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1
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Ehinger Y, Laguesse S, Phamluong K, Salvi A, Sei YJ, Hoisington ZW, Soneja D, Gunasekaran S, Nakamura K, Ron D. Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Mice Consuming Alcohol Attenuates Glycolysis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2023.11.29.569312. [PMID: 38076984 PMCID: PMC10705386 DOI: 10.1101/2023.11.29.569312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/30/2024]
Abstract
mTORC1 promotes protein translation, learning and memory, and neuroadaptations that underlie alcohol use and abuse. We report that activation of mTORC1 in the nucleus accumbens (NAc) of mice consuming alcohol promotes the translation of microRNA (miR) machinery components and the upregulation of microRNAs (miRs) expression including miR-34a-5p. In parallel, we detected a paradoxical mTORC1-dependent repression of translation of transcripts including Aldolase A, an essential glycolytic enzyme. We found that miR-34a-5p in the NAc targets Aldolase A for translation repression and promotes alcohol intake. Our data further suggest that glycolysis is inhibited in the NAc manifesting in an mTORC1-dependent attenuation of L-lactate, the end product of glycolysis. Finally, we show that systemic administration of L-lactate attenuates mouse excessive alcohol intake. Our data suggest that alcohol promotes paradoxical actions of mTORC1 on translation and glycolysis which in turn drive excessive alcohol use.
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2
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Huang L, Chen J, Fu L, Yang B, Zhou C, Mei S, Zhang L, Mao Z, Lu C, Xue C. Integrated mRNA-seq and miRNA-seq analysis reveals key transcription factors of HNF4α and KLF4 in ADPKD. Biochem Biophys Res Commun 2024; 735:150848. [PMID: 39432926 DOI: 10.1016/j.bbrc.2024.150848] [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: 09/16/2024] [Revised: 10/09/2024] [Accepted: 10/16/2024] [Indexed: 10/23/2024]
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent genetic disorder affecting the kidneys. Understanding epigenetic regulatory mechanisms and the role of microRNAs (miRNAs) is crucial for developing therapeutic interventions. Two mRNA datasets (GSE7869 and GSE35831) and miRNA expression data (GSE133530) from ADPKD patients were used to find differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs), with a focus on genes regulated by hub transcription factors (TFs) and their target genes. The expression of hub TFs was validated in human kidneys and animal models through Western Blot (WB) and RT-PCR analysis. The location of the hub TF proteins in kidney cells was observed by a laser confocal microscope. A total of 2037 DEGs were identified. DEM analysis resulted in 59 up-regulated and 107 down-regulated miRNAs. Predicted target DEGs of DEMs indicated two top dysregulated TFs: hepatocyte nuclear factor 4 alpha (HNF4α) and Kruppel-like factor 4 (KLF4). RT-PCR, WB, and immunochemistry results showed that mRNA and protein levels of HNF4α were significantly decreased while KLF4 levels were significantly up-regulated in human ADPKD kidneys and Pkd1 conditional knockout mice compared with normal controls. Laser confocal microscopy revealed that KLF4 was mainly located in the cytoplasm while HNF4α was in the nucleus. Functional enrichment analysis indicated that genes regulated by HNF4α were mainly associated with metabolic pathways, while KLF4-regulated genes were linked to kidney development. Drug response prediction analysis revealed potential drug candidates for ADPKD treatment, including BI-2536, Sepantronium, and AZD5582. This integrated analysis provides new epigenetic insights into the complex miRNA-TF-mRNA network in ADPKD and identifies HNF4α and KLF4 as key TFs. These findings offer valuable resources for further research and potential drug development for ADPKD.
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Affiliation(s)
- Linxi Huang
- Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200000, China; Department of Nephrology, 905th Hospital of PLA Navy, Shanghai, 200000, China
| | - Jiaxin Chen
- Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200000, China
| | - Lili Fu
- Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200000, China
| | - Bo Yang
- Department of Nephrology, Naval Medical Center of PLA, Naval Medical University, Shanghai, 200000, China
| | - Chenchen Zhou
- Outpatient Department, Yangpu Third Military Retreat, Yangpu first retirement, Shanghai, 200000, China
| | - Shuqin Mei
- Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200000, China
| | - Liming Zhang
- Department of Nephrology, Zhabei Central Hospital of JingAn District of Shanghai, Shanghai, 200000, China
| | - Zhiguo Mao
- Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200000, China
| | - Chunlai Lu
- Department of Nephrology, 905th Hospital of PLA Navy, Shanghai, 200000, China
| | - Cheng Xue
- Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200000, China.
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3
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Taeb S, Rostamzadeh D, Amini SM, Rahmati M, Eftekhari M, Safari A, Najafi M. MicroRNAs targeted mTOR as therapeutic agents to improve radiotherapy outcome. Cancer Cell Int 2024; 24:233. [PMID: 38965615 PMCID: PMC11229485 DOI: 10.1186/s12935-024-03420-3] [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: 11/03/2023] [Accepted: 06/22/2024] [Indexed: 07/06/2024] Open
Abstract
MicroRNAs (miRNAs) are small RNA molecules that regulate genes and are involved in various biological processes, including cancer development. Researchers have been exploring the potential of miRNAs as therapeutic agents in cancer treatment. Specifically, targeting the mammalian target of the rapamycin (mTOR) pathway with miRNAs has shown promise in improving the effectiveness of radiotherapy (RT), a common cancer treatment. This review provides an overview of the current understanding of miRNAs targeting mTOR as therapeutic agents to enhance RT outcomes in cancer patients. It emphasizes the importance of understanding the specific miRNAs that target mTOR and their impact on radiosensitivity for personalized cancer treatment approaches. The review also discusses the role of mTOR in cell homeostasis, cell proliferation, and immune response, as well as its association with oncogenesis. It highlights the different ways in which miRNAs can potentially affect the mTOR pathway and their implications in immune-related diseases. Preclinical findings suggest that combining mTOR modulators with RT can inhibit tumor growth through anti-angiogenic and anti-vascular effects, but further research and clinical trials are needed to validate the efficacy and safety of using miRNAs targeting mTOR as therapeutic agents in combination with RT. Overall, this review provides a comprehensive understanding of the potential of miRNAs targeting mTOR to enhance RT efficacy in cancer treatment and emphasizes the need for further research to translate these findings into improved clinical outcomes.
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Affiliation(s)
- Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Davoud Rostamzadeh
- Department of Immunology, University of Connecticut Health Center, Farmington, CT, USA
| | - Seyed Mohammad Amini
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Rahmati
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammad Eftekhari
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Arash Safari
- Department of Radiology, Ionizing and Non-Ionizing Radiation Protection Research Center (INIRPRC), School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, 71439-14693, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Medical Biology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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4
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Sato R, Vatic M, Peixoto da Fonseca GW, Anker SD, von Haehling S. Biological basis and treatment of frailty and sarcopenia. Cardiovasc Res 2024:cvae073. [PMID: 38828887 DOI: 10.1093/cvr/cvae073] [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: 07/27/2022] [Revised: 11/23/2022] [Accepted: 12/20/2022] [Indexed: 06/05/2024] Open
Abstract
In an ageing society, the importance of maintaining healthy life expectancy has been emphasized. As a result of age-related decline in functional reserve, frailty is a state of increased vulnerability and susceptibility to adverse health outcomes with a serious impact on healthy life expectancy. The decline in skeletal muscle mass and function, also known as sarcopenia, is key in the development of physical frailty. Both frailty and sarcopenia are highly prevalent in patients not only with advanced age but also in patients with illnesses that exacerbate their progression like heart failure (HF), cancer, or dementia, with the prevalence of frailty and sarcopenia in HF patients reaching up to 50-75% and 19.5-47.3%, respectively, resulting in 1.5-3 times higher 1-year mortality. The biological mechanisms of frailty and sarcopenia are multifactorial, complex, and not yet fully elucidated, ranging from DNA damage, proteostasis impairment, and epigenetic changes to mitochondrial dysfunction, cellular senescence, and environmental factors, many of which are further linked to cardiac disease. Currently, there is no gold standard for the treatment of frailty and sarcopenia, however, growing evidence supports that a combination of exercise training and nutritional supplement improves skeletal muscle function and frailty, with a variety of other therapies being devised based on the underlying pathophysiology. In this review, we address the involvement of frailty and sarcopenia in cardiac disease and describe the latest insights into their biological mechanisms as well as the potential for intervention through exercise, diet, and specific therapies.
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Affiliation(s)
- Ryosuke Sato
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Robert-Koch-Str. 40, 37075 Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany
| | - Mirela Vatic
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Robert-Koch-Str. 40, 37075 Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany
| | - Guilherme Wesley Peixoto da Fonseca
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, SP, Brazil
- School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
| | - Stefan D Anker
- Department of Cardiology (CVK) of German Heart Center Charité; German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin, Berlin, Germany
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
| | - Stephan von Haehling
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Robert-Koch-Str. 40, 37075 Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany
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5
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Hassan A, Khalaily N, Kilav-Levin R, Del Castello B, Manley NR, Ben-Dov IZ, Naveh-Many T. Dicer-Mediated mTORC1 Signaling and Parathyroid Gland Integrity and Function. J Am Soc Nephrol 2024; 35:00001751-990000000-00339. [PMID: 38819931 PMCID: PMC11387037 DOI: 10.1681/asn.0000000000000394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 05/20/2024] [Indexed: 06/02/2024] Open
Abstract
Key Points
Maintaining parathyroid gland integrity is a dynamic process regulated by the parathyroid microRNA–mechanistic target of rapamycin complex 1 axis.This axis is essential for preserving intact parathyroid glands throughout life, with relevance to CKD-induced secondary hyperparathyroidism.
Background
Secondary hyperparathyroidism of CKD contributes significantly to patient morbidity and mortality. The underlining mechanisms of CKD-induced secondary hyperparathyroidism remain elusive. We previously demonstrated that PT-Dicer
−/−
mice, with parathyroid-specific deletion of the microRNA (miRNA)-processing enzyme Dicer and consequently miRNA, maintain normal basal serum parathyroid hormone (PTH) levels but do not develop secondary hyperparathyroidism induced by CKD. In addition, we showed that the parathyroid mechanistic target of rapamycin complex 1 (mTORC1) pathway is activated in CKD. We now explored the roles of Dicer/miRNA and mTORC1 in parathyroid development and function.
Methods
We generated mice with parathyroid-specific Dicer (PT-Dicer
−/−
), mechanistic target of rapamycin (PT-mTOR
−/−
), or tuberous sclerosis complex 1 (PT-Tsc1
−/−
) deficiency combined with yellow fluorescent protein (YFP) or tdTomato expression to identify the parathyroids by fluorescence microscopy. CKD was induced by an adenine-rich high-phosphate diet.
Results
Despite normal basal serum PTH levels, PT-Dicer
−/−
mice displayed apoptotic loss of intact parathyroid glands postnatally and reduced mechanistic target of rapamycin activity. PT-mTOR
−/−
mice lacked intact parathyroid glands yet maintained normal serum PTH levels, mirroring the phenotype of PT-Dicer
−/−
mice. Conversely, PT-Tsc1
−/−
mice with hyperactivated mTORC1 exhibited enlarged glands along with elevated basal serum PTH and calcium levels. Significantly, PT-Dicer
−/−
;Tsc1
−/−
double knockout mice preserved intact parathyroid glands and reinstated CKD-induced secondary hyperparathyroidism.
Conclusions
mTORC1 operates downstream of Dicer and miRNA in the parathyroid and is essential for maintaining postnatal parathyroid gland integrity throughout life and for the pathogenesis of CKD-induced secondary hyperparathyroidism.
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Affiliation(s)
- Alia Hassan
- Minerva Center for Bone and Mineral Research, Nephrology Services, Hadassah Hebrew University Medical Center and Faculty of Medicine, Jerusalem, Israel
| | - Nareman Khalaily
- Minerva Center for Bone and Mineral Research, Nephrology Services, Hadassah Hebrew University Medical Center and Faculty of Medicine, Jerusalem, Israel
| | - Rachel Kilav-Levin
- Minerva Center for Bone and Mineral Research, Nephrology Services, Hadassah Hebrew University Medical Center and Faculty of Medicine, Jerusalem, Israel
- School of Nursing, Jerusalem College of Technology, Faculty of Life and Health Sciences, Jerusalem, Israel
| | - Barbara Del Castello
- Department of Genetics, University of Georgia, Athens, Georgia
- CRDF Global, Arlington, Virginia
| | - Nancy Ruth Manley
- Department of Genetics, University of Georgia, Athens, Georgia
- Current address: School of Life Sciences, Arizona State University, Tempe, Arizona
| | - Iddo Z Ben-Dov
- Laboratory of Medical Transcriptomics, Nephrology and Internal Medicine B, Hadassah Hebrew University Medical Center and Faculty of Medicine, Jerusalem, Israel
| | - Tally Naveh-Many
- Minerva Center for Bone and Mineral Research, Nephrology Services, Hadassah Hebrew University Medical Center and Faculty of Medicine, Jerusalem, Israel
- Wohl Institute for Translational Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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Riemann A, Rauschner M, Reime S, Thews O. The Role of microRNAs in Gene Expression and Signaling Response of Tumor Cells to an Acidic Environment. Int J Mol Sci 2023; 24:16919. [PMID: 38069241 PMCID: PMC10707721 DOI: 10.3390/ijms242316919] [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] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/23/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Many tumors are characterized by marked extracellular acidosis due to increased glycolytic metabolism, which affects gene expression and thereby tumor biological behavior. At the same time, acidosis leads to altered expression of several microRNAs (Mir7, Mir183, Mir203, Mir215). The aim of this study was to analyze whether the acidosis-induced changes in cytokines and tumor-related genes are mediated via pH-sensitive microRNAs. Therefore, the expression of Il6, Nos2, Ccl2, Spp1, Tnf, Acat2, Aox1, Crem, Gls2, Per3, Pink1, Txnip, and Ypel3 was examined in acidosis upon simultaneous transfection with microRNA mimics or antagomirs in two tumor lines in vitro and in vivo. In addition, it was investigated whether microRNA expression in acidosis is affected via known pH-sensitive signaling pathways (MAPK, PKC, PI3K), via ROS, or via altered intracellular Ca2+ concentration. pH-dependent microRNAs were shown to play only a minor role in modulating gene expression. Individual genes (e.g., Ccl2, Txnip, Ypel3) appear to be affected by Mir183, Mir203, or Mir215 in acidosis, but these effects are cell line-specific. When examining whether acid-dependent signaling affects microRNA expression, it was found that Mir203 was modulated by MAPK and ROS, Mir7 was affected by PKC, and Mir215 was dependent on the intracellular Ca2+ concentration. Mir183 could be increased by ROS scavenging. These correlations could possibly result in new therapeutic approaches for acidotic tumors.
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Affiliation(s)
| | | | | | - Oliver Thews
- Julius Bernstein Institute of Physiology, University of Halle-Wittenberg, 06108 Halle, Germany
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7
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Kiani M, Moraffah F, Khonsari F, Kharazian B, Dinarvand R, Shokrgozar MA, Atyabi F. Co-delivery of simvastatin and microRNA-21 through liposome could accelerates the wound healing process. BIOMATERIALS ADVANCES 2023; 154:213658. [PMID: 37866233 DOI: 10.1016/j.bioadv.2023.213658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 09/10/2023] [Accepted: 10/07/2023] [Indexed: 10/24/2023]
Abstract
The gene delivery approach, mainly microRNAs (miRNA) as key wound healing mediators, has recently received extensive attention. MicroRNA-21 (miR-21) has strongly impacted wound healing by affecting the inflammation and proliferation phases. Previous studies have also demonstrated the beneficial effect of simvastatin on wound healing. Therefore, we designed a dual-drug/gene delivery system using PEGylated liposomes that could simultaneously attain the co-encapsulation and co-delivery of miRNA and simvastatin (SIM) to explore the combined effect of this dual-drug delivery system on wound healing. The PEG-liposomes for simvastatin and miR-21 plasmid (miR-21-P/SIM/Liposomes) were prepared using the thin-film hydration method. The liposomes showed 85 % entrapment efficiency for SIM in the lipid bilayer and high physical entrapment of miR-21-P in the inner cavity. In vitro studies demonstrated no cytotoxicity for the carrier on normal human dermal fibroblast cells (NHDF) and 97 % cellular uptake over 2 h incubation. The scratch test revealed excellent cell proliferation and migration after treatment with miR-21-P/SIM/Liposomes. For the in vivo experiments, a full-thickness cutaneous wound model was used. The wound closure on day 8 was higher for Liposomal formulation containing miR-21-P promoting faster re-epithelialization. On day 12, all treated groups showed complete wound closure. However, following histological analysis, the miR-21-P/SIM/Liposomes revealed the best tissue regeneration, similar to normal functional skin, by reduced inflammation and increased re-epithelialization, collagen deposition and angiogenesis. In conclusion, the designed miR-21-P/SIM/Liposomes could significantly accelerate the process of wound healing, which provides a new strategy for the management of chronic wounds.
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Affiliation(s)
- Melika Kiani
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Moraffah
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Khonsari
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahar Kharazian
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Rassoul Dinarvand
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; School of Pharmacy, De Mont Fort University, Leicester, UK
| | | | - Fatemeh Atyabi
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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8
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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9
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Li J, Li S, Yu S, Yang J, Ke J, Li H, Chen H, Lu M, Sy MS, Gao Z, Li C. Persistent ER stress causes GPI anchor deficit to convert a GPI-anchored prion protein into pro-PrP via the ATF6-miR449c-5p-PIGV axis. J Biol Chem 2023; 299:104982. [PMID: 37390992 PMCID: PMC10388210 DOI: 10.1016/j.jbc.2023.104982] [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: 04/22/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 07/02/2023] Open
Abstract
Endoplasmic reticulum (ER) stress and unfolded protein response are cells' survival strategies to thwart disruption of proteostasis. Tumor cells are continuously being challenged by ER stress. The prion protein, PrP, normally a glycosylphosphatidylinositol (GPI)-anchored protein exists as a pro-PrP retaining its GPI-peptide signal sequence in human pancreatic ductal cell adenocarcinoma (PDAC). Higher abundance of pro-PrP indicates poorer prognosis in PDAC patients. The reason why PDAC cells express pro-PrP is unknown. Here, we report that persistent ER stress causes conversion of GPI-anchored PrP to pro-PrP via a conserved ATF6-miRNA449c-5p-PIGV axis. Mouse neurons and AsPC-1, a PDAC cell line, express GPI-anchored PrP. However, continuous culture of these cells with the ER stress inducers thapsigargin or brefeldin A results in the conversion of a GPI-anchored PrP to pro-PrP. Such a conversion is reversible; removal of the inducers allows the cells to re-express a GPI-anchored PrP. Mechanistically, persistent ER stress increases the abundance of an active ATF6, which increases the level of miRNA449c-5p (miR449c-5p). By binding the mRNA of PIGV at its 3'-UTRs, miR449c-5p suppresses the level of PIGV, a mannosyltransferase pivotal in the synthesis of the GPI anchor. Reduction of PIGV leads to disruption of the GPI anchor assembly, causing pro-PrP accumulation and enhancing cancer cell migration and invasion. The importance of ATF6-miR449c-5p-PIGV axis is recapitulated in PDAC biopsies as the higher levels of ATF6 and miR449c-5p and lower levels of PIGV are markers of poorer outcome for patients with PDAC. Drugs targeting this axis may prevent PDAC progression.
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Affiliation(s)
- JingFeng Li
- Wuhan Institute of Virology, Chinese Academy of Sciences, State Key Laboratory of Virology, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China
| | - SaSa Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China
| | - ShuPei Yu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China
| | - Jie Yang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China
| | - JingRu Ke
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huan Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China
| | - Heng Chen
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China
| | - MingJian Lu
- Department of Interventional Radiology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Man-Sun Sy
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - ZhenXing Gao
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China.
| | - Chaoyang Li
- Wuhan Institute of Virology, Chinese Academy of Sciences, State Key Laboratory of Virology, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China; Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China.
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10
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Matai L, Slack FJ. MicroRNAs in Age-Related Proteostasis and Stress Responses. Noncoding RNA 2023; 9:26. [PMID: 37104008 PMCID: PMC10143298 DOI: 10.3390/ncrna9020026] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/27/2023] [Accepted: 03/30/2023] [Indexed: 04/28/2023] Open
Abstract
Aging is associated with the accumulation of damaged and misfolded proteins through a decline in the protein homeostasis (proteostasis) machinery, leading to various age-associated protein misfolding diseases such as Huntington's or Parkinson's. The efficiency of cellular stress response pathways also weakens with age, further contributing to the failure to maintain proteostasis. MicroRNAs (miRNAs or miRs) are a class of small, non-coding RNAs (ncRNAs) that bind target messenger RNAs at their 3'UTR, resulting in the post-transcriptional repression of gene expression. From the discovery of aging roles for lin-4 in C. elegans, the role of numerous miRNAs in controlling the aging process has been uncovered in different organisms. Recent studies have also shown that miRNAs regulate different components of proteostasis machinery as well as cellular response pathways to proteotoxic stress, some of which are very important during aging or in age-related pathologies. Here, we present a review of these findings, highlighting the role of individual miRNAs in age-associated protein folding and degradation across different organisms. We also broadly summarize the relationships between miRNAs and organelle-specific stress response pathways during aging and in various age-associated diseases.
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Affiliation(s)
| | - Frank J. Slack
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
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11
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Wiebe S, Huang Z, Ladak RJ, Skalecka A, Cagnetta R, Lacaille JC, Aguilar-Valles A, Sonenberg N. Cell-type-specific translational control of spatial working memory by the cap-binding protein 4EHP. Mol Brain 2023; 16:9. [PMID: 36650535 PMCID: PMC9847188 DOI: 10.1186/s13041-023-00995-2] [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: 09/30/2022] [Accepted: 01/01/2023] [Indexed: 01/19/2023] Open
Abstract
The consolidation of learned information into long-lasting memories requires the strengthening of synaptic connections through de novo protein synthesis. Translation initiation factors play a cardinal role in gating the production of new proteins thereby regulating memory formation. Both positive and negative regulators of translation play a critical role in learning and memory consolidation. The eukaryotic initiation factor 4E (eIF4E) homologous protein (4EHP, encoded by the gene Eif4e2) is a pivotal negative regulator of translation but its role in learning and memory is unknown. To address this gap in knowledge, we generated excitatory (glutamatergic: CaMKIIα-positive) and inhibitory (GABAergic: GAD65-positive) conditional knockout mice for 4EHP, which were analyzed in various behavioral memory tasks. Knockout of 4EHP in Camk2a-expressing neurons (4EHP-cKOexc) did not impact long-term memory in either contextual fear conditioning or Morris water maze tasks. Similarly, long-term contextual fear memory was not altered in Gad2-directed 4EHP knockout mice (4EHP-cKOinh). However, when subjected to a short-term T-maze working memory task, both mouse models exhibited impaired cognition. We therefore tested the hypothesis that de novo protein synthesis plays a direct role in working memory. We discovered that phosphorylation of ribosomal protein S6, a measure of mTORC1 activity, is dramatically reduced in the CA1 hippocampus of 4EHP-cKOexc mice. Consistently, genetic reduction of mTORC1 activity in either excitatory or inhibitory neurons was sufficient to impair working memory. Taken together, these findings indicate that translational control by 4EHP and mTORC1 in both excitatory and inhibitory neurons are necessary for working memory.
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Affiliation(s)
- Shane Wiebe
- grid.14709.3b0000 0004 1936 8649Department of Biochemistry, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6 Canada ,Goodman Cancer Institute, 1160 Pine Avenue West, Room 614, Montreal, QC H3A 1A3 Canada
| | - Ziying Huang
- grid.14709.3b0000 0004 1936 8649Department of Biochemistry, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6 Canada ,Goodman Cancer Institute, 1160 Pine Avenue West, Room 614, Montreal, QC H3A 1A3 Canada
| | - Reese Jalal Ladak
- grid.14709.3b0000 0004 1936 8649Department of Biochemistry, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6 Canada ,Goodman Cancer Institute, 1160 Pine Avenue West, Room 614, Montreal, QC H3A 1A3 Canada
| | - Agnieszka Skalecka
- grid.14709.3b0000 0004 1936 8649Department of Biochemistry, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6 Canada ,Goodman Cancer Institute, 1160 Pine Avenue West, Room 614, Montreal, QC H3A 1A3 Canada
| | - Roberta Cagnetta
- grid.14709.3b0000 0004 1936 8649Department of Biochemistry, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6 Canada ,Goodman Cancer Institute, 1160 Pine Avenue West, Room 614, Montreal, QC H3A 1A3 Canada
| | - Jean-Claude Lacaille
- grid.14848.310000 0001 2292 3357Department of Neuroscience and CIRCA, University of Montreal, Succ. Downtown, P. O. Box 6128, Montreal, QC H3C 3J7 Canada
| | - Argel Aguilar-Valles
- grid.34428.390000 0004 1936 893XDepartment of Neuroscience, Carleton University, Health Sciences Building, 1125 Colonel By Drive, Ottawa, ON K1S 5B6 Canada
| | - Nahum Sonenberg
- grid.14709.3b0000 0004 1936 8649Department of Biochemistry, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6 Canada ,Goodman Cancer Institute, 1160 Pine Avenue West, Room 614, Montreal, QC H3A 1A3 Canada
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12
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Wen J, Deng J, Xiao T, Liu Y, Meng W. Adipose Rheb deficiency promotes miR-182-5p expression via the cAMP/PPARγ signaling pathway. J Genet Genomics 2023; 50:20-26. [PMID: 35550871 DOI: 10.1016/j.jgg.2022.04.013] [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: 02/11/2022] [Revised: 04/25/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023]
Abstract
Dysregulation of microRNAs (miRNAs) in adipocytes plays a critical role in the pathogenesis of obesity. However, the signaling mechanisms regulating miRNAs production in adipose tissue remain largely unclear. Here, we show that adipose tissue-specific knockout of Ras homolog enriched in brain (Rheb), a direct upstream activator of mTOR, increases miR-182-5p level in mouse subcutaneous white adipose tissues. Interestingly, the inhibition of mTOR signaling by rapamycin has no effect on miR-182-5p level in primary subcutaneous white adipocytes, suggesting the presence of a mTOR-independent mechanism regulating Rheb-mediated miR-182-5p expression. Consistent with this view, Rheb-ablation activates the cAMP/PPARγ signaling pathway. In addition, treatment of white adipocytes with pioglitazone, a PPARγ agonist, dramatically upregulates miR-182-5p levels. Our study reveals a unique mechanism by which Rheb regulates miR-182-5p in adipocytes. Given that increasing miR-182-5p in adipose tissue promotes beige fat development, our study also suggests a unique mechanism by which Rheb promotes thermogenesis and energy expenditure.
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Affiliation(s)
- Jie Wen
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Jiangming Deng
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Ting Xiao
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Yu Liu
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
| | - Wen Meng
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
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13
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Ismail A, El-Mahdy HA, Abulsoud AI, Sallam AAM, Eldeib MG, Elsakka EG, Zaki MB, Doghish AS. Beneficial and detrimental aspects of miRNAs as chief players in breast cancer: A comprehensive review. Int J Biol Macromol 2022; 224:1541-1565. [DOI: 10.1016/j.ijbiomac.2022.10.241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/12/2022] [Accepted: 10/24/2022] [Indexed: 11/05/2022]
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Casciano F, Zauli E, Rimondi E, Mura M, Previati M, Busin M, Zauli G. The role of the mTOR pathway in diabetic retinopathy. Front Med (Lausanne) 2022; 9:973856. [PMID: 36388931 PMCID: PMC9663464 DOI: 10.3389/fmed.2022.973856] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/05/2022] [Indexed: 07/30/2023] Open
Abstract
The retina, the part of the eye, translates the light signal into an electric current that can be sent to the brain as visual information. To achieve this, the retina requires fine-tuned vascularization for its energy supply. Diabetic retinopathy (DR) causes alterations in the eye vascularization that reduce the oxygen supply with consequent retinal neurodegeneration. During DR, the mammalian target of rapamycin (mTOR) pathway seems to coordinate retinal neurodegeneration with multiple anabolic and catabolic processes, such as autophagy, oxidative stress, cell death, and the release of pro-inflammatory cytokines, which are closely related to chronic hyperglycemia. This review outlines the normal anatomy of the retina and how hyperglycemia can be involved in the neurodegeneration underlying this disease through over activation or inhibition of the mTOR pathway.
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Affiliation(s)
- Fabio Casciano
- Department of Translational Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
- Interdepartmental Research Center for the Study of Multiple Sclerosis and Inflammatory and Degenerative Diseases of the Nervous System, University of Ferrara, Ferrara, Italy
| | - Enrico Zauli
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Erika Rimondi
- Department of Translational Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Marco Mura
- Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Maurizio Previati
- Department of Translational Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Massimo Busin
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Giorgio Zauli
- Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
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Koustas E, Trifylli EM, Sarantis P, Papadopoulos N, Papanikolopoulos K, Aloizos G, Damaskos C, Garmpis N, Garmpi A, Karamouzis MV. The Emerging Role of MicroRNAs and Autophagy Mechanism in Pancreatic Cancer Progression: Future Therapeutic Approaches. Genes (Basel) 2022; 13:1868. [PMID: 36292753 PMCID: PMC9602304 DOI: 10.3390/genes13101868] [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: 09/24/2022] [Revised: 10/10/2022] [Accepted: 10/13/2022] [Indexed: 11/04/2022] Open
Abstract
Pancreatic cancer constitutes the fourth most frequent cause of death due to malignancy in the US. Despite the new therapeutic modalities, the management of pancreatic ductal adenocarcinoma (PDAC) is considered a difficult task for clinicians due to the fact that is usually diagnosed in already advanced stages and it is relatively resistant to the current chemotherapeutic agents. The molecular background analysis of pancreatic malignant tumors, which includes various epigenetic and genetic alterations, opens new horizons for the development of novel diagnostic and therapeutic strategies. The interplay between miRNAs, autophagy pathway, and pancreatic carcinogenesis is in the spotlight of the current research. There is strong evidence that miRNAs take part in carcinogenesis either as tumor inhibitors that combat the oncogene expression or as promoters (oncomiRs) by acting as oncogenes by interfering with various cell functions such as proliferation, programmed cell death, and metabolic and signaling pathways. Deregulation of the expression levels of various miRNAs is closely associated with tumor growth, progression, and dissemination, as well as low sensitivity to chemotherapeutic agents. Similarly, autophagy despite constituting a pivotal homeostatic mechanism for cell survival has a binary role in PDAC, either as an inhibitor or promoter of carcinogenesis. The emerging role of miRNAs in autophagy gets a great deal of attention as it opens new opportunities for the development of novel therapeutic strategies for the management of this aggressive and chemoresistant malignancy. In this review, we will shed light on the interplay between miRNAs and the autophagy mechanism for pancreatic cancer development and progression.
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Affiliation(s)
- Evangelos Koustas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Equity Fund Hospital, 11521 Athens, Greece
| | - Eleni-Myrto Trifylli
- First Department of Internal Medicine, 417 Army Equity Fund Hospital, 11521 Athens, Greece
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527 Athens, Greece
| | - Nikolaos Papadopoulos
- First Department of Internal Medicine, 417 Army Equity Fund Hospital, 11521 Athens, Greece
| | | | - Georgios Aloizos
- First Department of Internal Medicine, 417 Army Equity Fund Hospital, 11521 Athens, Greece
| | - Christos Damaskos
- ‘N.S. Christeas’ Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527 Athens, Greece
- Renal Transplantation Unit, ‘Laiko’ General Hospital, 11527 Athens, Greece
| | - Nikolaos Garmpis
- Second Department of Propaedeutic Surgery, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527 Athens, Greece
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527 Athens, Greece
| | - Anna Garmpi
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527 Athens, Greece
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527 Athens, Greece
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MSC-Derived exosomes suppress colorectal cancer cell proliferation and metastasis via miR-100/mTOR/miR-143 pathway. Int J Pharm 2022; 627:122214. [PMID: 36152993 DOI: 10.1016/j.ijpharm.2022.122214] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/05/2022] [Accepted: 09/16/2022] [Indexed: 11/21/2022]
Abstract
Exosomes derived from mesenchymal stem cells (MSCs) are mostly responsible for the therapeutic effects of MSCs. To show the therapeutic effects of the human bone marrow MSC-derived exosomes (MSC-Exos) on colorectal cancer (CRC) and explore the molecular cross-talks between them, CRC cells were treated with the MSC-Exos. We found that MSC-Exos were enriched with miR-100 and miR-143, which effectively downregulated mTOR, Cyclin D1, K-RAS, HK2 while upregulated p-27 expression. All these effects were reversed by concurrent treatment with MSC-Exos and antagomiR-100, confirming that they were caused by exosomal transfer of miR-100 into recipient CRC cells. Moreover, exosomal miR-100 promoted endogenous miR-143 expression. The flow cytometry, MTT and trypan blue assays revealed that MSC-Exos could efficiently suppress proliferation and induce apoptosis of the CRC cells. Furthermore, wound healing, transwell migration and invasion assays confirmed their inhibitory effects on the migration and invasiveness of SW480 cells. We further confirmed these effects by analyzing the expression levels of epithelial to mesenchymal transition (EMT) factors and metastasis-related genes. Results showed that MSC-Exos significantly suppressed the expression of MMP2 and MMP9 (metastasis-related genes), SNAIL and TWIST (EMT-inducing transcription factors), Vimentin and N-cadherin (mesenchymal cell markers), whereas E-cadherin (epithelial cell marker) was remarkably up-regulated. Collectively, our data indicated that MSC-Exos could suppress proliferation, migration, invasion and metastasis while inducing the apoptosis of the CRC cells via miR-100/mTOR/miR-143 axis. Our findings highlight that MSC-Exo treatment as well as miR-100 restoration might be considered as potential therapeutic strategies for CRC.
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Li Y, Wei Y, Shao J. Diagnostic value of miR-101 levels in blood and urine of patients with hypertensive disorder complicating pregnancy. Clin Exp Hypertens 2022; 44:1-7. [PMID: 36047533 DOI: 10.1080/10641963.2022.2110258] [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: 01/27/2022] [Revised: 06/30/2022] [Accepted: 08/01/2022] [Indexed: 11/03/2022]
Abstract
OBJECTIVES This study explored the miR-101 clinical significance in hypertensive disorder complicating pregnancy (HDCP). METHODS Pregnant women with gestational hypertension (GH)/mild preeclampsia (mPE)/severe preeclampsia (sPE) were included. The miR-101 levels were measured. Correlation between miR-101 and soluble fmslike tyrosine kinase-1 (sFlt-1), miR-101 predictive value, and factors influencing HDCP grade were evaluated. RESULTS Serum miR-101 was down-regulated and negatively correlated with sFlt-1. miR-101 was an independent risk factor for HDCP and decreased with HDCP severity. The area under the curve of miR-101 in differentiating GH from mPE and mPE from sPE was 0.7764 and 0.8529. CONCLUSION Serum miR-101 level may be a biomarker for grading HDCP.
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Affiliation(s)
- Yushan Li
- Department of Obstetrics and Gynecology, Jincheng People's Hospital, Jincheng, China
| | - Yuanyuan Wei
- Department of Obstetrics and Gynecology, Jincheng People's Hospital, Jincheng, China
| | - Jiong Shao
- Department of Obstetrics and Gynecology, Jincheng People's Hospital, Jincheng, China
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18
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Non-coding RNAs in ferroptotic cancer cell death pathway: meet the new masters. Hum Cell 2022; 35:972-994. [PMID: 35415781 DOI: 10.1007/s13577-022-00699-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 04/01/2022] [Indexed: 02/08/2023]
Abstract
Despite the recent advances in cancer therapy, cancer chemoresistance looms large along with radioresistance, a major challenge in dire need of thorough and minute investigation. Not long ago, cancer cells were reported to have proven refractory to the ferroptotic cell death, a newly discovered form of regulated cell death (RCD), conspicuous enough to draw attention from scholars in terms of targeting ferroptosis as a prospective therapeutic strategy. However, our knowledge concerning the underlying molecular mechanisms through which cancer cells gain immunity against ferroptosis is still in its infancy. Of late, the implication of non-coding RNAs (ncRNAs), including circular RNAs (circRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) in ferroptosis has been disclosed. Nevertheless, precisely explaining the molecular mechanisms behind the contribution of ncRNAs to cancer radio/chemotherapy resistance remains a challenge, requiring further clarification. In this review, we have presented the latest available information on the ways and means of regulating ferroptosis by ncRNAs. Moreover, we have provided important insights about targeting ncRNAs implicated in ferroptosis with the hope of opening up new horizons for overcoming cancer treatment modalities. Though a long path awaits until we make this ambitious dream come true, recent progress in gene therapy, including gene-editing technology will aid us to be optimistic that ncRNAs-based ferroptosis targeting would soon be on stream as a novel therapeutic strategy for treating cancer.
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The Role of mTOR and eIF Signaling in Benign Endometrial Diseases. Int J Mol Sci 2022; 23:ijms23073416. [PMID: 35408777 PMCID: PMC8998789 DOI: 10.3390/ijms23073416] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/19/2022] [Accepted: 03/20/2022] [Indexed: 02/05/2023] Open
Abstract
Adenomyosis, endometriosis, endometritis, and typical endometrial hyperplasia are common non-cancerous diseases of the endometrium that afflict many women with life-impacting consequences. The mammalian target of the rapamycin (mTOR) pathway interacts with estrogen signaling and is known to be dysregulated in endometrial cancer. Based on this knowledge, we attempt to investigate the role of mTOR signaling in benign endometrial diseases while focusing on how the interplay between mTOR and eukaryotic translation initiation factors (eIFs) affects their development. In fact, mTOR overactivity is apparent in adenomyosis, endometriosis, and typical endometrial hyperplasia, where it promotes endometrial cell proliferation and invasiveness. Recent data show aberrant expression of various components of the mTOR pathway in both eutopic and ectopic endometrium of patients with adenomyosis or endometriosis and in hyperplastic endometrium as well. Moreover, studies on endometritis show that derangement of mTOR signaling is linked to the establishment of endometrial dysfunction caused by chronic inflammation. This review shows that inhibition of the mTOR pathway has a promising therapeutic effect in benign endometrial conditions, concluding that mTOR signaling dysregulation plays a critical part in their pathogenesis.
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Varco-Merth BD, Brantley W, Marenco A, Duell DD, Fachko DN, Richardson B, Busman-Sahay K, Shao D, Flores W, Engelman K, Fukazawa Y, Wong SW, Skalsky RL, Smedley J, Axthelm MK, Lifson JD, Estes JD, Edlefsen PT, Picker L, Cameron CM, Henrich TJ, Okoye AA. Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus-infected rhesus macaques on antiretroviral therapy. J Clin Invest 2022; 132:156063. [PMID: 35316218 PMCID: PMC9106346 DOI: 10.1172/jci156063] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 03/16/2022] [Indexed: 11/28/2022] Open
Abstract
Proliferation of latently infected CD4+ T cells with replication-competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating CD4+ memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA–treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of CD4+ TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir.
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Affiliation(s)
- Benjamin D Varco-Merth
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
| | - William Brantley
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
| | - Alejandra Marenco
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
| | - Derick D Duell
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
| | - Devin N Fachko
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
| | - Brian Richardson
- Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, United States of America
| | - Kathleen Busman-Sahay
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
| | - Danica Shao
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, United States of America
| | - Walter Flores
- MassBiologics, University of Massachusetts Medical School, Boston, United States of America
| | - Kathleen Engelman
- MassBiologics, University of Massachusetts Medical School, Boston, United States of America
| | - Yoshinori Fukazawa
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
| | - Scott W Wong
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
| | - Rebecca L Skalsky
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
| | - Jeremy Smedley
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America
| | - Michael K Axthelm
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America
| | - Jeffrey D Lifson
- AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, United States of America
| | - Jacob D Estes
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
| | - Paul T Edlefsen
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States of America
| | - Louis Picker
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
| | - Cheryl Ma Cameron
- Department of Nutrition, Case Western Reserve University, Cleveland, United States of America
| | - Timothy J Henrich
- Department of Medicine, UCSF, San Francisco, United States of America
| | - Afam A Okoye
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, United States of America
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Liu X, Cui MM, Zhu HZ, Fu PY, Wang GC, Huang L. MiR-199a-3p Overexpression Suppressed Cell Proliferation and Sensitized Chronic Myeloid Leukaemia Cells to Imatinib by Inhibiting mTOR Signalling. Acta Haematol 2022; 145:484-498. [PMID: 35313299 DOI: 10.1159/000524158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 02/26/2022] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm characterized by constitutive activity of the tyrosine kinase BCR-ABL1. Drug resistance remains one of the major challenges in CML therapy. MicroRNA (miR)-199a-3p plays an important role in many tumours but has rarely been investigated in CML. We aimed to analyse the role and mechanism of miR-199a-3p in regulating imatinib resistance in CML. METHODS The expression of miR-199a-3p and mammalian target of rapamycin (mTOR) in the serum of CML patients and CML cells was examined by quantitative real-time polymerase chain reaction. The levels of apoptosis-related proteins were determined using western blot. The relative cell survival rate and cell proliferation were determined using a CCK-8 assay and a bromodeoxyuridine (BrdU) assay, respectively. Cell cycle and apoptosis were analysed using flow cytometry. Moreover, a dual-luciferase reporter assay was performed to verify the correlation between miR-199a-3p and mTOR. RESULTS MiR-199a-3p was downregulated in the serum of CML patients and in CML cells, while mTOR was upregulated. Both miR-199a-3p overexpression and mTOR silencing inhibited CML cell proliferation, promoted CML cell apoptosis, and sensitized these cells to imatinib. mTOR silencing reversed the promoting effect of miR-199a-3p inhibition on the proliferation of CML cells and the inhibitory effects on cell apoptosis and sensitivity to imatinib. MiR-199a-3p directly targeted mTOR. CONCLUSION MiR-199a-3p suppressed cell propagation, facilitated apoptosis of CML cells, and sensitized CML cells to imatinib by downregulating mTOR signalling.
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MESH Headings
- Apoptosis
- Bromodeoxyuridine/pharmacology
- Bromodeoxyuridine/therapeutic use
- Cell Line, Tumor
- Cell Proliferation
- Humans
- Imatinib Mesylate/pharmacology
- Imatinib Mesylate/therapeutic use
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Luciferases/pharmacology
- Luciferases/therapeutic use
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Protein-Tyrosine Kinases
- TOR Serine-Threonine Kinases/genetics
- TOR Serine-Threonine Kinases/metabolism
- TOR Serine-Threonine Kinases/pharmacology
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Affiliation(s)
- Xin Liu
- Department of Clinical Laboratory, Guizhou Provincial People's Hospital, Guiyang, China
| | - Miao-Miao Cui
- Department of Clinical Laboratory, Guiyang Second People's Hospital, Guiyang, China
| | - Hai-Zhen Zhu
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Pei-Yi Fu
- Department of Clinical Laboratory, Guizhou Provincial People's Hospital, Guiyang, China
| | - Guo-Chuan Wang
- Department of Clinical Laboratory, Guizhou Provincial People's Hospital, Guiyang, China
| | - Ling Huang
- Department of Clinical Laboratory, Guizhou Provincial People's Hospital, Guiyang, China
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22
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Li F, Wang M, Li X, Long Y, Chen K, Wang X, Zhong M, Cheng W, Tian X, Wang P, Ji M, Ma X. Inflammatory-miR-301a circuitry drives mTOR and Stat3-dependent PSC activation in chronic pancreatitis and PanIN. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:970-982. [PMID: 35211358 PMCID: PMC8829454 DOI: 10.1016/j.omtn.2022.01.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 01/17/2022] [Indexed: 02/09/2023]
Abstract
Activated pancreatic stellate cells (PSCs) are the main cells involved in chronic pancreatitis and pancreatic intraepithelial neoplasia lesion (PanIN). Fine-tuning the precise molecular targets in PSC activation might help the development of PSC-specific therapeutic strategies to tackle progression of pancreatic cancer-related fibrosis. miR-301a is a pro-inflammatory microRNA known to be activated by multiple inflammatory factors in the tumor stroma. Here, we show that miR-301a is highly expressed in activated PSCs in mice, sustained tissue fibrosis in caerulein-induced chronic pancreatitis, and accelerated PanIN formation. Genetic ablation of miR-301a reduced pancreatic fibrosis in mouse models with chronic pancreatitis and PanIN. Cell proliferation and activation of PSCs was inhibited by downregulation of miR-301a via two of its targets, Tsc1 and Gadd45g. Moreover, aberrant PSC expression of miR-301a and Gadd45g restricted the interplay between PSCs and pancreatic cancer cells in tumorigenesis. Our findings suggest that miR-301a activates two major cell proliferation pathways, Tsc1/mTOR and Gadd45g/Stat3, in vivo, to facilitate development of inflammatory-induced PanIN and maintenance of PSC activation and desmoplasia in pancreatic cancer.
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Affiliation(s)
- Fugui Li
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, 528403 Zhongshan, China
| | - Miaomiao Wang
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, Institute for Brain Research and Rehabilitation, South China Normal University, 510631 Guangzhou, China
| | - Xun Li
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, Institute for Brain Research and Rehabilitation, South China Normal University, 510631 Guangzhou, China
| | - Yihao Long
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, Institute for Brain Research and Rehabilitation, South China Normal University, 510631 Guangzhou, China
| | - Kaizhao Chen
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, Institute for Brain Research and Rehabilitation, South China Normal University, 510631 Guangzhou, China
| | - Xinjie Wang
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, Institute for Brain Research and Rehabilitation, South China Normal University, 510631 Guangzhou, China
| | - Mingtian Zhong
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, Institute for Brain Research and Rehabilitation, South China Normal University, 510631 Guangzhou, China
| | - Weimin Cheng
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, 528403 Zhongshan, China
| | - Xuemei Tian
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, Institute for Brain Research and Rehabilitation, South China Normal University, 510631 Guangzhou, China
| | - Ping Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120 Guangdong Province, China
| | - Mingfang Ji
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, 528403 Zhongshan, China
| | - Xiaodong Ma
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, Institute for Brain Research and Rehabilitation, South China Normal University, 510631 Guangzhou, China
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23
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p70 S6 kinase as a therapeutic target in cancers: More than just an mTOR effector. Cancer Lett 2022; 535:215593. [PMID: 35176419 DOI: 10.1016/j.canlet.2022.215593] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/25/2022] [Accepted: 02/06/2022] [Indexed: 11/23/2022]
Abstract
p70 S6 kinase (p70S6K) is best-known for its regulatory roles in protein synthesis and cell growth by phosphorylating its primary substrate, ribosomal protein S6, upon mitogen stimulation. The enhanced expression/activation of p70S6K has been correlated with poor prognosis in some cancer types, suggesting that it may serve as a biomarker for disease monitoring. p70S6K is a critical downstream effector of the oncogenic PI3K/Akt/mTOR pathway and its activation is tightly regulated by an ordered cascade of Ser/Thr phosphorylation events. Nonetheless, it should be noted that other upstream mechanisms regulating p70S6K at both the post-translational and post-transcriptional levels also exist. Activated p70S6K could promote various aspects of cancer progression such as epithelial-mesenchymal transition, cancer stemness and drug resistance. Importantly, novel evidence showing that p70S6K may also regulate different cellular components in the tumor microenvironment will be discussed. Therapeutic targeting of p70S6K alone or in combination with traditional chemotherapies or other microenvironmental-based drugs such as immunotherapy may represent promising approaches against cancers with aberrant p70S6K signaling. Currently, the only clinically available p70S6K inhibitors are rapamycin analogs (rapalogs) which target mTOR. However, there are emerging p70S6K-selective drugs which are going through active preclinical or clinical trial phases. Moreover, various screening strategies have been used for the discovery of novel p70S6K inhibitors, hence bringing new insights for p70S6K-targeted therapy.
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24
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Almohsen F, Al-Rubaie HA, Habib MA, Nasr SA, Perni R, Al-Quraishi L. Circulating miR-126-3p and miR-423-5p Expression in de novo Adult Acute Myeloid Leukemia: Correlations with Response to Induction Therapy and the 2-Year Overall Survival. J Blood Med 2022; 13:83-92. [PMID: 35210895 PMCID: PMC8863343 DOI: 10.2147/jbm.s347397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/20/2022] [Indexed: 12/02/2022] Open
Abstract
Background Purpose Patients and Methods Results Conclusion
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Affiliation(s)
- Faez Almohsen
- College of Medicine, University of Baghdad, Baghdad, Iraq
- Correspondence: Faez Almohsen, College of Medicine, University of Baghdad, Baghdad, Iraq, Tel +964 7902834062, Email
| | | | - Manal A Habib
- College of Medicine, University of Baghdad, Baghdad, Iraq
| | - Sherif A Nasr
- siParadigm Diagnostic Informatics, New Jersey, NJ, USA
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25
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Lu Y, Cao G, Lan H, Liao H, Hu Y, Feng H, Liu X, Huang P. Chondrocyte-derived Exosomal miR-195 Inhibits Osteosarcoma Cell Proliferation and Anti-Apoptotic by Targeting KIF4A in vitro and in vivo. Transl Oncol 2021; 16:101289. [PMID: 34952333 PMCID: PMC8695354 DOI: 10.1016/j.tranon.2021.101289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 11/11/2021] [Accepted: 11/19/2021] [Indexed: 12/14/2022] Open
Abstract
Osteosarcoma (OS) chemoresistance and distant metastasis are directly associated with OS recurrence and dismal patient prognosis, which are serious concerns for the medical community. However, current knowledge on OS pathogenesis and treatment remains limited. We found that kinesin superfamily protein 4A (KIF4A) acts as a potential OS biomarker. KIF4A promoted OS cell proliferation and anti-apoptotic in vitro and enhanced tumor growth in vivo. Our results indicate that miR-195 inhibits the expression of KIF4A by directly targeting its 3’-untranslated region Hence, targeting KIF4A could be a novel therapeutic strategy for OS and miR-195 may be a potential KIF4A-targeting drug. Furthermore, this study demonstrates that normal human chondrocytes can be used to produce miR-195-carrying exosomes to successfully deliver miR-195 into OS cells. Thus, our results suggest that chondrocyte-derived exosomal miR-195 may be developed into a potential adjuvant chemotherapeutic drug. Background Osteosarcoma (OS) is a primary malignant tumor of the bone that occurs in adolescents and is characterized by a young age at onset, high malignancy, high rate of metastasis, and poor prognosis. However, the factors influencing disease progression and prognosis remain unclear. Methods In this study, we aimed to investigate the role of chondrocyte-derived exosomal miR-195 in OS. We used normal human chondrocytes to form miR-195-carrying exosomes to deliver miR-195 into OS cells. Xenograft tumor experiments were performed in mice intratumorally injected with exosomal miR-195. We found that kinesin superfamily protein 4A (KIF4A) promoted OS tumor progression and anti-apoptotic. Resules We demonstrated that miR-195 inhibited the expression of KIF4A by directly targeting its 3’-untranslated region. Moreover, we observed that exosomal miR-195 successfully inhibited OS cell tumor growth and antiapoptotic in vitro and suppressed tumor growth in vivo. Conclusion Collectively, these results demonstrate that normal human chondrocyte-derived exosomal miR-195 can be internalized by OS cells and inhibit tumor growth and antiapoptotic by targeting KIF4A, providing a new direction for clarifying the molecular mechanism underlying OS development.
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Affiliation(s)
- Yao Lu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Gaolu Cao
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Haiying Lan
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Hua Liao
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Yaqiong Hu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Haihua Feng
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010-3000, USA
| | - Xiaojian Liu
- Department of Surgery, Tongxiang First People's Hospital, Jiaxing, Zhejiang 314500, China.
| | - Panpan Huang
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China.
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26
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Cui D, Qu R, Liu D, Xiong X, Liang T, Zhao Y. The Cross Talk Between p53 and mTOR Pathways in Response to Physiological and Genotoxic Stresses. Front Cell Dev Biol 2021; 9:775507. [PMID: 34869377 PMCID: PMC8638743 DOI: 10.3389/fcell.2021.775507] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/03/2021] [Indexed: 12/25/2022] Open
Abstract
The tumor suppressor p53 is activated upon multiple cellular stresses, including DNA damage, oncogene activation, ribosomal stress, and hypoxia, to induce cell cycle arrest, apoptosis, and senescence. Mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine protein kinase, serves as a central regulator of cell growth, proliferation, and survival by coordinating nutrients, energy, growth factors, and oxygen levels. p53 dysfunction and mTOR pathway hyperactivation are hallmarks of human cancer. The balance between response to stresses or commitment to cell proliferation and survival is governed by various regulatory loops between the p53 and mTOR pathways. In this review, we first briefly introduce the tumor suppressor p53 and then describe the upstream regulators and downstream effectors of the mTOR pathway. Next, we discuss the role of p53 in regulating the mTOR pathway through its transcriptional and non-transcriptional effects. We further describe the complicated role of the mTOR pathway in modulating p53 activity. Finally, we discuss the current knowledge and future perspectives on the coordinated regulation of the p53 and mTOR pathways.
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Affiliation(s)
- Danrui Cui
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
| | - Ruirui Qu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Dian Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiufang Xiong
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
| | - Yongchao Zhao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
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27
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Sadeghi H, Kamal A, Ahmadi M, Najafi H, Sharifi Zarchi A, Haddad P, Shayestehpour B, Kamkar L, Salamati M, Geranpayeh L, Lashkari M, Totonchi M. A novel panel of blood-based microRNAs capable of discrimination between benign breast disease and breast cancer at early stages. RNA Biol 2021; 18:747-756. [PMID: 34793290 DOI: 10.1080/15476286.2021.1989218] [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: 12/21/2022] Open
Abstract
Breast cancer (BC) as a leading cause of cancer death among women, exhibits a wide range of genetic heterogeneity in affected individuals. Satisfactory management of BC depends on early diagnosis and proper monitoring of patients' response to therapy. In this study, we aimed to assess the relation between the expression patterns of blood-based microRNAs (miRNAs) with demographic characteristics of the patients with BC in an attempt to find novel diagnostic markers for BC with acceptable precision in clinical applications. To this end, we performed comprehensive statistical analysis of the data of the Cancer Genome Atlas (TCGA) database and the blood miRNome dataset (GSE31309). As a result, 21 miRNAs were selected for experimental verification by quantitative RT-PCR on blood samples of 70 BC patients and 60 normal individuals (without any lesions or benign breast diseases). Statistical one-way ANOVA revealed no significant difference in the blood levels of the selected miRNAs in BC patients compared to any lesions or benign breast diseases. However, the multi-marker panel consisting of hsa-miR-106b-5p, -126-3p, -140-3p, -193a-5p, and -10b-5p could detect early-stages of BC with 0.79 sensitivity, 0.86 specificity and 0.82 accuracy. Furthermore, this multi-marker panel showed the potential of detecting benign breast diseases from BC patients with 0.67 sensitivity, 0.80 specificity, and 0.74 accuracy. In conclusion, these data indicate that the present panel might be considered an asset in detecting benign breast disease and BC.
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Affiliation(s)
- Hanieh Sadeghi
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Acecr, Tehran, Iran
| | - Aryan Kamal
- Department of Clinical Bioinformatics, Saarland University, Saarbrücken, Germany
| | - Marzieh Ahmadi
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Acecr, Tehran, Iran
| | - Hadi Najafi
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Acecr, Tehran, Iran
| | - Ali Sharifi Zarchi
- Department of Computer Engineering, Sharif University of Technology, Tehran, Iran
| | - Peyman Haddad
- Radiation Oncology Research Center, Iran Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahareh Shayestehpour
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Acecr, Tehran, Iran
| | - Leila Kamkar
- Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Masoumeh Salamati
- Department of Reproductive Imaging, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Acecr, Tehran, Iran
| | - Loabat Geranpayeh
- Department of Surgery, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Marzieh Lashkari
- Radiation Oncology Research Center, Iran Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Totonchi
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Acecr, Tehran, Iran
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Akbarzadeh M, Mihanfar A, Akbarzadeh S, Yousefi B, Majidinia M. Crosstalk between miRNA and PI3K/AKT/mTOR signaling pathway in cancer. Life Sci 2021; 285:119984. [PMID: 34592229 DOI: 10.1016/j.lfs.2021.119984] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/09/2021] [Accepted: 09/19/2021] [Indexed: 01/07/2023]
Abstract
Phosphoinositide-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is one of the most important proliferative signaling pathways with critical undeniable function in various aspects of cancer initiation/progression, including proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. On the other hand, numerous genetic alterations in the key genes involved in the PI3K/AKT/mTOR signaling pathway have been identified in multiple solid and hematological tumors. In addition, accumulating recent evidences have demonstrated a reciprocal interaction between this signaling pathway and microRNAs, a large group of small non-coding RNAs. Therefore, in this review, it was attempted to discuss about the interaction between key components of PI3K/AKT/mTOR signaling pathway with various miRNAs and their importance in cancer biology.
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Affiliation(s)
- Maryam Akbarzadeh
- Department of biochemistry, Urmia University of Medical Sciences, Urmia, Iran
| | - Ainaz Mihanfar
- Department of biochemistry, Urmia University of Medical Sciences, Urmia, Iran
| | - Shabnam Akbarzadeh
- Department of Physical Education and Sport Medicine, University of Tabriz, Tabriz, Iran
| | - Bahman Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran.
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Zhang S, Lin X, Hou Q, Hu Z, Wang Y, Wang Z. Regulation of mTORC1 by amino acids in mammalian cells: A general picture of recent advances. ACTA ACUST UNITED AC 2021; 7:1009-1023. [PMID: 34738031 PMCID: PMC8536509 DOI: 10.1016/j.aninu.2021.05.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 05/13/2021] [Accepted: 05/18/2021] [Indexed: 12/11/2022]
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) integrates various types of signal inputs, such as energy, growth factors, and amino acids to regulate cell growth and proliferation mainly through the 2 direct downstream targets, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and ribosomal protein S6 kinase 1 (S6K1). Most of the signal arms upstream of mTORC1 including energy status, stress signals, and growth factors converge on the tuberous sclerosis complex (TSC) - Ras homologue enriched in brain (Rheb) axis. Amino acids, however, are distinct from other signals and modulate mTORC1 using a unique pathway. In recent years, the transmission mechanism of amino acid signals upstream of mTORC1 has been gradually elucidated, and some sensors or signal transmission pathways for individual amino acids have also been discovered. With the help of these findings, we propose a general picture of recent advances, which demonstrates that various amino acids from lysosomes, cytoplasm, and Golgi are sensed by their respective sensors. These signals converge on mTORC1 and form a huge and complicated signal network with multiple synergies, antagonisms, and feedback mechanisms.
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Affiliation(s)
- Shizhe Zhang
- Key Laboratory of Ruminant Nutrition and Physiology, College of Animal Science and Technology, Shandong Agricultural University, No. 61, Daizong Street, Tai'an, Shandong, China
| | - Xueyan Lin
- Key Laboratory of Ruminant Nutrition and Physiology, College of Animal Science and Technology, Shandong Agricultural University, No. 61, Daizong Street, Tai'an, Shandong, China
| | - Qiuling Hou
- Key Laboratory of Ruminant Nutrition and Physiology, College of Animal Science and Technology, Shandong Agricultural University, No. 61, Daizong Street, Tai'an, Shandong, China
| | - Zhiyong Hu
- Key Laboratory of Ruminant Nutrition and Physiology, College of Animal Science and Technology, Shandong Agricultural University, No. 61, Daizong Street, Tai'an, Shandong, China
| | - Yun Wang
- Key Laboratory of Ruminant Nutrition and Physiology, College of Animal Science and Technology, Shandong Agricultural University, No. 61, Daizong Street, Tai'an, Shandong, China
| | - Zhonghua Wang
- Key Laboratory of Ruminant Nutrition and Physiology, College of Animal Science and Technology, Shandong Agricultural University, No. 61, Daizong Street, Tai'an, Shandong, China
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Al-Rawaf HA, Alghadir AH, Gabr SA. Circulating microRNAs and Molecular Oxidative Stress in Older Adults with Neuroprogression Disorders. DISEASE MARKERS 2021; 2021:4409212. [PMID: 34721735 PMCID: PMC8556086 DOI: 10.1155/2021/4409212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 09/28/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND circulating microRNAs are potential blood biomarkers differentially expressed in many diseases including neuro depression disorders. It controls the expression of human genes and associated cellular and physiological processes in normal and diseased cells. We aimed to evaluate the potential role of circulating miRNAs and their association with both stress hormones and cellular oxidative stress in neuro depression disorders occurred among older adults. METHODS a total of 70 healthy subjects were included in this study. Based upon the profile of mood states (POMS-32 score), the participants classified into two groups; healthy subjects (n =30) and depression (n =40). The expression of microRNAs; miR-124, miR-34a-5p, miR-135, and miR-451-a and their correlation with cellular oxidative stress parameters; cellular NO, genes of SOD2, CAT and iNOS, and hormones; cortisol and serotonin were estimated by a quantitative real-time RT-PCR, high-performance liquid chromatography, and ELISA Immunoassay techniques, respectively. RESULTS depression was reported in 57.14% of the participants. The results showed a significant increase (p =0.01) in the total mood scores, and relative depression domains in older adults with depression compared to healthy controls. The relative expression levels of miR-124, miR-34a-5p significantly increased and the expression levels of miR-135, and miR-451-a significantly decreased in older adults with depression compared to healthy controls. In addition, the levels of cortisol significantly increased and serotonin (5HT) significantly reduced in all participants with depression. Cellular oxidative stress analysis for depressed subjects showed that serum NO levels and the expression of iNO gene significantly increased conversely with a decline in the molecular expression antioxidative genes; SOD2, CAT, respectively. The results showed that cellular oxidative stress parameters correlated positively with depression scores, cortisol, and negatively with cellular serotonin levels. In depressed subjects, the relative expression of microRNAs correlated positively with depression score, NO, iNOS, cortisol, and negatively associated with SOD2, CAT, and serotonin. CONCLUSION The combination of cellular oxidative stress and hormonal levels strongly supports a role for circulating miRNAs; miR-124, miR-34a-5p, miR-135, and miR-451-a in the regulation of depression and mood disorders among older adults. The expressed microRNAs with their related association to cellular oxidative stress and adrenal hormones are a step towards understanding the role of these small RNA molecules in the progression of depression among older adults. Thus, cellular miRNAs might have a prognostic role in the diagnosis and as a target for treatment strategies in depressed subjects.
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Affiliation(s)
- Hadeel A. Al-Rawaf
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Ahmad H. Alghadir
- Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Sami A. Gabr
- Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
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Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation. Int J Mol Sci 2021; 22:ijms22189799. [PMID: 34575957 PMCID: PMC8464755 DOI: 10.3390/ijms22189799] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/27/2021] [Accepted: 09/07/2021] [Indexed: 12/14/2022] Open
Abstract
Liver fibrosis is characterized by the accumulation of extracellular matrix (ECM) resulting in the formation of fibrous scars. In the clinic, liver biopsies are the standard diagnostic method despite the potential for clinical complications. miRNAs are single-stranded, non-coding RNAs that can be detected in tissues, body fluids and cultured cells. The regulation of many miRNAs has been linked to tissue damage, including liver fibrosis in patients, resulting in aberrant miRNA expression/release. Experimental evidence also suggests that miRNAs are regulated in a similar manner in vitro and could thus serve as translational in vitro–in vivo biomarkers. In this work, we set out to identify and characterize biomarkers for liver fibrosis that could be used in vitro and clinically for research and diagnostic purposes. We focused on miRNAs released from hepatic 3D cultures exposed to methotrexate (MTX), which causes fibrosis, and acetaminophen (APAP), an acute hepatotoxicant with no clinically relevant association to liver fibrosis. Using a 3D in vitro model, we corroborated compound-specific responses as we show MTX induced a fibrotic response, and APAP did not. Performing miRNA-seq of cell culture supernatants, we identified potential miRNA biomarkers (miR-199a-5p, miR-214-3p, niRNA-125a-5p and miR-99b-5p) that were associated with a fibrotic phenotype and not with hepatocellular damage alone. Moreover, transfection of HSC with miR-199a-5p led to decreased expression of caveolin-1 and increased α-SMA expression, suggesting its role in HSC activation. In conclusion, we propose that extracellular miR-214-3p, miR-99b-5p, miR-125a-5p and specifically miR-199a-5p could contribute towards a panel of miRNAs for identifying liver fibrosis and that miR-199a-5p, miR-214-3p and miR-99b-5p are promoters of HSC activation.
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Corà D, Bussolino F, Doronzo G. TFEB Signalling-Related MicroRNAs and Autophagy. Biomolecules 2021; 11:985. [PMID: 34356609 PMCID: PMC8301958 DOI: 10.3390/biom11070985] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/28/2021] [Accepted: 06/30/2021] [Indexed: 12/26/2022] Open
Abstract
The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to stress factors such as nutrient and growth factor deficiency, hypoxia, lysosomal stress, and mitochondrial damage. To reach the final functional status, TFEB is regulated in multimodal ways, including transcriptional rate, post-transcriptional regulation, and post-translational modifications. Post-transcriptional regulation is in part mediated by miRNAs. miRNAs have been linked to many cellular processes involved both in physiology and pathology, such as cell migration, proliferation, differentiation, and apoptosis. miRNAs also play a significant role in autophagy, which exerts a crucial role in cell behaviour during stress or survival responses. In particular, several miRNAs directly recognise TFEB transcript or indirectly regulate its function by targeting accessory molecules or enzymes involved in its post-translational modifications. Moreover, the transcriptional programs triggered by TFEB may be influenced by the miRNA-mediated regulation of TFEB targets. Finally, recent important studies indicate that the transcription of many miRNAs is regulated by TFEB itself. In this review, we describe the interplay between miRNAs with TFEB and focus on how these types of crosstalk affect TFEB activation and cellular functions.
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Affiliation(s)
- Davide Corà
- Department of Translational Medicine, Piemonte Orientale University, 28100 Novara, Italy;
- Center for Translational Research on Autoimmune and Allergic Diseases—CAAD, 28100 Novara, Italy
| | - Federico Bussolino
- Department of Oncology, University of Torino, 10060 Candiolo, Italy
- Candiolo Cancer Institute-IRCCS-FPO, Laboratory of Vascular Oncology, 10060 Candiolo, Italy
| | - Gabriella Doronzo
- Department of Oncology, University of Torino, 10060 Candiolo, Italy
- Candiolo Cancer Institute-IRCCS-FPO, Laboratory of Vascular Oncology, 10060 Candiolo, Italy
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Mahmoud MM, Sanad EF, Hamdy NM. MicroRNAs' role in the environment-related non-communicable diseases and link to multidrug resistance, regulation, or alteration. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:36984-37000. [PMID: 34046834 DOI: 10.1007/s11356-021-14550-w] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/19/2021] [Indexed: 05/28/2023]
Abstract
The discovery of microRNAs (miRNAs) 20 years ago has advocated a new era of "small molecular genetics." About 2000 miRNAs are present that regulate one third of the genome. MiRNA dysregulated expression arising as a response to our environment insult or stress or changes may contribute to several diseases, namely non-communicable diseases, including tumor growth. Their presence in body fluids, reflecting level alteration in various cancers, merit circulating miRNAs as the "next-generation biomarkers" for early-stage tumor diagnosis and/or prognosis. Herein, we performed a comprehensive literature search focusing on the origin, biosynthesis, and role of miRNAs and summarized the foremost studies centering on miR value as non-invasive biomarkers in different environment-related non-communicable diseases, including various cancer types. Moreover, during chemotherapy, many miRNAs were linked to multidrug resistance, via modulating numerous, environment triggered or not, biological processes and/or pathways that will be highlighted as well.
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Affiliation(s)
- Marwa M Mahmoud
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, 11566, Abassia, Cairo, Egypt
| | - Eman F Sanad
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, 11566, Abassia, Cairo, Egypt
| | - Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, 11566, Abassia, Cairo, Egypt.
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Yu L, Wei J, Liu P. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Semin Cancer Biol 2021; 85:69-94. [PMID: 34175443 DOI: 10.1016/j.semcancer.2021.06.019] [Citation(s) in RCA: 319] [Impact Index Per Article: 79.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/10/2021] [Accepted: 06/22/2021] [Indexed: 02/08/2023]
Abstract
Cancer is the second leading cause of human death globally. PI3K/Akt/mTOR signaling is one of the most frequently dysregulated signaling pathways observed in cancer patients that plays crucial roles in promoting tumor initiation, progression and therapy responses. This is largely due to that PI3K/Akt/mTOR signaling is indispensable for many cellular biological processes, including cell growth, metastasis, survival, metabolism, and others. As such, small molecule inhibitors targeting major kinase components of the PI3K/Akt/mTOR signaling pathway have drawn extensive attention and been developed and evaluated in preclinical models and clinical trials. Targeting a single kinase component within this signaling usually causes growth arrest rather than apoptosis associated with toxicity-induced adverse effects in patients. Combination therapies including PI3K/Akt/mTOR inhibitors show improved patient response and clinical outcome, albeit developed resistance has been reported. In this review, we focus on revealing the mechanisms leading to the hyperactivation of PI3K/Akt/mTOR signaling in cancer and summarizing efforts for developing PI3K/Akt/mTOR inhibitors as either mono-therapy or combination therapy in different cancer settings. We hope that this review will facilitate further understanding of the regulatory mechanisms governing dysregulation of PI3K/Akt/mTOR oncogenic signaling in cancer and provide insights into possible future directions for targeted therapeutic regimen for cancer treatment, by developing new agents, drug delivery systems, or combination regimen to target the PI3K/Akt/mTOR signaling pathway. This information will also provide effective patient stratification strategy to improve the patient response and clinical outcome for cancer patients with deregulated PI3K/Akt/mTOR signaling.
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Affiliation(s)
- Le Yu
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | | | - Pengda Liu
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Nazari N, Jafari F, Ghalamfarsa G, Hadinia A, Atapour A, Ahmadi M, Dolati S, Rostamzadeh D. The emerging role of microRNA in regulating the mTOR signaling pathway in immune and inflammatory responses. Immunol Cell Biol 2021; 99:814-832. [PMID: 33988889 DOI: 10.1111/imcb.12477] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 05/10/2021] [Accepted: 05/10/2021] [Indexed: 01/01/2023]
Abstract
The mechanistic/mammalian target of rapamycin (mTOR) is considered to be an atypical protein kinase that plays a critical role in integrating different cellular and environmental inputs in the form of growth factors, nutrients and energy and, subsequently, in regulating different cellular events, including cell metabolism, survival, homeostasis, growth and cellular differentiation. Immunologically, mTOR is a critical regulator of immune function through integrating numerous signals from the immune microenvironment, which coordinates the functions of immune cells and T cell fate decisions. The crucial role of mTOR in immune responses has been lately even more appreciated. MicroRNAs (miRNAs) are endogenous, small, noncoding single-stranded RNAs that act as molecular regulators involved in multiple processes during immune cells development, homeostasis, activation and effector polarization. Several studies have recently indicated that a range of miRNAs are involved in regulating the phosphoinositide 3-kinase/protein kinase B/mTOR (PI3K/AKT/mTOR) signaling pathway by targeting multiple components of this signaling pathway and modulating the expression and function of these targets. Current evidence has revealed the interplay between miRNAs and the mTOR pathway circuits in various immune cell types. The expression of individual miRNA can affect the function of mTOR signaling to determine the cell fate decisions in immune responses through coordinating immune signaling and cell metabolism. Dysregulation of the mTOR pathway/miRNAs crosstalk has been reported in cancers and various immune-related diseases. Thus, expression profiles of dysregulated miRNAs could influence the mTOR pathway, resulting in the promotion of aberrant immunity. This review summarizes the latest information regarding the reciprocal role of the mTOR signaling pathway and miRNAs in orchestrating immune responses.
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Affiliation(s)
- Nazanin Nazari
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farzaneh Jafari
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ghasem Ghalamfarsa
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Abolghasem Hadinia
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Amir Atapour
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanam Dolati
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Davood Rostamzadeh
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.,Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
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36
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Ding L, Tian W, Zhang H, Li W, Ji C, Wang Y, Li Y. MicroRNA-486-5p Suppresses Lung Cancer via Downregulating mTOR Signaling In Vitro and In Vivo. Front Oncol 2021; 11:655236. [PMID: 34094949 PMCID: PMC8172781 DOI: 10.3389/fonc.2021.655236] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/23/2021] [Indexed: 11/13/2022] Open
Abstract
Lung cancer is one of the central causes of tumor-related deaths globally, of which non-small cell lung cancer (NSCLC) takes up about 85%. As key regulators of various biological processes, microRNAs (miRNAs) have been verified as crucial factors in NSCLC. To elucidate the role of miR-486-5p in the mTOR pathway, we investigated its role in NSCLC and related signaling. Our results confirmed that miR-486-5p was downregulated in most of human NSCLC tissue samples and cell lines. Further study confirmed that it inhibited NSCLC through repression of the mTOR pathway via targeting both ribosomal proteins S6 kinase A1 (RPS6KA1, RSK) and ribosomal proteins S6 kinase B1 (RPS6KB1, p70S6K), which are critical components of the mTOR signaling. Additionally, miR-486-5p impeded tumor growth in vivo and inhibited tumor metastasis through repression of the epithelial-mesenchymal transition (EMT). Taken together, our study verified the role that miR-486-5p exerts in NSCLC, and its expression pattern in the different stages and morphologies of NSCLC makes it a promising biomarker in the early diagnosis of the disease.
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Affiliation(s)
- Lei Ding
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai, China.,Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
| | - Wu Tian
- Department of General Surgery, Orthopedics Hospital of Guizhou Province, Guiyang, China
| | - Hui Zhang
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai, China
| | - Wanqiu Li
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai, China
| | - Chunyu Ji
- Department of Thoracic Surgery, Shanghai Chest Hospital, Jiaotong University Medical School, Shanghai, China
| | - Yuanyuan Wang
- Department of Respiratory and Critical Care Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yanli Li
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai, China
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Pacheco JM, Canal MV, Pereyra CM, Welchen E, Martínez-Noël GMA, Estevez JM. The tip of the iceberg: emerging roles of TORC1, and its regulatory functions in plant cells. JOURNAL OF EXPERIMENTAL BOTANY 2021; 72:4085-4101. [PMID: 33462577 DOI: 10.1093/jxb/eraa603] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 12/19/2020] [Indexed: 06/12/2023]
Abstract
Target of Rapamycin (TOR) is an evolutionarily conserved protein kinase that plays a central role in coordinating cell growth with light availability, the diurnal cycle, energy availability, and hormonal pathways. TOR Complex 1 (TORC1) controls cell proliferation, growth, metabolism, and defense in plants. Sugar availability is the main signal for activation of TOR in plants, as it also is in mammals and yeast. Specific regulators of the TOR kinase pathway in plants are inorganic compounds in the form of major nutrients in the soils, and light inputs via their impact on autotrophic metabolism. The lack of TOR is embryo-lethal in plants, whilst dysregulation of TOR signaling causes major alterations in growth and development. TOR exerts control as a regulator of protein translation via the action of proteins such as S6K, RPS6, and TAP46. Phytohormones are central players in the downstream systemic physiological TOR effects. TOR has recently been attributed to have roles in the control of DNA methylation, in the abundance of mRNA splicing variants, and in the variety of regulatory lncRNAs and miRNAs. In this review, we summarize recent discoveries in the plant TOR signaling pathway in the context of our current knowledge of mammalian and yeast cells, and highlight the most important gaps in our understanding of plants that need to be addressed in the future.
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Affiliation(s)
| | - María Victoria Canal
- Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Cátedra de Biología Celular y Molecular, Facultad de Bioquímica y Ciencias Biológicas,, Universidad Nacional del Litoral, Santa Fe, Argentina
| | - Cintia M Pereyra
- Instituto de Investigaciones en Biodiversidad y Biotecnología (INBIOTEC-CONICET) and Fundación para Investigaciones Biológicas Aplicadas (FIBA), Vieytes, Mar Del Plata, Argentina
| | - Elina Welchen
- Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Cátedra de Biología Celular y Molecular, Facultad de Bioquímica y Ciencias Biológicas,, Universidad Nacional del Litoral, Santa Fe, Argentina
| | - Giselle M A Martínez-Noël
- Instituto de Investigaciones en Biodiversidad y Biotecnología (INBIOTEC-CONICET) and Fundación para Investigaciones Biológicas Aplicadas (FIBA), Vieytes, Mar Del Plata, Argentina
| | - José M Estevez
- Fundación Instituto Leloir and IIBBA-CONICET, Buenos Aires CP, Argentina
- Centro de Biotecnología Vegetal (CBV), Facultad de Ciencias de la Vida (FCsV), Universidad Andres Bello, Santiago, Chile and Millennium Institute for Integrative Biology (iBio), Santiago, Chile
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38
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Bozack AK, Colicino E, Rodosthenous R, Bloomquist TR, Baccarelli AA, Wright RO, Wright RJ, Lee AG. Associations between maternal lifetime stressors and negative events in pregnancy and breast milk-derived extracellular vesicle microRNAs in the programming of intergenerational stress mechanisms (PRISM) pregnancy cohort. Epigenetics 2021; 16:389-404. [PMID: 32777999 PMCID: PMC7996083 DOI: 10.1080/15592294.2020.1805677] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/17/2020] [Accepted: 07/30/2020] [Indexed: 01/02/2023] Open
Abstract
Maternal stress is associated with adverse child health. Breast milk microRNAs encapsulated in extracellular vesicles (EVs) are involved in mother-infant biochemical communication during early-life programming. We leverage the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort to investigate associations between maternal stress and breast milk EV-microRNAs. Lifetime stress and negative life events (NLEs) during pregnancy were assessed using the Life Stressor Checklist-Revised (LSCR) and the Crisis in Family Systems-Revised surveys, respectively. RNA was extracted from breast milk EVs (N = 80; collected 6.1 ± 5.9 weeks postnatally), and microRNAs were profiled using the TaqMan OpenArray Human miRNA panel. Associations between stress scores and detection (yes/no) of 173 microRNAs identified in 20-80% of samples were assessed using logistic regression; associations with expression levels of 205 EV-microRNAs identified in >50% of samples were assessed using linear regression. In adjusted models, detection of 60 and 44 EV-microRNAs was associated with higher LSCR and NLE scores, respectively (p < 0.05). Expression level of 8 and 17 EV-microRNAs was associated with LSCR and NLE scores, respectively, at our a priori criteria of p < 0.05 and |Bregression|>0.2. Enriched KEGG pathways for microRNAs associated with stress scores included fatty acid metabolism and the Hippo signaling pathway. Maternal lifetime stress and NLEs during pregnancy were both associated with detection and expression level of breast milk EV-microRNAs, although associations with microRNA profiles differed between stress measures. Further research is needed to identify biological pathways impacted by associated microRNAs and investigate relationships with child health outcomes.Abbreviations: EV: extracellular vesicle; PRISM: PRogramming of Intergenerational Stress Mechanisms pregnancy cohort; LSCR: Life Stressor Checklist-Revised survey; NLE: negative life event; CRISYS-R: Crisis in Family Systems-Revised survey; KEGG: Kyoto Encyclopaedia of Genes and Genomes; NYC: New York City; SD: standard deviation; IQR: interquartile range; Cq: relative cycle threshold values; PCA: principal component analysis.
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Affiliation(s)
- Anne K. Bozack
- Division of Pulmonary Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Environmental Medicine and Public Health, New York, NY, USA
| | - Elena Colicino
- Department of Environmental Medicine and Public Health, New York, NY, USA
| | | | - Tessa R. Bloomquist
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Andrea A. Baccarelli
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Robert O. Wright
- Department of Environmental Medicine and Public Health, New York, NY, USA
| | - Rosalind J. Wright
- Department of Environmental Medicine and Public Health, New York, NY, USA
| | - Alison G. Lee
- Division of Pulmonary Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
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Negative Regulation of ULK1 by microRNA-106a in Autophagy Induced by a Triple Drug Combination in Colorectal Cancer Cells In Vitro. Genes (Basel) 2021; 12:genes12020245. [PMID: 33572255 PMCID: PMC7915601 DOI: 10.3390/genes12020245] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/27/2021] [Accepted: 02/01/2021] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is among the top three most deadly cancers worldwide. The survival rate for this disease has not been reduced despite the treatments, the reason why the search for therapeutic alternatives continues to be a priority issue in oncology. In this research work, we tested our successful pharmacological combination of three drugs, metformin, doxorubicin, and sodium oxamate (triple therapy, or TT), as an autophagy inducer. Firstly, we employed western blot (WB) assays, where we observed that after 8 h of stimulation with TT, the proteins Unc-51 like autophagy activating kinase 1(ULK1), becline-1, autophagy related 1 protein (Atg4), and LC3 increased in the CRC cell lines HCT116 and SW480 in contrast to monotherapy with doxorubicin. The overexpression of these proteins indicated the beginning of autophagy flow through the activation of ULK1 and the hyperlipidation of LC3 at the beginning of this process. Moreover, we confirm that ULK1 is a bona fide target of hsa-miR-106a-5p (referred to from here on as miR-106a) in HCT116. We also observed through the GFP-LC3 fusion protein that in the presence of miR-106a, the accumulation of autophagy vesicles in cells stimulated with TT is inhibited. These results show that the TT triggered autophagy to modulate miR-106a/ULK1 expression, probably affecting different cellular pathways involved in cellular proliferation, survivance, metabolic maintenance, and cell death. Therefore, considering the importance of autophagy in cancer biology, the study of miRNAs that regulate autophagy in cancer will allow a better understanding of malignant tumors and lead to the development of new disease markers and therapeutic strategies.
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Gora IM, Ciechanowska A, Ladyzynski P. NLRP3 Inflammasome at the Interface of Inflammation, Endothelial Dysfunction, and Type 2 Diabetes. Cells 2021; 10:314. [PMID: 33546399 PMCID: PMC7913585 DOI: 10.3390/cells10020314] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/24/2021] [Accepted: 01/30/2021] [Indexed: 01/08/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM), accounting for 90-95% cases of diabetes, is characterized by chronic inflammation. The mechanisms that control inflammation activation in T2DM are largely unexplored. Inflammasomes represent significant sensors mediating innate immune responses. The aim of this work is to present a review of links between the NLRP3 inflammasome, endothelial dysfunction, and T2DM. The NLRP3 inflammasome activates caspase-1, which leads to the maturation of pro-inflammatory cytokines interleukin 1β and interleukin 18. In this review, we characterize the structure and functions of NLRP3 inflammasome as well as the most important mechanisms and molecules engaged in its activation. We present evidence of the importance of the endothelial dysfunction as the first key step to activating the inflammasome, which suggests that suppressing the NLRP3 inflammasome could be a new approach in depletion hyperglycemic toxicity and in averting the onset of vascular complications in T2DM. We also demonstrate reports showing that the expression of a few microRNAs that are also known to be involved in either NLRP3 inflammasome activation or endothelial dysfunction is deregulated in T2DM. Collectively, this evidence suggests that T2DM is an inflammatory disease stimulated by pro-inflammatory cytokines. Finally, studies revealing the role of glucose concentration in the activation of NLRP3 inflammasome are analyzed. The more that is known about inflammasomes, the higher the chances to create new, effective therapies for patients suffering from inflammatory diseases. This may offer potential novel therapeutic perspectives in T2DM prevention and treatment.
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Affiliation(s)
- Ilona M. Gora
- Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Ks. Trojdena 4, 02-109 Warsaw, Poland; (A.C.); (P.L.)
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Deng K, Yin H, Xiong F, Feng L, Dong P, Ren M. Genome-wide miRNA expression profiling in potato ( Solanum tuberosum L.) reveals TOR-dependent post-transcriptional gene regulatory networks in diverse metabolic pathway. PeerJ 2021; 9:e10704. [PMID: 33520467 PMCID: PMC7811781 DOI: 10.7717/peerj.10704] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 12/14/2020] [Indexed: 12/29/2022] Open
Abstract
Target of rapamycin (TOR) operates as a hub of the signal transduction that integrates nutrient and energy signaling to promote cell proliferation and growth through mediating the transcriptional and post- transcriptional regulator networks in all eukaryotic species. MicroRNAs (miRNAs) are widespread classes of small, single-stranded, non-coding endogenous RNAs and are widely found in eukaryotes, which play a vital role in regulating gene expression by degrading targeted mRNAs or translational repression at post-transcriptional level. Recent studies found that there were necessarily close connections between miRNA and TOR pathways in mammals. However, there is little information about the interplay between the miRNA and TOR in plants. Thus, the aim of this study was to identify potential TOR-miRNA-mRNA regulatory networks in TOR signaling through global mRNA and microRNA expression profiling in potato. Based on the previous high-throughput transcriptome sequencing and filtering, a total of 2,899 genes were significantly differentially expressed in potato under TOR inhibitors treatment. Pathway analysis revealed that these genes were significantly enriched in multiple metabolic processes. Similarly, in the present study, suppression of TOR resulted in 41 miRNAs up-regulated and 45 down-regulated, revealing that TOR plays a crucial role in the regulation of miRNA regulatory network. Furthermore, integrated mRNA and miRNA expression profiling uncovered that these miRNAs participated in large-scale metabolic process in the TOR signal pathway in potato, such as regulation of autophagy and ubiquitination, and biosynthesis of secondary metabolites. Overall, the results shed new insight into TOR related post-transcriptional gene regulatory networks in potato and suggesting TOR-miRNA-targeting genes relevant networks as a potential genetic resource for potato improvement.
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Affiliation(s)
- Kexuan Deng
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Huan Yin
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Fangjie Xiong
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Li Feng
- Zhengzhou Research Base, State Key Laboratory of Cotton Biology, Zhengzhou University, Zhengzhou, China.,Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu, China
| | - Pan Dong
- School of Life Sciences, Chongqing University, Chongqing, China.,Chongqing Key Laboratory of Biology and Genetic Breeding for Tuber and Root Crops, Chongqing, China
| | - Maozhi Ren
- School of Life Sciences, Chongqing University, Chongqing, China.,Zhengzhou Research Base, State Key Laboratory of Cotton Biology, Zhengzhou University, Zhengzhou, China.,Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu, China
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Taheri M, Shoorei H, Tondro Anamag F, Ghafouri-Fard S, Dinger ME. LncRNAs and miRNAs participate in determination of sensitivity of cancer cells to cisplatin. Exp Mol Pathol 2021; 123:104602. [PMID: 33422487 DOI: 10.1016/j.yexmp.2021.104602] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/27/2020] [Accepted: 12/31/2020] [Indexed: 02/08/2023]
Abstract
Cisplatin is an extensively used chemotherapeutic substance for various types of human malignancies including sarcomas, carcinomas and lymphomas. Yet, the vast application of this drug is hampered by the emergence of chemoresistance in some treated patients. Several mechanisms such as degradation of the membrane transporters by cisplatin have been implicated in the pathogenesis of this event. Recent researches have also indicated the role of long non-coding RNAs (lncRNAs) as well as micoRNAs (miRNAs) in the emergence of resistance to cisplatin in several cancer types. For instance, up-regulation of miR-21 has been associated with resistance to this agent in ovarian cancer, oral squamous cell cancer, gastric malignancy and non-small cell lung cancer (NSCLC). On the other hand, down-regulation of miR-218 has been implicated in emergence of chemoresistance in breast cancer and esophageal squamous cell carcinoma. MALAT1 is implicated in the chemoresistance of bladder cancer cells, NSCLC, gastric cancer and cervical cancer. Most notably, the expression profile of resistance-associated miRNAs and lncRNAs can predict overall survival of cancer patients. Mechanistic assays have revealed that interference with expression of some miRNAs and lncRNAs can reverse the resistance phenotype in cancer cells. In this paper, we review the scientific writings on the role of lncRNAs and miRNAs in the evolution of chemoresistance to cisplatin in cancer cells.
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Affiliation(s)
- Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Marcel E Dinger
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
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Mendonça DB, Nguyen JT, Haidar F, Fox AL, Ray C, Amatullah H, Liu F, Kim JK, Krebsbach PH. MicroRNA-1911-3p targets mEAK-7 to suppress mTOR signaling in human lung cancer cells. Heliyon 2020; 6:e05734. [PMID: 33364499 PMCID: PMC7753913 DOI: 10.1016/j.heliyon.2020.e05734] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 11/03/2020] [Accepted: 12/11/2020] [Indexed: 12/11/2022] Open
Abstract
Regulation of mTOR signaling depends on an intricate interplay of post-translational protein modification. Recently, mEAK-7 (mTOR associated protein, eak-7 homolog) was identified as a positive activator of mTOR signaling via an alternative mTOR complex. However, the upstream regulation of mEAK-7 in human cells is not known. Because microRNAs are capable of modulating protein translation of RNA in eukaryotes, we conducted a bioinformatic search for relevant mEAK-7 targeting microRNAs using the Exiqon miRSearch V3.0 algorithm. Based on the score obtained through miRSearch V3.0, the top predicted miRNA (miR-1911-3p) was studied. miR-1911-3p mimics decreased protein levels of both mEAK-7 and mTORC1 downstream effectors p-S6 and p-4E-BP1 in non-small cell lung carcinoma (NSCLC) cell lines H1975 and H1299. miR-1911-3p levels and MEAK7 mRNA/mEAK-7/mTOR signaling levels were negatively correlated between normal lung and NSCLC cells. miR-1911-3p directly interacted with MEAK7 mRNA at the 3′-UTR to negatively regulate mEAK-7 and significantly decreased mTOR localization to the lysosome. Furthermore, miR-1911-3p significantly decreased cell proliferation and migration in both H1975 and H1299 cells. Thus, miR-1911-3p functions as a suppressor of mTOR signaling through the regulation of MEAK7 mRNA translation in human cancer cells.
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Affiliation(s)
- Daniela Baccelli Mendonça
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA.,Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Joe Truong Nguyen
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA.,Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Fatima Haidar
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA.,Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Alexandra Lucienne Fox
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA.,Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Connor Ray
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA.,Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Halimah Amatullah
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA.,Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Fei Liu
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Jin Koo Kim
- Section of Periodontics, University of California, Los Angeles, School of Dentistry, Los Angeles, CA, 90095, USA
| | - Paul H Krebsbach
- Section of Periodontics, University of California, Los Angeles, School of Dentistry, Los Angeles, CA, 90095, USA
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Fernandes J, Miranda RL, de Lemos ERS, Guterres A. MicroRNAs and Mammarenaviruses: Modulating Cellular Metabolism. Cells 2020; 9:E2525. [PMID: 33238430 PMCID: PMC7709035 DOI: 10.3390/cells9112525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/04/2020] [Accepted: 11/11/2020] [Indexed: 12/11/2022] Open
Abstract
Mammarenaviruses are a diverse genus of emerging viruses that include several causative agents of severe viral hemorrhagic fevers with high mortality in humans. Although these viruses share many similarities, important differences with regard to pathogenicity, type of immune response, and molecular mechanisms during virus infection are different between and within New World and Old World viral infections. Viruses rely exclusively on the host cellular machinery to translate their genome, and therefore to replicate and propagate. miRNAs are the crucial factor in diverse biological processes such as antiviral defense, oncogenesis, and cell development. The viral infection can exert a profound impact on the cellular miRNA expression profile, and numerous RNA viruses have been reported to interact directly with cellular miRNAs and/or to use these miRNAs to augment their replication potential. Our present study indicates that mammarenavirus infection induces metabolic reprogramming of host cells, probably manipulating cellular microRNAs. A number of metabolic pathways, including valine, leucine, and isoleucine biosynthesis, d-Glutamine and d-glutamate metabolism, thiamine metabolism, and pools of several amino acids were impacted by the predicted miRNAs that would no longer regulate these pathways. A deeper understanding of mechanisms by which mammarenaviruses handle these signaling pathways is critical for understanding the virus/host interactions and potential diagnostic and therapeutic targets, through the inhibition of specific pathologic metabolic pathways.
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Affiliation(s)
- Jorlan Fernandes
- Hantaviruses and Rickettsiosis Laboratory, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil;
| | - Renan Lyra Miranda
- Neurochemistry Interactions Laboratory, Universidade Federal Fluminense, Niterói 24020-150, Brazil;
| | - Elba Regina Sampaio de Lemos
- Hantaviruses and Rickettsiosis Laboratory, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil;
| | - Alexandro Guterres
- Hantaviruses and Rickettsiosis Laboratory, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil;
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Kipkeeva F, Muzaffarova T, Korotaeva A, Nikulin M, Grishina K, Mansorunov D, Apanovich P, Karpukhin A. MicroRNA in Gastric Cancer Development: Mechanisms and Biomarkers. Diagnostics (Basel) 2020; 10:E891. [PMID: 33142817 PMCID: PMC7692123 DOI: 10.3390/diagnostics10110891] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/20/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is one of the most common and difficult diseases to treat. The study of signaling pathway regulation by microRNA provides information on the mechanisms of GC development and is the basis for biomarker creation. In this study, a circuit of microRNA interactions with signaling pathways was constructed. The microRNAs, associated with metastasis and chemoresistance, are described. In most cases, microRNAs in GC regulate the Wnt/β-catenin, PI3K/AKT/mTOR, RAS/RAF/ERK/MAPK, NF-kB, TGF-β, and JAK/STAT pathways. Part of the microRNA acts on several target genes that function in different pathways. This often leads to an intensification of the induced processes. MicroRNAs have also been described that have the opposite effect on different pathways, causing different functional consequences. By acting on several target genes, or genes associated with several pathways, microRNAs can function in a signaling network. MicroRNAs associated with metastasis most often interact with the Wnt/β-catenin pathway. MicroRNAs affecting chemoresistance, in most cases, affect the regulators of apoptosis and are associated with the PI3K/AKT/mTOR pathway. The characteristics of microRNAs proposed as candidates for GC biomarkers were analyzed. The currently developed diagnostic and prognostic panels of microRNAs are also considered.
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Affiliation(s)
- Fatimat Kipkeeva
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Tatyana Muzaffarova
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Alexandra Korotaeva
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Maxim Nikulin
- N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, 24 Kashirskoe Shosse, Moscow 115478, Russia;
| | - Kristina Grishina
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Danzan Mansorunov
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Pavel Apanovich
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
| | - Alexander Karpukhin
- Research Centre for Medical Genetics, 1 Moskvorechye St., Moscow 115522, Russia; (F.K.); (T.M.); (A.K.); (K.G.); (D.M.); (P.A.)
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Abstract
Important advances have been made regarding the diagnosis and management of polycystic kidney diseases. Care of patients with polycystic kidney diseases has moved beyond supportive care for complications and chronic kidney disease to new potentially disease-modifying therapies. Recently, the role of noncoding RNAs, in particular microRNAs, has been described in polycystic kidney diseases. microRNAs are involved in the regulation of gene expression, in which PKD1, PKD2, and other genes that contribute to the pathogenesis of polycystic kidney diseases are considerable participants. Seminal studies have highlighted the potential importance of microRNAs as new therapeutic targets and innovative diagnostic and/or prognostic biomarkers. Furthermore, an anti-miR-17 drug has advanced through preclinical autosomal dominant polycystic disease studies, and an anti-miR-21 drug has already cleared a phase 1 clinical trial. Most probably, new drugs in the microRNA research field will be yielded as a result of ongoing and planned therapeutic trials. To provide a foundation for understanding microRNA functions as a disease-modifying therapeutic drug in novel targeted therapies, in this narrative review we present an overview of the current knowledge of microRNAs in the pathogenesis of polycystic kidney diseases.
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Affiliation(s)
| | - Liangzhong Sun
- Address for Correspondence: Liangzhong Sun, PhD, Department of Pediatrics, Nanfang Hospital, Southern Medical University, No. 1838, North Road, Guangzhou Avenue, Baiyun District, Guangzhou 510515, Guangdong Province, China.
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Ait-Aissa K, Nguyen QM, Gabani M, Kassan A, Kumar S, Choi SK, Gonzalez AA, Khataei T, Sahyoun AM, Chen C, Kassan M. MicroRNAs and obesity-induced endothelial dysfunction: key paradigms in molecular therapy. Cardiovasc Diabetol 2020; 19:136. [PMID: 32907629 PMCID: PMC7488343 DOI: 10.1186/s12933-020-01107-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 08/28/2020] [Indexed: 01/17/2023] Open
Abstract
The endothelium plays a pivotal role in maintaining vascular health. Obesity is a global epidemic that has seen dramatic increases in both adult and pediatric populations. Obesity perturbs the integrity of normal endothelium, leading to endothelial dysfunction which predisposes the patient to cardiovascular diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that play important roles in a variety of cellular processes such as differentiation, proliferation, apoptosis, and stress response; their alteration contributes to the development of many pathologies including obesity. Mediators of obesity-induced endothelial dysfunction include altered endothelial nitric oxide synthase (eNOS), Sirtuin 1 (SIRT1), oxidative stress, autophagy machinery and endoplasmic reticulum (ER) stress. All of these factors have been shown to be either directly or indirectly caused by gene regulatory mechanisms of miRNAs. In this review, we aim to provide a comprehensive description of the therapeutic potential of miRNAs to treat obesity-induced endothelial dysfunction. This may lead to the identification of new targets for interventions that may prevent or delay the development of obesity-related cardiovascular disease.
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Affiliation(s)
- Karima Ait-Aissa
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
| | - Quynh My Nguyen
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, USA
| | - Mohanad Gabani
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Adam Kassan
- Department of Pharmaceutical Sciences, School of Pharmacy, West Coast University, Los Angeles, USA
| | - Santosh Kumar
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Soo-Kyoung Choi
- Department of Physiology, College of Medicine, Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, South Korea
| | - Alexis A Gonzalez
- Instituto de Química, Pontificia, Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Tahsin Khataei
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Amal M Sahyoun
- Department of Food Science and Agriculture Chemistry, McGill University, Montreal, QC, Canada
| | - Cheng Chen
- Department of emergency and Critical Care, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Modar Kassan
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
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Chen SD, Pan HY, Huang JB, Liu XP, Li JH, Ho CJ, Tsai MH, Yang JL, Chen SF, Chen NC, Chuang YC. Circulating MicroRNAs from Serum Exosomes May Serve as a Putative Biomarker in the Diagnosis and Treatment of Patients with Focal Cortical Dysplasia. Cells 2020; 9:cells9081867. [PMID: 32785072 PMCID: PMC7465068 DOI: 10.3390/cells9081867] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/03/2020] [Accepted: 08/08/2020] [Indexed: 12/12/2022] Open
Abstract
Focal cortical dysplasia (FCD) is a congenital malformation of cortical development where the cortical neurons located in the brain area fail to migrate in the proper formation. Epilepsy, particularly medically refractory epilepsy, is the most common clinical presentation for all types of FCD. This study aimed to explore the expression change of circulating miRNAs in patients with FCD from serum exosomes. A total of nine patients with FCD and four healthy volunteers were enrolled in this study. The serum exosomes were isolated from the peripheral blood of the subjects. Transmission electron microscopy (TEM) was used to identify the exosomes. Both exosomal markers and neuronal markers were detected by Western blotting analysis to prove that we could obtain central nervous system-derived exosomes from the circulation. The expression profiles of circulating exosomal miRNAs were assessed using next-generation sequencing analysis (NGS). We obtained a total of 107 miRNAs with dominant fold change (>2-fold) from both the annotated 5p-arm and 3p-arm of 2780 mature miRNAs. Based on the integrated platform of HMDD v3.2, miRway DB and DIANA-miRPath v3.0 online tools, and confirmed by MiRBase analysis, four potentially predicted miRNAs from serum exosomes in patients with FCD were identified, including miR194-2-5p, miR15a-5p, miR-132-3p, and miR-145-5p. All four miRNAs presented upregulated expression in patients with FCD compared with controls. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and pathway category of four target miRNAs, we found eight possible signaling pathways that may be related to FCD. Among them, we suggest that the mTOR signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway, and cell cycle regulation and TGF-beta signaling pathway are high-risk pathways that play a crucial role in the pathogenesis of FCD and refractory epilepsy. Our results suggest that the circulating miRNAs from exosomes may provide a potential biomarker for diagnostic, prognostic, and therapeutic adjuncts in patients with FCD and refractory epilepsy.
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Affiliation(s)
- Shang-Der Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.); (J.-L.Y.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Hsiu-Yung Pan
- Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (H.-Y.P.); (J.-B.H.)
| | - Jyun-Bin Huang
- Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (H.-Y.P.); (J.-B.H.)
| | - Xuan-Ping Liu
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.); (J.-L.Y.)
| | - Jie-Hau Li
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.); (J.-L.Y.)
| | - Chen-Jui Ho
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
| | - Meng-Han Tsai
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Jenq-Lin Yang
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.); (J.-L.Y.)
| | - Shu-Fang Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
| | - Nai-Ching Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
| | - Yao-Chung Chuang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.); (J.-L.Y.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Neurology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Biological Science, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
- Correspondence:
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Chehade M, Bullock M, Glover A, Hutvagner G, Sidhu S. Key MicroRNA's and Their Targetome in Adrenocortical Cancer. Cancers (Basel) 2020; 12:E2198. [PMID: 32781574 PMCID: PMC7465134 DOI: 10.3390/cancers12082198] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 12/23/2022] Open
Abstract
Adrenocortical Carcinoma (ACC) is a rare but aggressive malignancy with poor prognosis and limited response to available systemic therapies. Although complete surgical resection gives the best chance for long-term survival, ACC has a two-year recurrence rate of 50%, which poses a therapeutic challenge. High throughput analyses focused on characterizing the molecular signature of ACC have revealed specific micro-RNAs (miRNAs) that are associated with aggressive tumor phenotypes. MiRNAs are small non-coding RNA molecules that regulate gene expression by inhibiting mRNA translation or degrading mRNA transcripts and have been generally implicated in carcinogenesis. This review summarizes the current insights into dysregulated miRNAs in ACC tumorigenesis, their known functions, and specific targetomes. In addition, we explore the possibility of particular miRNAs to be exploited as clinical biomarkers in ACC and as potential therapeutics.
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Affiliation(s)
- Marthe Chehade
- Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia; (M.C.); (M.B.); (A.G.)
- Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, Sydney, NSW 2065, Australia
| | - Martyn Bullock
- Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia; (M.C.); (M.B.); (A.G.)
- Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, Sydney, NSW 2065, Australia
| | - Anthony Glover
- Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia; (M.C.); (M.B.); (A.G.)
- Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, Sydney, NSW 2065, Australia
- Endocrine Surgery Unit, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, St. Leonards, Sydney, NSW 2007, Australia
| | - Gyorgy Hutvagner
- School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Stan Sidhu
- Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia; (M.C.); (M.B.); (A.G.)
- Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, Sydney, NSW 2065, Australia
- Endocrine Surgery Unit, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, St. Leonards, Sydney, NSW 2007, Australia
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50
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Lin X, Dinglin X, Cao S, Zheng S, Wu C, Chen W, Li Q, Hu Q, Zheng F, Wu Z, Lin DC, Yao Y, Xu X, Xie Z, Liu Q, Yao H, Hu H. Enhancer-Driven lncRNA BDNF-AS Induces Endocrine Resistance and Malignant Progression of Breast Cancer through the RNH1/TRIM21/mTOR Cascade. Cell Rep 2020; 31:107753. [PMID: 32521278 DOI: 10.1016/j.celrep.2020.107753] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 04/20/2020] [Accepted: 05/19/2020] [Indexed: 12/12/2022] Open
Abstract
Epigenomic alterations can give rise to various tumor-promoting properties, including therapeutic resistance of cancer cells. Here, we identify an lncRNA, BDNF-AS, whose overexpression is specifically driven by a MEF2A-regulated enhancer in endocrine-resistant and triple-negative breast cancer (TNBC). High levels of BDNF-AS in breast cancer tissues not only feature endocrine resistance in hormone receptor (HR)-positive patients but also correlate with poor outcomes in both HR-positive and TNBC patients. Mechanistically, BDNF-AS acts as a molecular scaffold to promote RNH1 protein degradation via TRIM21-mediated ubiquitination of RNH1 at K225. Subsequently, BDNF-AS abolishes RNH1-regulated and RISC-mediated mTOR mRNA decay, therefore sustaining the activation of mTOR signaling. Importantly, mTOR inhibitor, but not PI3K inhibitor, could reverse tamoxifen resistance induced by the overexpression of BDNF-AS. These results point toward a master regulatory role of an enhancer-activated cascade of BDNF-AS/RNH1/TRIM21/mTOR in endocrine resistance and malignant progression of breast cancer.
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Affiliation(s)
- Xiaorong Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Diagnosis and Treatment Center of Breast Diseases, Shantou Affiliated Hospital, Sun Yat-sen University, Shantou 515031, People's Republic of China
| | - Xiaoxiao Dinglin
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Siting Cao
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510030, People's Republic of China
| | - Senyou Zheng
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Cheng Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510663, People's Republic of China
| | - Wenying Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Qingjian Li
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Qian Hu
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Fang Zheng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Zhiyong Wu
- Diagnosis and Treatment Center of Breast Diseases, Shantou Affiliated Hospital, Sun Yat-sen University, Shantou 515031, People's Republic of China
| | - De-Chen Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Yandan Yao
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Zhi Xie
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510663, People's Republic of China
| | - Qiang Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Herui Yao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China.
| | - Hai Hu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China.
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