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Schütz F, Longo L, Keingeski MB, Filippi-Chiela E, Uribe-Cruz C, Álvares-da-Silva MR. Lipophagy and epigenetic alterations are related to metabolic dysfunction-associated steatotic liver disease progression in an experimental model. World J Hepatol 2024; 16:1468-1479. [DOI: 10.4254/wjh.v16.i12.1468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 08/31/2024] [Accepted: 09/19/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Genetic and epigenetic alterations are related to metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis.
AIM To evaluate micro (mi)RNAs and lipophagy markers in an experimental model of metabolic dysfunction-associated steatohepatitis (MASH).
METHODS Adult male Sprague Dawley rats were randomized into two groups: Control group (n = 10) fed a standard diet; and intervention group (n = 10) fed a high-fat-choline-deficient diet for 16 weeks. Molecular evaluation of lipophagy markers in liver tissue [sirtuin-1, p62/sequestosome-1, transcription factor-EB, perilipin-2 (Plin2), Plin3, Plin5, lysosome-associated membrane proteins-2, rubicon, and Cd36], and serum miRNAs were performed.
RESULTS Animals in the intervention group developed MASH and showed a significant decrease in sirtuin-1 (P = 0.020) and p62/sequestosome-1 (P < 0.001); the opposite was reported for transcription factor-EB (P = 0.020), Plin2 (P = 0.003), Plin3 (P = 0.031), and Plin5 (P = 0.005) compared to the control group. There was no significant difference between groups for lysosome-associated membrane proteins-2 (P = 0.715), rubicon (P = 0.166), and Cd36 (P = 0.312). The intervention group showed a significant increase in miR-34a (P = 0.005) and miR-21 (P = 0.043) compared to the control. There was no significant difference between groups for miR-375 (P = 0.905), miR-26b (P = 0.698), and miR-155 (P = 0.688).
CONCLUSION Animals with MASH presented expression changes in markers related to lysosomal stress and autophagy as well as in miRNAs related to inflammation and fibrogenesis, processes that promote MASLD progression.
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Affiliation(s)
- Felipe Schütz
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
| | - Larisse Longo
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
| | - Melina Belén Keingeski
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
| | - Eduardo Filippi-Chiela
- Center of Biotechnology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
- Department of Morphological Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
| | - Carolina Uribe-Cruz
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Facultad de Ciencias de la Salud, Universidad Católica de las Misiones, Posadas 3300, Misiones, Argentina
| | - Mário Reis Álvares-da-Silva
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasilia 71.605-001, Distrito Federal, Brazil
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Chuang YC, Ou JHJ. Hepatitis B virus entry, assembly, and egress. Microbiol Mol Biol Rev 2024; 88:e0001424. [PMID: 39440957 DOI: 10.1128/mmbr.00014-24] [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] [Indexed: 10/25/2024] Open
Abstract
SUMMARYHepatitis B virus (HBV) is an important human pathogen that chronically infects approximately 250 million people in the world, resulting in ~1 million deaths annually. This virus is a hepatotropic virus and can cause severe liver diseases including cirrhosis and hepatocellular carcinoma. The entry of HBV into hepatocytes is initiated by the interaction of its envelope proteins with its receptors. This is followed by the delivery of the viral nucleocapsid to the nucleus for the release of its genomic DNA and the transcription of viral RNAs. The assembly of the viral capsid particles may then take place in the nucleus or the cytoplasm and may involve cellular membranes. This is followed by the egress of the virus from infected cells. In recent years, significant research progresses had been made toward understanding the entry, the assembly, and the egress of HBV particles. In this review, we discuss the molecular pathways of these processes and compare them with those used by hepatitis delta virus and hepatitis C virus , two other hepatotropic viruses that are also enveloped. The understanding of these processes will help us to understand how HBV replicates and causes diseases, which will help to improve the treatments for HBV patients.
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Affiliation(s)
- Yu-Chen Chuang
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - J-H James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
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3
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Wei J, Wang X, Yu D, Tu Y, Yu Y. MicroRNA-mediated autophagy and drug resistance in cancer: mechanisms and therapeutic strategies. Discov Oncol 2024; 15:662. [PMID: 39549162 PMCID: PMC11569378 DOI: 10.1007/s12672-024-01525-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 11/04/2024] [Indexed: 11/18/2024] Open
Abstract
This paper provides an exhaustive overview of the intricate interplay between microRNAs (miRNAs) and autophagy in the context of human cancers, underscoring the pivotal role these non-coding RNAs play in modulating autophagic pathways and their implications for cancer development, progression, and resistance to therapy. MiRNAs, as critical regulators of gene expression post-transcription, influence various biological processes, including autophagy, a catabolic mechanism essential for cellular homeostasis, stress response, and survival. The review meticulously delineates the mechanisms through which miRNAs impact autophagy by targeting specific genes and signaling pathways, thereby affecting cancer cell proliferation, metastasis, and response to chemotherapy. It highlights several miRNAs with dual roles, acting either as oncogenes or tumor suppressors based on the cellular context and the specific autophagic pathways they regulate. The paper further explores the therapeutic potential of targeting miRNA-autophagy axis, offering insights into novel strategies for cancer treatment through modulation of this axis. Emphasizing the complexity of the miRNA-autophagy relationship, the review calls for more in-depth studies to unravel the nuanced regulatory networks between miRNAs and autophagy in cancer, which could pave the way for the development of innovative therapeutic interventions and diagnostic tools.
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Affiliation(s)
- Jinxing Wei
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China
| | - Xianghui Wang
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China
| | - Duo Yu
- Department of Biopharmaceutics School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China
| | - Yanyang Tu
- Research Center, The Huizhou Central People's Hospital, Guangdong Medical University, No. 41 Eling North Road, Huizhou, Guangdong, China.
| | - Yaoyu Yu
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China.
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4
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Amin W, Enam SA, Sufiyan S, Ghias K, Bajwa MH, Ilyas S, Laghari AA, Naeem S, Abidi SH, Mughal N. Autophagy-associated biomarkers ULK2, UVRAG, and miRNAs miR-21, miR-126, and miR-374: Prognostic significance in glioma patients. PLoS One 2024; 19:e0311308. [PMID: 39348350 PMCID: PMC11441661 DOI: 10.1371/journal.pone.0311308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 09/06/2024] [Indexed: 10/02/2024] Open
Abstract
As the pioneering study from Pakistan, our research distinctly focuses on validating the roles of autophagy-associated genes and MicroRNAs (miRs) in the unique context of our population for glioma prognosis. The study delves into the nuanced interplay of autophagy within a miR-modulated environment, prompting an exploration of its potential impact on glioma development and survival. Employing real-time PCR (qPCR), we meticulously assessed the expression profiles of autophagy genes and miRs in glioma tissues, complemented by immunohistochemistry on Formalin-fixed paraffin-embedded tissues from the same patients. Our comprehensive statistical analyses, including the data normality hypothesis Shapiro-Wilk test, the Mann-Whitney U-test, Spearman correlation test, and Kaplan-Meier survival analysis, were tailored to unravel the intricate associations specific to low- and high-grade glioma within our population. Clinicopathological analysis revealed a predominance of male patients (66%) with a median age of 35 years. Glioblastoma (32%) and Astrocytoma (36%) were the most prevalent histopathological subtypes. Molecular analysis showed significant correlations between prognostic markers (Ki-67, IDH-1, p53) and clinicopathological factors, including age, histological type, radiotherapy, and chemotherapy. In high-grade glioma, increased expression of AKT and miR-21, coupled with reduced ULK2 and LC3 expression was distinctly observed. While correlation analysis identified a strong positive correlation between ULK2 and UVRAG, PTEN, miR-7, and miR-100 in low-grade glioma, unveiling distinctive molecular signatures unique to our study. Furthermore, a moderate positive correlation emerged between ULK2 and mTOR, miR-7, miR-30, miR-100, miR-204, and miR-374, also between miR-21 and miR-126. Similarly, a positive correlation appeared between ULK2 and AKT, LC3, PI3K, PTEN, ULK1, VPS34, mTOR, Beclin1, UVRAG, miR-7 and miR-374. AKT positively correlated with LC3, PI3K, PTEN, ULK1, VPS34, mTOR, Beclin1, UVRAG, miR-7, miR-30, miR-204, miR-374, miR-126 and miR-21 weakly correlated with AKT and miR-30 in high-grade glioma, providing further insights into the autophagy pathway within our population. The enrichment analysis for miR-21, miR-126, and miR-374 showed MAPK pathway as a common pathway along with Ras, PI3K, and mTOR pathway. The low ULK2, UVRAG, and miR-374 expression group exhibited significantly poor overall survival in glioma, while miR-21 over-expression indicated a poor prognosis in glioma patients, validating it in our population. This study provides comprehensive insights into the molecular landscape of gliomas, highlighting the dysregulation of autophagy genes ULK2, and UVRAG and the associated miR-21, miR-126 and miR-374 as potential prognostic biomarkers and emphasizing their unique significance in shaping survival outcomes in gliomas within the specific context of the Pakistani population.
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Affiliation(s)
- Wajiha Amin
- Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan
| | - Syed Ather Enam
- Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan
- Center of Oncological Research in Surgery, Aga Khan University, Karachi, Pakistan
| | - Sufiyan Sufiyan
- Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan
| | - Kulsoom Ghias
- Department of Biological & Biomedical Science, Aga Khan University Hospital, Karachi, Pakistan
| | | | - Sahar Ilyas
- Center of Oncological Research in Surgery, Aga Khan University, Karachi, Pakistan
| | - Altaf Ali Laghari
- Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan
| | - Sana Naeem
- Center of Oncological Research in Surgery, Aga Khan University, Karachi, Pakistan
| | - Syed Hani Abidi
- Department of Biological & Biomedical Science, Aga Khan University Hospital, Karachi, Pakistan
- Department of Biomedical Sciences, Nazarbayev School of Medicine, Nazarbayev University, Astana, Kazakhstan
- Department of Life Sciences, Western Caspian University, Baku, Azerbaijan
| | - Nouman Mughal
- Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan
- Center of Oncological Research in Surgery, Aga Khan University, Karachi, Pakistan
- Department of Biological & Biomedical Science, Aga Khan University Hospital, Karachi, Pakistan
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5
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Hussain MS, Moglad E, Afzal M, Gupta G, Hassan Almalki W, Kazmi I, Alzarea SI, Kukreti N, Gupta S, Kumar D, Chellappan DK, Singh SK, Dua K. Non-coding RNA mediated regulation of PI3K/Akt pathway in hepatocellular carcinoma: Therapeutic perspectives. Pathol Res Pract 2024; 258:155303. [PMID: 38728793 DOI: 10.1016/j.prp.2024.155303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/07/2024] [Accepted: 04/08/2024] [Indexed: 05/12/2024]
Abstract
Hepatocellular carcinoma (HCC) is among the primary reasons for fatalities caused by cancer globally, highlighting the need for comprehensive knowledge of its molecular aetiology to develop successful treatment approaches. The PI3K/Akt system is essential in the course of HCC, rendering it an intriguing candidate for treatment. Non-coding RNAs (ncRNAs), such as long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are important mediators of the PI3K/Akt network in HCC. The article delves into the complex regulatory functions of ncRNAs in influencing the PI3K/Akt system in HCC. The study explores how lncRNAs, miRNAs, and circRNAs impact the expression as well as the function of the PI3K/Akt network, either supporting or preventing HCC growth. Additionally, treatment strategies focusing on ncRNAs in HCC are examined, such as antisense oligonucleotide-based methods, RNA interference, and small molecule inhibitor technologies. Emphasizing the necessity of ensuring safety and effectiveness in clinical settings, limitations, and future approaches in using ncRNAs as therapies for HCC are underlined. The present study offers useful insights into the complex regulation system of ncRNAs and the PI3K/Akt cascade in HCC, suggesting possible opportunities for developing innovative treatment approaches to address this lethal tumor.
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Affiliation(s)
- Md Sadique Hussain
- School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, Rajasthan 302017, India
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Gaurav Gupta
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India; Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates.
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341, Sakaka, Aljouf, Saudi Arabia
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Saurabh Gupta
- Chameli Devi Institute of Pharmacy, Department of Pharmacology, Khandwa Road, Village Umrikheda, Near Toll Booth, Indore, Madhya Pradesh 452020, India
| | - Dinesh Kumar
- School of Pharmacy, Chitkara University, Himachal Pradesh, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia; School of Medical and Life Sciences, Sunway University, 47500 Sunway City, Malaysia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.
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6
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Chen Z, Li C, Huang H, Shi YL, Wang X. Research Progress of Aging-related MicroRNAs. Curr Stem Cell Res Ther 2024; 19:334-350. [PMID: 36892029 DOI: 10.2174/1574888x18666230308111043] [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: 10/22/2022] [Revised: 01/02/2023] [Accepted: 01/11/2023] [Indexed: 03/10/2023]
Abstract
Senescence refers to the irreversible state in which cells enter cell cycle arrest due to internal or external stimuli. The accumulation of senescent cells can lead to many age-related diseases, such as neurodegenerative diseases, cardiovascular diseases, and cancers. MicroRNAs are short non-coding RNAs that bind to target mRNA to regulate gene expression after transcription and play an important regulatory role in the aging process. From nematodes to humans, a variety of miRNAs have been confirmed to alter and affect the aging process. Studying the regulatory mechanisms of miRNAs in aging can further deepen our understanding of cell and body aging and provide a new perspective for the diagnosis and treatment of aging-related diseases. In this review, we illustrate the current research status of miRNAs in aging and discuss the possible prospects for clinical applications of targeting miRNAs in senile diseases.
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Affiliation(s)
- Zhongyu Chen
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
| | - Chenxu Li
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
| | - Haitao Huang
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
| | - Yi-Ling Shi
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
| | - Xiaobo Wang
- School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China
- Key Laboratory of University Cell Biology, Dali, Yunnan, 671000, China
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7
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Jouve M, Carpentier R, Kraiem S, Legrand N, Sobolewski C. MiRNAs in Alcohol-Related Liver Diseases and Hepatocellular Carcinoma: A Step toward New Therapeutic Approaches? Cancers (Basel) 2023; 15:5557. [PMID: 38067261 PMCID: PMC10705678 DOI: 10.3390/cancers15235557] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 06/29/2024] Open
Abstract
Alcohol-related Liver Disease (ALD) is the primary cause of chronic liver disorders and hepatocellular carcinoma (HCC) development in developed countries and thus represents a major public health concern. Unfortunately, few therapeutic options are available for ALD and HCC, except liver transplantation or tumor resection for HCC. Deciphering the molecular mechanisms underlying the development of these diseases is therefore of major importance to identify early biomarkers and to design efficient therapeutic options. Increasing evidence indicate that epigenetic alterations play a central role in the development of ALD and HCC. Among them, microRNA importantly contribute to the development of this disease by controlling the expression of several genes involved in hepatic metabolism, inflammation, fibrosis, and carcinogenesis at the post-transcriptional level. In this review, we discuss the current knowledge about miRNAs' functions in the different stages of ALD and their role in the progression toward carcinogenesis. We highlight that each stage of ALD is associated with deregulated miRNAs involved in hepatic carcinogenesis, and thus represent HCC-priming miRNAs. By using in silico approaches, we have uncovered new miRNAs potentially involved in HCC. Finally, we discuss the therapeutic potential of targeting miRNAs for the treatment of these diseases.
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Affiliation(s)
- Mickaël Jouve
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Rodolphe Carpentier
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Sarra Kraiem
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Noémie Legrand
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Cyril Sobolewski
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France
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8
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Crosstalk between Glycogen-Selective Autophagy, Autophagy and Apoptosis as a Road towards Modifier Gene Discovery and New Therapeutic Strategies for Glycogen Storage Diseases. Life (Basel) 2022; 12:life12091396. [PMID: 36143432 PMCID: PMC9504455 DOI: 10.3390/life12091396] [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: 07/16/2022] [Revised: 08/23/2022] [Accepted: 09/01/2022] [Indexed: 11/30/2022] Open
Abstract
Glycogen storage diseases (GSDs) are rare metabolic monogenic disorders characterized by an excessive accumulation of glycogen in the cell. However, monogenic disorders are not simple regarding genotype–phenotype correlation. Genes outside the major disease-causing locus could have modulatory effect on GSDs, and thus explain the genotype–phenotype inconsistencies observed in these patients. Nowadays, when the sequencing of all clinically relevant genes, whole human exomes, and even whole human genomes is fast, easily available and affordable, we have a scientific obligation to holistically analyze data and draw smarter connections between genotype and phenotype. Recently, the importance of glycogen-selective autophagy for the pathophysiology of disorders of glycogen metabolism have been described. Therefore, in this manuscript, we review the potential role of genes involved in glycogen-selective autophagy as modifiers of GSDs. Given the small number of genes associated with glycogen-selective autophagy, we also include genes, transcription factors, and non-coding RNAs involved in autophagy. A cross-link with apoptosis is addressed. All these genes could be analyzed in GSD patients with unusual discrepancies between genotype and phenotype in order to discover genetic variants potentially modifying their phenotype. The discovery of modifier genes related to glycogen-selective autophagy and autophagy will start a new chapter in understanding of GSDs and enable the usage of autophagy-inducing drugs for the treatment of this group of rare-disease patients.
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9
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Ma L, Zhang M, Cao F, Han J, Han P, Wu Y, Deng R, Zhang G, An X, Zhang L, Song Y, Cao B. Effect of MiR-100-5p on proliferation and apoptosis of goat endometrial stromal cell in vitro and embryo implantation in vivo. J Cell Mol Med 2022; 26:2543-2556. [PMID: 35411593 PMCID: PMC9077292 DOI: 10.1111/jcmm.17226] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/05/2022] [Accepted: 01/10/2022] [Indexed: 12/13/2022] Open
Abstract
The growth of endometrial stromal cells (ESCs) at implantation sites may be a potential factor affecting the success rate of embryo implantation. Incremental proofs demonstrated that ncRNAs (e.g. miRNAs, lncRNAs and circRNAs) were involved in various biological procedures, including proliferation and apoptosis. In this study, the role of miR‐100‐5p on proliferation and apoptosis of goat ESCs in vitro and embryo implantation in vivo was determined. The mRNA expression of miR‐100‐5p was significantly inhibited in the receptive phase (RE) rather than in the pre‐receptive phase (PE). Overexpression of miR‐100‐5p suppressed ESCs proliferation and induced apoptosis. The molecular target of MiR‐100‐5p, HOXA1, was confirmed by 3′‐UTR assays. Meanwhile, the product of HOXA1 mRNA RT‐PCR increased in the RE more than that in the PE. The HOXA1‐siRNA exerted significant negative effects on growth arrest. Instead, incubation of ESCs with miR‐100‐5p inhibitor or overexpressed HOXA1 promoted the cell proliferation. In addition, Circ‐9110 which acted as a sponge for miR‐100‐5p reversed the relevant biological effects of miR‐100‐5p. The intrinsic apoptosis pathway was suppressed in ESCs, revealing a crosstalk between Circ‐9110/miR‐100‐5p/HOXA1 axis, PI3K/AKT/mTOR, and ERK1/2 pathways. To further evaluate the progress in study on embryo implantation regulating mechanism of miR‐100‐5p in vivo, the pinopodes of two phases were observed and analysed, suggesting that, as similar as in situ, miR‐100‐5p was involved in significantly regulating embryo implantation in vivo. Mechanistically, miR‐100‐5p performed its embryo implantation function through regulation of PI3K/AKT/mTOR and ERK1/2 pathways by targeting Circ‐9110/miR‐100‐5p/HOXA1 axis in vivo.
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Affiliation(s)
- Li Ma
- College of Animal Science and Technology, Northwest A&F University, Yangling, China.,Shaanxi University of Chinese Medicine, Xianyang, China
| | - Meng Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Fangjun Cao
- College of Animal Science and Technology, Northwest A&F University, Yangling, China.,Shaanxi Institute of Zoology, Xi'an, China
| | - Jincheng Han
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Peng Han
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Yeting Wu
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Renyi Deng
- Department of Foreign Languages, Northwest A&F University, Yangling, China
| | - Guanghui Zhang
- College of Innovation and Experiment, Northwest A&F University, Yangling, China
| | - Xiaopeng An
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Lei Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Yuxuan Song
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Binyun Cao
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
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10
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El-Mahdy HA, Sallam AAM, Ismail A, Elkhawaga SY, Elrebehy MA, Doghish AS. miRNAs inspirations in hepatocellular carcinoma: Detrimental and favorable aspects of key performers. Pathol Res Pract 2022; 233:153886. [PMID: 35405621 DOI: 10.1016/j.prp.2022.153886] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/23/2022] [Accepted: 04/01/2022] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. HCC initiation, progression, and therapy failure are all influenced by various variables, including microRNAs (miRNAs). miRNAs are short non-coding RNA sequences that modulate target mRNA expression by deteriorating or repressing translation. miRNAs play an imperative role in HCC pathogenesis by triggering the induction of cancer stem cells (CSCs) and their proliferation, while also delaying apoptosis, sustaining the cell cycle, and inspiring angiogenesis, invasion, and metastasis. Additionally, miRNAs modulate crucial HCC-related molecular pathways such as the p53 pathway, the Wnt/β-catenin pathway, VEGFR2, and PTEN/PI3K/AKT pathway. Consequently, the goal of this review was to give an up-to-date overview of oncogenic and tumor suppressor (TS) miRNAs, as well as their potential significance in HCC pathogenesis and treatment responses, highlighting their underpinning molecular pathways in HCC initiation and progression. Similarly, the biological importance and clinical application of miRNAs in HCC are summarized.
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Affiliation(s)
- Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
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11
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Wang H, Xu F, Lu L, Yang F, Huang X, Lv L, Hu H, Jiang Y. The diagnostic and prognostic significance of small nuclear ribonucleoprotein Sm D1 aberrantly high expression in hepatocellular carcinoma. J Cancer 2022; 13:184-201. [PMID: 34976182 PMCID: PMC8692702 DOI: 10.7150/jca.65225] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 11/09/2021] [Indexed: 12/29/2022] Open
Abstract
Small nuclear ribonucleoprotein Sm D1 (SNRPD1), one of the crucial genes encoding core spliceosome components, was abnormally highly expressed in multiple types of tumors. In this study, we investigated the diagnostic and prognostic significance of SNRPD1 in hepatocellular carcinoma (HCC). The investigation of datasets from GEO and TCGA databases revealed that SNRPD1 expression in HCC was significantly higher than adjacent normal liver tissues, which was validated by immunohistochemistry (IHC). Both GO, KEGG analysis showed that the SNRPD1 co-expressed genes mainly enriched in Cell division, Nuclear import, mRNA splicing via spliceosome, Ribosome, Cell cycle, etc. Survival analysis from the GSE14520 dataset and 154 HCC cohorts exhibited a significant association of high SNRPD1 expression with poor overall survival and recurrence-free survival. ROC analysis showed that the abnormally high SNRPD1 mRNA expression has diagnostic significance in distinguishing between HCC and normal liver tissue (AUC = 0.819). Gene set enrichment analysis (GSEA) demonstrated that the high expression of SNRPD1 might regulate HCC tumorigenesis and progression by affecting the cell cycle, mismatch repair, DNA replication, and RNA degradation, etc. The luciferase report assay revealed that SNRPD1 was the direct target gene of miR-100 manifested by decreased SNRPD1 expression and luciferase activity in the HCC cells upon miR-100 overexpression. Finally, SNRPD1 may as an oncogene affecting the progression of HCC through regulates the mTOR pathway and autophagy.
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Affiliation(s)
- Huaxiang Wang
- The Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350025, PR China
| | - Fengfeng Xu
- The Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350025, PR China
- Department of Hepatobiliary Surgery, 900 Hospital of the Joint Logistic Team, Fuzhou, Fujian 350025, PR China
| | - Lingling Lu
- The Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350025, PR China
| | - Fang Yang
- The Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350025, PR China
- Department of Hepatobiliary Surgery, 900 Hospital of the Joint Logistic Team, Fuzhou, Fujian 350025, PR China
| | - Xinghua Huang
- The Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350025, PR China
- Department of Hepatobiliary Surgery, 900 Hospital of the Joint Logistic Team, Fuzhou, Fujian 350025, PR China
| | - Lizhi Lv
- The Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350025, PR China
- Department of Hepatobiliary Surgery, 900 Hospital of the Joint Logistic Team, Fuzhou, Fujian 350025, PR China
| | - Huanzhang Hu
- The Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350025, PR China
- Department of Hepatobiliary Surgery, 900 Hospital of the Joint Logistic Team, Fuzhou, Fujian 350025, PR China
| | - Yi Jiang
- The Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350025, PR China
- Department of Hepatobiliary Surgery, 900 Hospital of the Joint Logistic Team, Fuzhou, Fujian 350025, PR China
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12
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Sadri Nahand J, Salmaninejad A, Mollazadeh S, Tamehri Zadeh SS, Rezaee M, Sheida AH, Sadoughi F, Dana PM, Rafiyan M, Zamani M, Taghavi SP, Dashti F, Mirazimi SMA, Bannazadeh Baghi H, Moghoofei M, Karimzadeh M, Vosough M, Mirzaei H. Virus, Exosome, and MicroRNA: New Insights into Autophagy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1401:97-162. [DOI: 10.1007/5584_2022_715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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13
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Palihaderu PADS, Mendis BILM, Premarathne JMKJK, Dias WKRR, Yeap SK, Ho WY, Dissanayake AS, Rajapakse IH, Karunanayake P, Senarath U, Satharasinghe DA. Potential role of microRNAs in selective hepatic insulin resistance: From paradox to the paradigm. Front Endocrinol (Lausanne) 2022; 13:1028846. [PMID: 36479211 PMCID: PMC9720316 DOI: 10.3389/fendo.2022.1028846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/31/2022] [Indexed: 11/22/2022] Open
Abstract
The paradoxical action of insulin on hepatic glucose metabolism and lipid metabolism in the insulin-resistant state has been of much research interest in recent years. Generally, insulin resistance would promote hepatic gluconeogenesis and demote hepatic de novo lipogenesis. The underlying major drivers of these mechanisms were insulin-dependent, via FOXO-1-mediated gluconeogenesis and SREBP1c-mediated lipogenesis. However, insulin-resistant mouse models have shown high glucose levels as well as excess lipid accumulation. As suggested, the inert insulin resistance causes the activation of the FOXO-1 pathway promoting gluconeogenesis. However, it does not affect the SREBP1c pathway; therefore, cells continue de novo lipogenesis. Many hypotheses were suggested for this paradoxical action occurring in insulin-resistant rodent models. A "downstream branch point" in the insulin-mediated pathway was suggested to act differentially on the FOXO-1 and SREBP1c pathways. MicroRNAs have been widely studied for their action of pathway mediation via suppressing the intermediate protein expressions. Many in vitro studies have postulated the roles of hepato-specific expressions of miRNAs on insulin cascade. Thus, miRNA would play a pivotal role in selective hepatic insulin resistance. As observed, there were confirmations and contradictions between the outcomes of gene knockout studies conducted on selective hepatic insulin resistance and hepato-specific miRNA expression studies. Furthermore, these studies had evaluated only the effect of miRNAs on glucose metabolism and few on hepatic de novo lipogenesis, limiting the ability to conclude their role in selective hepatic insulin resistance. Future studies conducted on the role of miRNAs on selective hepatic insulin resistance warrant the understanding of this paradoxical action of insulin.
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Affiliation(s)
| | | | | | | | - Swee Keong Yeap
- China-ASEAN College of Marine Sciences, Xiamen University Malaysia, Sepang, Selangor, Malaysia
| | - Wan Yong Ho
- Faculty of Sciences and Engineering, University of Nottingham Malaysia, Semenyih, Malaysia
| | | | | | - Panduka Karunanayake
- Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Upul Senarath
- Department of Community Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Dilan Amila Satharasinghe
- Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine and Animal Science, University of Peradeniya, Peradeniya, Sri Lanka
- *Correspondence: Dilan Amila Satharasinghe,
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14
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Kim Y, Lee DH, Park SH, Jeon TI, Jung CH. The interplay of microRNAs and transcription factors in autophagy regulation in nonalcoholic fatty liver disease. Exp Mol Med 2021; 53:548-559. [PMID: 33879861 PMCID: PMC8102505 DOI: 10.1038/s12276-021-00611-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/11/2021] [Accepted: 03/15/2021] [Indexed: 02/07/2023] Open
Abstract
The autophagy-lysosomal degradation system has an important role in maintaining liver homeostasis by removing unnecessary intracellular components. Impaired autophagy has been linked to nonalcoholic fatty liver disease (NAFLD), which includes hepatitis, steatosis, fibrosis, and cirrhosis. Thus, gaining an understanding of the mechanisms that regulate autophagy and how autophagy contributes to the development and progression of NAFLD has become the focus of recent studies. Autophagy regulation has been thought to be primarily regulated by cytoplasmic processes; however, recent studies have shown that microRNAs (miRNAs) and transcription factors (TFs) also act as key regulators of autophagy by targeting autophagy-related genes. In this review, we summarize the miRNAs and TFs that regulate the autophagy pathway in NAFLD. We further focus on the transcriptional and posttranscriptional regulation of autophagy and discuss the complex regulatory networks involving these regulators in autophagy. Finally, we highlight the potential of targeting miRNAs and TFs involved in the regulation of autophagy for the treatment of NAFLD.
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Affiliation(s)
- Yumi Kim
- grid.418974.70000 0001 0573 0246Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Jeollabuk-do 55365 Republic of Korea
| | - Da-Hye Lee
- grid.17635.360000000419368657Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455 USA
| | - So-Hyun Park
- grid.418974.70000 0001 0573 0246Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Jeollabuk-do 55365 Republic of Korea ,grid.412786.e0000 0004 1791 8264Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - Tae-Il Jeon
- grid.14005.300000 0001 0356 9399Department of Animal Science, Chonnam National University, Gwangju, Republic of Korea
| | - Chang Hwa Jung
- grid.418974.70000 0001 0573 0246Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Jeollabuk-do 55365 Republic of Korea ,grid.412786.e0000 0004 1791 8264Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
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15
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MicroRNA-100 Mediates Hydrogen Peroxide-Induced Apoptosis of Human Retinal Pigment Epithelium ARPE-19 Cells. Pharmaceuticals (Basel) 2021; 14:ph14040314. [PMID: 33915898 PMCID: PMC8067261 DOI: 10.3390/ph14040314] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 03/19/2021] [Accepted: 03/25/2021] [Indexed: 11/20/2022] Open
Abstract
This study investigated the regulatory role of microRNA 100 (miR-100) in hydrogen peroxide (H2O2)-induced apoptosis of human retinal pigment epithelial ARPE-19 cells. H2O2 induced oxidative cell death of cultured ARPE-19 cells was measured by cytotoxicity assay. qRT-PCR was used to quantify cytosolic and extracellular contents of miR-100. Kinase and miR-100 inhibition treatments were applied to determine the regulatory signaling pathways involved in cell death regulation. H2O2 dose-dependently reduced viability of ARPE-19 cells and simultaneously upregulated miR-100 levels in both cytosolic and extracellular compartments. Western blotting detection indicated that H2O2 elicited hyperphosphorylation of PI3K/Akt, ERK1/2, JNK, p38 MAPK, and p65 NF-κB. Further kinase inhibition experiments demonstrated that PI3K, p38 MAPK, and NF-κB activities were involved in oxidative-stress-induced miR-100 upregulation in ARPE-19 cells, while blockade of PI3K, JNK, and NF-κB signaling significantly attenuated the oxidative cell death. Intriguingly, MiR-100 antagomir treatment exerted a cytoprotective effect against the H2O2-induced oxidative cell death through attenuating the oxidation-induced AMPK hyperphosphorylation, restoring cellular mTOR and p62/SQSTM1 levels and upregulating heme oxygenase-1 expression. These findings support that miR-100 at least in part mediates H2O2-induced cell death of ARPE-19 cells and can be regarded as a preventive and therapeutic target for retinal degenerative disease.
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16
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Shan C, Chen X, Cai H, Hao X, Li J, Zhang Y, Gao J, Zhou Z, Li X, Liu C, Li P, Wang K. The Emerging Roles of Autophagy-Related MicroRNAs in Cancer. Int J Biol Sci 2021; 17:134-150. [PMID: 33390839 PMCID: PMC7757044 DOI: 10.7150/ijbs.50773] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
Autophagy is a conserved catabolic process involving the degradation and recycling of damaged biomacromolecules or organelles through lysosomal-dependent pathways and plays a crucial role in maintaining cell homeostasis. Consequently, abnormal autophagy is associated with multiple diseases, such as infectious diseases, neurodegenerative diseases and cancer. Currently, autophagy is considered to be a dual regulator in cancer, functioning as a suppressor in the early stage while supporting the growth and metastasis of cancer cells in the later stage and may also produce therapeutic resistance. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level by silencing targeted mRNA. MiRNAs have great regulatory potential for several fundamental biological processes, including autophagy. In recent years, an increasing number of studies have linked miRNA dysfunction to the growth, metabolism, migration, metastasis, and responses of cancer cells to therapy. Therefore, the study of autophagy-related miRNAs in cancer will provide insights into cancer biology and lead to the development of novel anti-cancer strategies. In the present review, we summarise the current knowledge of miRNA dysregulation during autophagy in cancer, focusing on the relationship between autophagy and miRNAs, and discuss their involvement in cancer biology and cancer treatment.
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Affiliation(s)
- Chan Shan
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xinzhe Chen
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Hongjing Cai
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xiaodan Hao
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jing Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yinfeng Zhang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jinning Gao
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Zhixia Zhou
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xinmin Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Cuiyun Liu
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Peifeng Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Kun Wang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
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17
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Eniafe J, Jiang S. MicroRNA-99 family in cancer and immunity. WILEY INTERDISCIPLINARY REVIEWS-RNA 2020; 12:e1635. [PMID: 33230974 DOI: 10.1002/wrna.1635] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 12/19/2022]
Abstract
The microRNA (miR)-99 family comprising miR-99a, miR-99b, and miR-100 is an evolutionarily conserved family with existence dating prior to the bilaterians. Members are typically oncogenic in leukemia while their functional roles in other cancers alternate between that of a tumor suppressor and a tumor promoter. Targets of the miR-99 family rank in the lists of oncogenes and tumor suppressors, thereby illustrating the dual role of this miR family as oncogenic miRs (oncomiRs) and tumor suppressing miRs (TSmiRs) in different cellular contexts. In addition to their functional roles in cancers, miR-99 family is implicated in the modulation of macrophage inflammatory responses and T-cell subsets biology, thereby exerting critical roles in the maintenance of tissue homeostasis, establishment of peripheral tolerance as well as resolution of an inflammatory reaction. Here, we review emerging knowledge of this miR family and discuss remaining concerns linked to their activities. A better dissection of the functional roles of miR-99 family members in cancer and immunity will help in the development of novel miR-99-based therapeutics for the treatment of human cancer and immune-related diseases. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Joseph Eniafe
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
| | - Shuai Jiang
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
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18
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Pourhanifeh MH, Vosough M, Mahjoubin-Tehran M, Hashemipour M, Nejati M, Abbasi-Kolli M, Sahebkar A, Mirzaei H. Autophagy-related microRNAs: Possible regulatory roles and therapeutic potential in and gastrointestinal cancers. Pharmacol Res 2020; 161:105133. [DOI: 10.1016/j.phrs.2020.105133] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/23/2020] [Accepted: 08/07/2020] [Indexed: 02/08/2023]
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19
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Liu PF, Farooqi AA, Peng SY, Yu TJ, Dahms HU, Lee CH, Tang JY, Wang SC, Shu CW, Chang HW. Regulatory effects of noncoding RNAs on the interplay of oxidative stress and autophagy in cancer malignancy and therapy. Semin Cancer Biol 2020; 83:269-282. [PMID: 33127466 DOI: 10.1016/j.semcancer.2020.10.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/15/2020] [Accepted: 10/18/2020] [Indexed: 12/15/2022]
Abstract
Noncoding RNAs (ncRNAs) regulation of various diseases including cancer has been extensively studied. Reactive oxidative species (ROS) elevated by oxidative stress are associated with cancer progression and drug resistance, while autophagy serves as an ROS scavenger in cancer cells. However, the regulatory effects of ncRNAs on autophagy and ROS in various cancer cells remains complex. Here, we explore how currently investigated ncRNAs, mainly miRNAs and lncRNAs, are involved in ROS production through modulating antioxidant genes. The regulatory effects of miRNAs and lncRNAs on autophagy-related (ATG) proteins to control autophagy activity in cancer cells are discussed. Moreover, differential expression of ncRNAs in tumor and normal tissues of cancer patients are further analyzed using The Cancer Genome Atlas (TCGA) database. This review hypothesizes links between ATG genes- or antioxidant genes-modulated ncRNAs and ROS production, which might result in tumorigenesis, malignancy, and cancer recurrence. A better understanding of the regulation of ROS and autophagy by ncRNAs might advance the use of ncRNAs as diagnostic and prognostic markers as well as therapeutic targets in cancer therapy.
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Affiliation(s)
- Pei-Feng Liu
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
| | - Ammad Ahmad Farooqi
- Department of Molecular Oncology, Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
| | - Sheng-Yao Peng
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Tzu-Jung Yu
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Hans-Uwe Dahms
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
| | - Cheng-Hsin Lee
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Jen-Yang Tang
- Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Sheng-Chieh Wang
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Chih-Wen Shu
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
| | - Hsueh-Wei Chang
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
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20
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Figueroa-González G, Carrillo-Hernández JF, Perez-Rodriguez I, Cantú de León D, Campos-Parra AD, Martínez-Gutiérrez AD, Coronel-Hernández J, García-Castillo V, López-Camarillo C, Peralta-Zaragoza O, Jacobo-Herrera NJ, Guardado-Estrada M, Pérez-Plasencia C. Negative Regulation of Serine Threonine Kinase 11 (STK11) through miR-100 in Head and Neck Cancer. Genes (Basel) 2020; 11:1058. [PMID: 32911741 PMCID: PMC7563199 DOI: 10.3390/genes11091058] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/18/2020] [Accepted: 08/25/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Serine Threonine Kinase 11 (STK11), also known as LKB1, is a tumor suppressor gene that regulates several biological processes such as apoptosis, energetic metabolism, proliferation, invasion, and migration. During malignant progression, different types of cancer inhibit STK11 function by mutation or epigenetic inactivation. In Head and Neck Cancer, it is unclear what mechanism is involved in decreasing STK11 levels. Thus, the present work aims to determine whether STK11 expression might be regulated through epigenetic or post-translational mechanisms. METHODS Expression levels and methylation status for STK11 were analyzed in 59 cases of head and neck cancer and 10 healthy tissue counterparts. Afterward, we sought to identify candidate miRNAs exerting post-transcriptional regulation of STK11. Then, we assessed a luciferase gene reporter assay to know if miRNAs directly target STK11 mRNA. The expression levels of the clinical significance of mir-100-3p, -5p, and STK11 in 495 HNC specimens obtained from the TCGA database were further analyzed. Finally, the Kaplan-Meier method was used to estimate the prognostic significance of the miRNAs for Overall Survival, and survival curves were compared through the log-rank test. RESULTS STK11 was under-expressed, and its promoter region was demethylated or partially methylated. miR-17-5p, miR-106a-5p, miR-100-3p, and miR-100-5p could be negative regulators of STK11. Our experimental data suggested evidence that miR-100-3p and -5p were over-expressed in analyzed tumor patient samples. Luciferase gene reporter assay experiments showed that miR-100-3p targets and down-regulates STK11 mRNA directly. With respect to overall survival, STK11 expression level was significant for predicting clinical outcomes. CONCLUSION This is, to our knowledge, the first report of miR-100-3p targeting STK11 in HNC. Together, these findings may support the importance of regulation of STK11 through post-transcriptional regulation in HNC and the possible contribution to the carcinogenesis process in this neoplasia.
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Affiliation(s)
- Gabriela Figueroa-González
- Unidad Multidisciplinaria de Investigación Experimental Zaragoza (UMIEZ), Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Mexico City 09230, Mexico;
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico; (J.F.C.-H.); (I.P.-R.); (D.C.d.L.); (A.D.C.-P.); (A.D.M.-G.); (J.C.-H.)
| | - José F. Carrillo-Hernández
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico; (J.F.C.-H.); (I.P.-R.); (D.C.d.L.); (A.D.C.-P.); (A.D.M.-G.); (J.C.-H.)
| | - Itzel Perez-Rodriguez
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico; (J.F.C.-H.); (I.P.-R.); (D.C.d.L.); (A.D.C.-P.); (A.D.M.-G.); (J.C.-H.)
| | - David Cantú de León
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico; (J.F.C.-H.); (I.P.-R.); (D.C.d.L.); (A.D.C.-P.); (A.D.M.-G.); (J.C.-H.)
| | - Alma D. Campos-Parra
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico; (J.F.C.-H.); (I.P.-R.); (D.C.d.L.); (A.D.C.-P.); (A.D.M.-G.); (J.C.-H.)
| | - Antonio D. Martínez-Gutiérrez
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico; (J.F.C.-H.); (I.P.-R.); (D.C.d.L.); (A.D.C.-P.); (A.D.M.-G.); (J.C.-H.)
| | - Jossimar Coronel-Hernández
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico; (J.F.C.-H.); (I.P.-R.); (D.C.d.L.); (A.D.C.-P.); (A.D.M.-G.); (J.C.-H.)
| | - Verónica García-Castillo
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica del Cáncer, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Edo.Mex, Mexico;
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City 09790, Mexico;
| | - Oscar Peralta-Zaragoza
- Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca 62100, Morelos, Mexico;
| | - Nadia J. Jacobo-Herrera
- Unidad de Bioquímica, Instituto Nacional de Nutrición y Ciencias Médicas, Salvador Zubirán, Mexico City 14000, Mexico;
| | - Mariano Guardado-Estrada
- Laboratorio de Genética, Licenciatura en Ciencia Forense, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04360, Mexico;
| | - Carlos Pérez-Plasencia
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico; (J.F.C.-H.); (I.P.-R.); (D.C.d.L.); (A.D.C.-P.); (A.D.M.-G.); (J.C.-H.)
- Unidad de Investigación Biomédica en Cáncer, Laboratorio de Genómica del Cáncer, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Edo.Mex, Mexico;
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Fan J, Shi Y, Peng Y. Autophagy and Liver Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1207:497-528. [PMID: 32671772 DOI: 10.1007/978-981-15-4272-5_37] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Autophagy plays an important role in the physiology and pathology of the liver. It is involved in the development of many liver diseases such as α-1-antitrypsin deficiency, chronic hepatitis virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, and liver cancer. Autophagy has thus become a new target for the treatment of liver diseases. How to treat liver diseases by regulating autophagy has been a hot topic.
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Affiliation(s)
- Jia Fan
- Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, China.
| | - Yinghong Shi
- Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, China
| | - Yuanfei Peng
- Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, China
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22
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Pourhanifeh MH, Mahjoubin-Tehran M, Karimzadeh MR, Mirzaei HR, Razavi ZS, Sahebkar A, Hosseini N, Mirzaei H, Hamblin MR. Autophagy in cancers including brain tumors: role of MicroRNAs. Cell Commun Signal 2020; 18:88. [PMID: 32517694 PMCID: PMC7285723 DOI: 10.1186/s12964-020-00587-w] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 04/27/2020] [Indexed: 12/14/2022] Open
Abstract
Autophagy has a crucial role in many cancers, including brain tumors. Several types of endogenous molecules (e.g. microRNAs, AKT, PTEN, p53, EGFR, and NF1) can modulate the process of autophagy. Recently miRNAs (small non-coding RNAs) have been found to play a vital role in the regulation of different cellular and molecular processes, such as autophagy. Deregulation of these molecules is associated with the development and progression of different pathological conditions, including brain tumors. It was found that miRNAs are epigenetic regulators, which influence the level of proteins coded by the targeted mRNAs with any modification of the genetic sequences. It has been revealed that various miRNAs (e.g., miR-7-1-3p, miR-340, miR-17, miR-30a, miR-224-3p, and miR-93), as epigenetic regulators, can modulate autophagy pathways within brain tumors. A deeper understanding of the underlying molecular targets of miRNAs, and their function in autophagy pathways could contribute to the development of new treatment methods for patients with brain tumors. In this review, we summarize the various miRNAs, which are involved in regulating autophagy in brain tumors. Moreover, we highlight the role of miRNAs in autophagy-related pathways in different cancers.
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