissues and LUAD-derived cell lines. And miR-340-3p suppressed the proliferation and migration ability of LUAD cells. Further, miR-340-3p inhibits HUS1 expression, which was higher expressed in LUAD tissues and promoted the proliferation and migration ability of LUAD cells. Moreover, higher HUS1 expression was associated with poor survival rate and shorter survival time in patients with LUAD, and HUS1 expression was negative correlated with that of miR-340-3p in clinical samples. In addition, overexpression of HUS1 counteracted the downregulation of cell growth by miR-340-3p. SIGNIFICANCE The study mainly indicated that miR-340-3p may play a tumor suppressor role in the progression of LUAD, with the function of restraining HUS1 expression, highlighting a potential therapeutic target for LUAD.
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Affiliation(s)
- Kaiming Ren
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China
| | - Yong Yu
- Department of Ophthalmology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China
| | - Xiwen Wang
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China
| | - Haijun Liu
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China
| | - Jungang Zhao
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China.
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Puckett DL, Alquraishi M, Chowanadisai W, Bettaieb A. The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs. Int J Mol Sci 2021; 22:1171. [PMID: 33503959 PMCID: PMC7865720 DOI: 10.3390/ijms22031171] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 01/17/2023] Open
Abstract
Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.
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Affiliation(s)
- Dexter L. Puckett
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996, USA; (D.L.P.); (M.A.)
| | - Mohammed Alquraishi
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996, USA; (D.L.P.); (M.A.)
| | - Winyoo Chowanadisai
- Department of Nutrition, Oklahoma State University, Stillwater, OK 74078, USA;
| | - Ahmed Bettaieb
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996, USA; (D.L.P.); (M.A.)
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Liu Y, Liu X, Lin C, Jia X, Zhu H, Song J, Zhang Y. Noncoding RNAs regulate alternative splicing in Cancer. J Exp Clin Cancer Res 2021; 40:11. [PMID: 33407694 PMCID: PMC7789004 DOI: 10.1186/s13046-020-01798-2] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 12/03/2020] [Indexed: 12/14/2022] Open
Abstract
AS (alternative splicing) is a fundamental process by which a gene can generate multiple distinct mRNA transcripts to increase protein diversity. Defects in AS influence the occurrence and development of many diseases, including cancers, and are frequently found to participate in various aspects of cancer biology, such as promoting invasion, metastasis, apoptosis resistance and drug resistance. NcRNAs (noncoding RNAs) are an abundant class of RNAs that do not encode proteins. NcRNAs include miRNAs (microRNAs), lncRNAs (long noncoding RNAs), circRNAs (circular RNAs) and snRNAs (small nuclear RNAs) and have been proven to act as regulatory molecules that mediate cancer processes through AS. NcRNAs can directly or indirectly influence a plethora of molecular targets to regulate cis-acting elements, trans-acting factors, or pre-mRNA transcription at multiple levels, affecting the AS process and generating alternatively spliced isoforms. Consequently, ncRNA-mediated AS outcomes affect multiple cellular signaling pathways that promote or suppress cancer progression. In this review, we summarize the current mechanisms by which ncRNAs regulate AS in cancers and discuss their potential clinical applications as biomarkers and therapeutic targets.
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Affiliation(s)
- Yunze Liu
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
- Department of Traditional Chinese Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Xin Liu
- Department of Endocrinology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Changwei Lin
- Department of Gastrointestinal Surgery, the Third XiangYa Hospital of Central South University, Changsha, 410013, China
| | - Xianhong Jia
- Department of Traditional Chinese Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Hongmei Zhu
- Department of Traditional Chinese Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Jun Song
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China.
| | - Yi Zhang
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China.
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Zheng H, Zhang M, Ke X, Deng X, Li D, Wang Q, Yan S, Xue Y, Wang Q. LncRNA XIST/miR-137 axis strengthens chemo-resistance and glycolysis of colorectal cancer cells by hindering transformation from PKM2 to PKM1. Cancer Biomark 2021; 30:395-406. [PMID: 33386794 DOI: 10.3233/cbm-201740] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Glycolysis was an essential driver of chemo-resistance in colorectal cancer (CRC), albeit with limited molecular explanations. OBJECTIVE We strived to elucidate the involvement of lncRNA XIST/miR-137/PKM axis in chemo-tolerance and glycolysis of CRC. METHODS Altogether 212 pairs of tumor tissues and adjacent normal tissues were collected from CRC patients. Moreover, human CRC epithelial cell lines, including HT29, SW480, SW620 and LoVo, were purchased in advance, and their activity was estimated after transfection of si-XIST or miR-137 mimic. Furthermore, 5-FU/cisplatin-resistance of CRC cells was determined through MTT assay, and glycolytic potential of CRC cells was appraised based on oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). RESULTS Highly-expressed XIST were predictive of severe symptoms and unfavorable 3-year survival of CRC patients (P< 0.05). Besides, silencing of XIST not only diminished proliferative, migratory and invasive power of CRC cells (P< 0.05), but also enhanced sensitivity of CRC cells responding to 5-FU/cisplatin (P< 0.05). Glycolytic potency of CRC cells was also undermined by si-XIST, with decreased maximal respiration and maximal glycolytic capacity in the si-XIST group as relative to NC group (P< 0.05). Nevertheless, miR-137 mimic attenuated the facilitating effect of pcDNA3.1-XIST on proliferation, migration, invasion, 5-FU/cisplatin-resistance and glycolysis of CRC cells (P< 0.05). Ultimately, ratio of PKM2 mRNA and PKM1 mRNA, despite being up-regulated by pcDNA3.1-XIST, was markedly lowered when miR-137 mimic was co-transfected (P< 0.05). CONCLUSIONS LncRNA XIST/miR-137 axis reinforced glycolysis and chemo-tolerance of CRC by elevating PKM2/PKM1 ratio, providing an alternative to boost chemo-therapeutic efficacy of CRC patients.
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Affiliation(s)
- Hailun Zheng
- Department of Gastroenterology, the First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Mei Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Bengbu Medical College, Anhui, China
- Graduate School of Bengbu Medical College, Anhui, China
- Clinical Medical Colleges of Bengbu Medical College, Anhui, China
| | - Xiquan Ke
- Department of Gastroenterology, the First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Xiaojing Deng
- Department of Gastroenterology, the First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Dapeng Li
- Department of Gastroenterology, the First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Qizhi Wang
- Department of Gastroenterology, the First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Shanjun Yan
- Department of Gastroenterology, the First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Yongju Xue
- Department of Gastroenterology, the First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Qiangwu Wang
- Department of Gastroenterology, the First Affiliated Hospital of Bengbu Medical College, Anhui, China
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42
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Taniguchi K, Uchiyama K, Akao Y. PTBP1-targeting microRNAs regulate cancer-specific energy metabolism through the modulation of PKM1/M2 splicing. Cancer Sci 2021; 112:41-50. [PMID: 33070451 PMCID: PMC7780020 DOI: 10.1111/cas.14694] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 10/10/2020] [Accepted: 10/12/2020] [Indexed: 02/03/2023] Open
Abstract
Understanding of the microRNAs (miRNAs) regulatory system has become indispensable for physiological/oncological research. Tissue and organ specificities are key features of miRNAs that should be accounted for in cancer research. Further, cancer-specific energy metabolism, referred to as the Warburg effect, has been positioned as a key cancer feature. Enhancement of the glycolysis pathway in cancer cells is what primarily characterizes the Warburg effect. Pyruvate kinase M1/2 (PKM1/2) are key molecules of the complex glycolytic system; their distribution is organ-specific. In fact, PKM2 overexpression has been detected in various cancer cells. PKM isoforms are generated by alternative splicing by heterogeneous nuclear ribonucleoproteins. In addition, polypyrimidine tract-binding protein 1 (PTBP1) is essential for the production of PKM2 in cancer cells. Recently, several studies focusing on non-coding RNA elucidated PTBP1 or PKM2 regulatory mechanisms, including control by miRNAs, and their association with cancer. In this review, we discuss the strong relationship between the organ-specific distribution of miRNAs and the expression of PKM in the context of PTBP1 gene regulation. Moreover, we focus on the impact of PTBP1-targeting miRNA dysregulation on the Warburg effect.
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Affiliation(s)
- Kohei Taniguchi
- Department of General and Gastroenterological SurgeryOsaka Medical CollegeOsakaJapan
- Translational Research ProgramOsaka Medical CollegeOsakaJapan
| | - Kazuhisa Uchiyama
- Department of General and Gastroenterological SurgeryOsaka Medical CollegeOsakaJapan
| | - Yukihiro Akao
- United Graduate School of Drug Discovery and Medical Information SciencesGifu UniversityGifuJapan
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Li J, Liang L, Yang Y, Li X, Ma Y. N 6-methyladenosine as a biological and clinical determinant in colorectal cancer: progression and future direction. Theranostics 2021; 11:2581-2593. [PMID: 33456561 PMCID: PMC7806471 DOI: 10.7150/thno.52366] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 12/04/2020] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers and one of the leading causes of cancer death. Recent studies have provided evidence that N6-methyladenosine (m6A), the most abundant RNA modifications in eukaryote, performs many functions in RNA metabolism including translation, splicing, storage, trafficking and degradation. Aberrant regulation of m6A modification in mRNAs and noncoding RNAs found in CRC tissues is crucial for cancer formation, progression, invasion and metastasis. Further, m6A regulators and m6A-related RNAs may become promising biomarkers, prognosis predictors as well as therapeutic targets. Here, we review the biological and clinical roles of m6A modification in CRC, and discuss the potential of m6A in clinical translation.
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Huang Z, Xu Y, Wan M, Zeng X, Wu J. miR-340: A multifunctional role in human malignant diseases. Int J Biol Sci 2021; 17:236-246. [PMID: 33390846 PMCID: PMC7757049 DOI: 10.7150/ijbs.51123] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 11/09/2020] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of short non-coding RNAs of approximately 22 nucleotides in length, which function by binding to the 3' UTR sequences of their target mRNAs. It has been reported that dysregulated miRNAs play pivotal roles in numerous diseases, including cancers, such as gastric, breast, colorectal, ovarian, and other cancers. Recent research efforts have been devoted to translating these basic discoveries into clinical applications that could improve the therapeutic outcome in patients with cancer. Early studies have shown that miR-340 may act either as an oncogene or a tumor suppressor by targeting genes related to proliferation, apoptosis, and metastasis, as well as those associated with diagnosis, treatment, chemoresistance, and prognosis. miR-340 has been shown to have a role in other diseases, such as autoimmune diseases, acute stroke, and alcoholic steatohepatitis. Nevertheless, the roles of miR-340 in human malignancies are still unclear, and the associated mechanisms are complex, involving a variety of signaling pathways, such as Wnt/β-catenin and the JAK-STAT pathways. Herein, we review the crucial roles of miR-340 in human cancers through the analysis of the latest research studies, with the aim of clarifying miR-340 function in malignant disease diagnosis, treatment, and prognosis, and to propose further investigations.
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Affiliation(s)
- Zheng Huang
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P.R. China
- Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, P.R. China
| | - Yesha Xu
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P.R. China
| | - Maoping Wan
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P.R. China
| | - Xixi Zeng
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P.R. China
| | - Jianmin Wu
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P.R. China
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Algaber A, Al-Haidari A, Madhi R, Rahman M, Syk I, Thorlacius H. MicroRNA-340-5p inhibits colon cancer cell migration via targeting of RhoA. Sci Rep 2020; 10:16934. [PMID: 33037251 PMCID: PMC7547089 DOI: 10.1038/s41598-020-73792-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 09/11/2020] [Indexed: 12/12/2022] Open
Abstract
Colon cancer is the third most common cancer and a significant cause of cancer-related deaths worldwide. Metastasis is the most insidious aspect of cancer progression. Convincing data suggest that microRNAs (miRs) play a key function in colon cancer biology. We examined the role of miR-340-5p in regulating RhoA expression as well as cell migration and invasion in colon cancer cells. Levels of miR-340-5p and RhoA mRNA varied inversely in serum-free and serum-grown HT-29 and AZ-97 colon cancer cells. It was found transfection with miR-340-5p not only decreased expression of RhoA mRNA and protein levels in HT-29 cells but also reduced colon cancer cell migration and invasion. Bioinformatics analysis predicted one putative binding sites at the 3'-UTR of RhoA mRNA. Targeting this binding site with a specific blocker reversed mimic miR-340-5p-induced inhibition of RhoA activation and colon cancer cell migration and invasion. These novel results suggest that miR-340-5p is an important regulator of colon cancer cell motility via targeting of RhoA and further experiments are warranted to evaluate the role of miR-340-5p in colon cancer metastasis.
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Affiliation(s)
- Anwar Algaber
- Section for Surgery, Department of Clinical Sciences, Skåne University Hospital, Lund University, 20502, Malmö, Sweden
| | - Amr Al-Haidari
- Section for Surgery, Department of Clinical Sciences, Skåne University Hospital, Lund University, 20502, Malmö, Sweden
| | - Raed Madhi
- Section for Surgery, Department of Clinical Sciences, Skåne University Hospital, Lund University, 20502, Malmö, Sweden
| | - Milladur Rahman
- Section for Surgery, Department of Clinical Sciences, Skåne University Hospital, Lund University, 20502, Malmö, Sweden
| | - Ingvar Syk
- Section for Surgery, Department of Clinical Sciences, Skåne University Hospital, Lund University, 20502, Malmö, Sweden
| | - Henrik Thorlacius
- Section for Surgery, Department of Clinical Sciences, Skåne University Hospital, Lund University, 20502, Malmö, Sweden.
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Xu J, Wu G, Zhao Y, Han Y, Zhang S, Li C, Zhang J. Long Noncoding RNA DSCAM-AS1 Facilitates Colorectal Cancer Cell Proliferation and Migration via miR-137/Notch1 Axis. J Cancer 2020; 11:6623-6632. [PMID: 33046983 PMCID: PMC7545673 DOI: 10.7150/jca.46562] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 07/17/2020] [Indexed: 12/11/2022] Open
Abstract
Growing evidences demonstrate that long noncoding RNAs (lncRNAs) participate in various cancers including colorectal cancer (CRC). In the current study, we found that the expression of DSCAM-AS1 in CRC tissues and cell lines was significantly upregulated, and was positively correlated with metastasis status and advanced stage of CRC. In addition, Kaplan-Meier assays also indicated that the expression of DSCAM-AS1 was correlated with poor prognosis in patients with CRC. Silence of DSCAM-AS1 inhibited proliferation and migration of CRC cells. Subcellular fractionation and FISH analyses suggested that DSCAM-AS1 was majorly distributed in cytoplasm of HT29 and LOVO cells. Thus, DSCAM-AS1 might act as a competing endogenous RNA (ceRNA). Subsequently, RT-qPCR results displayed that the expression of miR-137 in CRC tissues was relatively lower than that in the neighboring normal tissues. The interaction between miR-137 and DSCAM-AS1 was demonstrated by luciferase reporter assay. Functionally, miR-137 reversed the pro-proliferation and -metastasis effect of DSCAM-AS1 on CRC cells. Collectively, DSCAM-AS1 promotes CRC progression via sponging miR-137. MiR-137 can suppress the expression of Notch-1, a novel signaling regulating cell proliferation and EMT, by working on the 3'UTR of Notch-1. At last, Notch-1 overexpression or miR-137 inhibition could restore the DSCAM-AS1 silencing-mediated repressive function on cell proliferation and migration. The above data suggested that, DSCAM-AS1 may contribute to CRC cell proliferation and migration by targeting miR-137/Notch-1 axis.
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Affiliation(s)
- Jing Xu
- Department of General Surgery, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121, PR China
| | - Guanghai Wu
- Department of General Surgery, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121, PR China
| | - Yongjie Zhao
- Department of General Surgery, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121, PR China
| | - Youkui Han
- Department of General Surgery, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121, PR China
| | - Shuai Zhang
- Department of General Surgery, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121, PR China
| | - Chao Li
- Department of General Surgery, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121, PR China
| | - Judong Zhang
- Department of General Surgery, Tianjin Union Medical Center, Jieyuan Road 190, Hongqiao District, Tianjin, 300121, PR China
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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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Gonzalez-Villarreal CA, Quiroz-Reyes AG, Islas JF, Garza-Treviño EN. Colorectal Cancer Stem Cells in the Progression to Liver Metastasis. Front Oncol 2020; 10:1511. [PMID: 32974184 PMCID: PMC7468493 DOI: 10.3389/fonc.2020.01511] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 07/14/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal carcinoma (CRC) is a leading cause of cancer mortality. Tumorigenesis is a dynamic process wherein cancer stem cells (CSCs) and their microenvironment promote initiation, progression, and metastasis. Metastatic colonization is an inefficient process that is very complex and is poorly understood; however, in most cases, metastatic disease is not curable, and resistance mechanisms tend to develop against conventional treatments. An understanding of the underlying mechanisms and factors that contribute to the development of metastasis in CRC can aid in the search for specific therapeutic targets for improving standard treatments. In this review, we summarize current knowledge regarding tumor biology and the use of stroma cells as prognostic factors and inflammatory inducers associated with the use of tumor microenvironments as a promoter of cancer metastasis. Moreover, we look into the importance of CSC, pericytes, and circulating tumor cells as mechanisms that lead to liver metastasis, and we also focus on the cellular and molecular pathways that modulate and regulate epithelial–mesenchymal transition. Finally, we discuss a novel therapeutic target that can potentially eliminate CSCs as a CRC treatment.
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Affiliation(s)
| | - Adriana G Quiroz-Reyes
- Universidad Autonoma de Nuevo Leon Facultad de Medicina, Departamento de Bioquimica y Medicina Molecular, San Nicolás de los Garza, Mexico
| | - Jose F Islas
- Universidad Autonoma de Nuevo Leon Facultad de Medicina, Departamento de Bioquimica y Medicina Molecular, San Nicolás de los Garza, Mexico
| | - Elsa N Garza-Treviño
- Universidad Autonoma de Nuevo Leon Facultad de Medicina, Departamento de Bioquimica y Medicina Molecular, San Nicolás de los Garza, Mexico
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Li C, Yu Z, Ye J. MicroRNA-513a-3p regulates colorectal cancer cell metabolism via targeting hexokinase 2. Exp Ther Med 2020; 20:572-580. [PMID: 32537015 DOI: 10.3892/etm.2020.8727] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 11/05/2019] [Indexed: 01/05/2023] Open
Abstract
Disruption of cell metabolism is a hallmark of cancer cells. Accumulating evidence suggests that microRNAs (miRNAs/miRs) are involved in almost all physiological and pathological processes. The aberrant expression of miRNAs induces metabolic reprogramming in cancer cells and thus, promotes proliferation. In the current study, miR-513a-3p was identified as a significantly downregulated miRNA in colorectal cancer cells and tumors. Overexpression of miR-513a-3p in colorectal cancer cells inhibited proliferation and glycolysis. A well-documented metabolic regulator, hexokinase 2 (HK2), was predicted and validated HK2to be a target gene of miR-513a-3p in colorectal cancer cells. In addition, overexpression of HK2 reversed the miR-513a-3p mimic-induced inhibition of proliferation. The association between HK2 and miR-513a-3p was further observed in tumors collected from patients with colorectal cancer. The findings suggest that miR-513a-5p may inhibit glycolysis in colorectal cancer cells via repressing HK2 expression, indicating that miR-513a-5p may be a tumor suppressor in colorectal cancer.
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Affiliation(s)
- Chen Li
- Department of Digestive Endocrine, People's Hospital of Boluo County, Huizhou, Guangdong 516100, P.R. China
| | - Zhijin Yu
- Department of Gastroenterology, Huizhou Municipal Central Hospital, Huizhou, Guangdong 516002, P.R. China
| | - Jinpeng Ye
- Department of Digestive Endocrine, People's Hospital of Boluo County, Huizhou, Guangdong 516100, P.R. China
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50
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Jian X, He H, Zhu J, Zhang Q, Zheng Z, Liang X, Chen L, Yang M, Peng K, Zhang Z, Liu T, Ye Y, Jiao H, Wang S, Zhou W, Ding Y, Li T. Hsa_circ_001680 affects the proliferation and migration of CRC and mediates its chemoresistance by regulating BMI1 through miR-340. Mol Cancer 2020; 19:20. [PMID: 32005118 PMCID: PMC6993513 DOI: 10.1186/s12943-020-1134-8] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 01/09/2020] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Accumulating evidence indicates that circular RNAs (circRNAs) act as microRNA (miRNA) sponges to directly inhibit specific miRNAs and alter their ability to regulate gene expression at the post-transcriptional level; this mechanism is believed to occur in various cancers. However, the expression level, precise function and mechanism of circ_001680 in colorectal carcinoma (CRC) are largely unknown. METHODS qRT-PCR was used to detect the expression of circ_001680 and miR-340 in human CRC tissues and their matched normal tissues. Bioinformatics analyses and dual-fluorescence reporter assays were used to evaluate whether circ_001680 could bind to miR-340. Circ_001680 overexpression and knockdown cell lines were constructed to investigate the proliferation and migration abilities in vivo and in vitro through function-based experiments, including CCK8, plate clone formation, transwell, and wounding healing assays. The relationships among circ_001680, miR-340 and BMI1 were investigated by bioinformatics analyses, dual-fluorescence reporter system, FISH, RIP and RNA pull down assays. Sphere forming assays and flow cytometry analyses were used to assess the effect of circ_001680 on the stemness characteristics of CRC cells. RESULTS Circ_001680 was more highly expressed in of CRC tissue than in matched adjacent normal tissues from the same patients. Circ_001680 was observed to enhance the proliferation and migration capacity of CRC cells. Furthermore, dual-fluorescence reporter assays confirmed that circ_001680 affects the expression of BMI1 by targeting miR-340. More importantly, we also found that circ_001680 could promote the cancer stem cell (CSC) population in CRC and induce irinotecan therapeutic resistance by regulating the miR-340 target gene BMI1. CONCLUSIONS Our results demonstrated that circ_001680 is a part of a novel strategy to induce chemotherapy resistance in CRC through BMI1 upregulation. Moreover, circ_001680 may be a promising diagnostic and prognostic marker to determine the success of irinotecan-based chemotherapy.
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Affiliation(s)
- Xiangyu Jian
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Han He
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiehong Zhu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Qi Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhongxin Zheng
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiangjing Liang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Liuyan Chen
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Meiling Yang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Kaiyue Peng
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhaowen Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Tengfei Liu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yaping Ye
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Hongli Jiao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Shuyang Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Weijie Zhou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yanqing Ding
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Tingting Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
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