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1.
PLoS Pathog ; 19(1): e1011131, 2023 01.
Article in English | MEDLINE | ID: mdl-36701392

ABSTRACT

The rapid emergence of SARS-CoV-2 variants of concern, the complexity of infection, and the functional redundancy of host factors, underscore an urgent need for broad-spectrum antivirals against the continuous COVID-19 pandemic, with drug repurposing as a viable therapeutic strategy. Here we report the potential of RNA G-quadruplex (RG4)-targeting therapeutic strategy for SARS-CoV-2 entry. Combining bioinformatics, biochemical and biophysical approaches, we characterize the existence of RG4s in several SARS-CoV-2 host factors. In silico screening followed by experimental validation identify Topotecan (TPT) and Berbamine (BBM), two clinical approved drugs, as RG4-stabilizing agents with repurposing potential for COVID-19. Both TPT and BBM can reduce the protein level of RG4-containing host factors, including ACE2, AXL, FURIN, and TMPRSS2. Intriguingly, TPT and BBM block SARS-CoV-2 pseudovirus entry into target cells in vitro and murine tissues in vivo. These findings emphasize the significance of RG4 in SARS-CoV-2 pathogenesis and provide a potential broad-spectrum antiviral strategy for COVID-19 prevention and treatment.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Animals , Mice , SARS-CoV-2/metabolism , RNA , Pandemics , Antiviral Agents/metabolism , Virus Internalization , Spike Glycoprotein, Coronavirus
2.
Hepatology ; 79(1): 79-95, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-37125628

ABSTRACT

BACKGROUND AND AIMS: Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes and emerge as a class of crucial yet less characterized oncogenic drivers. However, the structure, composition, genome-wide frequency, and contribution of eccDNAs in HCC, one of the most fatal and prevalent cancers, remain unexplored. In this study, we provide a comprehensive characterization of eccDNAs in human HCC and demonstrate an oncogenic role of microRNA (miRNA)-17-92-containing eccDNAs in tumor progression. APPROACH AND RESULTS: Using the circle-sequencing method, we identify and characterize more than 230,000 eccDNAs from 4 paired samples of HCC tumor and adjacent nontumor liver tissues. EccDNAs are highly enriched in HCC tumors, preferentially originate from certain chromosomal hotspots, and are correlated with differential gene expression. Particularly, a series of eccDNAs carrying the miRNA-17-92 cluster are validated by outward PCR and Sanger sequencing. Quantitative PCR analyses reveal that miRNA-17-92-containing eccDNAs, along with the expression of their corresponding miRNAs, are elevated in HCC tumors and associated with poor outcomes and the age of HCC patients. More intriguingly, exogenous expression of artificial DNA circles harboring the miR-17-92 cluster, which is synthesized by the ligase-assisted minicircle accumulation method, can significantly accelerate HCC cell proliferation and migration. CONCLUSIONS: These findings delineate the genome-wide eccDNAs profiling of HCC and highlight the functional significance of miRNA-containing eccDNAs in tumorigenesis, providing insight into HCC pathogenesis and cancer therapy, as well as eccDNA and miRNA biology.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , MicroRNAs , Multigene Family , Humans , Carcinoma, Hepatocellular/genetics , DNA, Circular/genetics , Liver Neoplasms/genetics , MicroRNAs/genetics , Polymerase Chain Reaction
3.
Cell Immunol ; 401-402: 104845, 2024.
Article in English | MEDLINE | ID: mdl-38909549

ABSTRACT

CD147 is a T cell activation-associated molecule which is closely involved in the formation of the immune synapse (IS). However, the precise role of CD147 in T cell activation and IS formation remains unclear. In the present study, we demonstrated that CD147 translocated to the IS upon T cell activation and was primarily distributed in the peripheral super molecular cluster (p-SMAC). The knock down of CD147 expression in T cells, but not in B cells, impaired IS formation. CD147 participated in IS formation between T cells and different types of antigen-presenting cells (APCs), including macrophages and dendritic cells. Ligation of CD147 with its monoclonal antibody (mAb) HAb18 effectively inhibited T cell activation and IL-2 secretion. CD98, a critical molecule interacting with CD147, was distributed in IS in a CD147-dependent way. Phosphorylation levels of T cell receptor (TCR) related molecules, like ZAP-70, ERK, and cJun, were down-regulated by CD147 ligation, which is crucial for the interaction of CD147 and TCR signaling transduction. CD147 is indispensable for the formation of immune synapses and plays an important role in the regulation of its function.


Subject(s)
Basigin , Immunological Synapses , Lymphocyte Activation , T-Lymphocytes , Basigin/metabolism , Basigin/immunology , Immunological Synapses/metabolism , Immunological Synapses/immunology , Lymphocyte Activation/immunology , Humans , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Signal Transduction/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Phosphorylation , Antibodies, Monoclonal/immunology , Macrophages/immunology , Macrophages/metabolism , B-Lymphocytes/immunology , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Interleukin-2/metabolism , Interleukin-2/immunology , Animals , Jurkat Cells
4.
Cardiovasc Diabetol ; 23(1): 344, 2024 Sep 16.
Article in English | MEDLINE | ID: mdl-39285459

ABSTRACT

Diabetic macroangiopathy is a leading cause of diabetes-related mortality worldwide. Both genetic and environmental factors, through a multitude of underlying molecular mechanisms, contribute to the pathogenesis of diabetic macroangiopathy. MicroRNAs (miRNAs), a class of non-coding RNAs known for their functional diversity and expression specificity, are increasingly recognized for their roles in the initiation and progression of diabetes and diabetic macroangiopathy. In this review, we will describe the biogenesis of miRNAs, and summarize their functions in diabetic macroangiopathy, including atherosclerosis, peripheral artery disease, coronary artery disease, and cerebrovascular disease, which are anticipated to provide new insights into future perspectives of miRNAs in basic, translational and clinical research, ultimately advancing the diagnosis, prevention, and treatment of diabetic macroangiopathy.


Subject(s)
Diabetic Angiopathies , MicroRNAs , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Diabetic Angiopathies/genetics , Diabetic Angiopathies/diagnosis , Diabetic Angiopathies/therapy , Animals , Gene Expression Regulation , Genetic Markers , Prognosis , Signal Transduction , Coronary Artery Disease/genetics , Coronary Artery Disease/therapy , Peripheral Arterial Disease/genetics , Peripheral Arterial Disease/therapy , Peripheral Arterial Disease/diagnosis
5.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 53(4): 460-471, 2024 Aug 25.
Article in English, Zh | MEDLINE | ID: mdl-39183055

ABSTRACT

OBJECTIVES: To investigate the expression of signal recognition particle 14 (SRP14) in hepatocellular carcinoma (HCC) and its clinical significance. METHODS: The data of SRP14 expression in HCC were obtained from bioinformatics study, and from investigation with quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemical staining and Western blotting in clinical samples. The Kaplan-Meier analysis was used to determine the associations between SRP14 mRNA expression and the overall survival, progression-free survival, and disease-specific survival of HCC patients. The effect of SRP14 on the proliferation and migration of HCC cells were determined by EdU staining, MTS, Transwell and wound-healing assays. The potential mechanism for SRP14 regulating HCC was explored through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis as well as qRT-PCR. RESULTS: According to the data from GSE14520, TNMplot database and clinical samples, compared with paired tumor-adjacent tissues, non-paired tumor-adjacent tissues and normal tissues, the mRNA expression of SPR14 in HCC tissues was upregulated (all P<0.05). In clinical samples, compared with paired tumor-adjacent tissues, the protein expression of SPR14 in HCC tissues was increased (P<0.05). The increased mRNA expression of SRP14 was associated with good overall survival, progression-free survival, and disease-specific survival in HCC patients. SRP14 inhibited the proliferation and migration of HCC cells in vitro. According to the KEGG and GO enrichment analysis, in non-specific HCC, the genes co-expressed with SRP14 may predominantly regulate protein synthesis, processing, and transport, while in nonalcoholic fatty liver disease related HCC, the genes co-expressed with SRP14 could control multiple signaling pathways such as MAPK, cAMP, PI3K-Akt, and Wnt. Mechanistically, SRP14 up-regulated the mRNA expression of tumor suppressor gene GPRC5A inHCC cells (P<0.05). CONCLUSIONS: SRP14 may regulate HCC progression and influence patient prognosis.


Subject(s)
Carcinoma, Hepatocellular , Cell Proliferation , Disease Progression , Liver Neoplasms , Female , Humans , Male , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/mortality , Cell Line, Tumor , Cell Movement , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/genetics , Liver Neoplasms/mortality , Prognosis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Recognition Particle/metabolism , Signal Recognition Particle/genetics
6.
Hum Mol Genet ; 30(5): 321-330, 2021 04 27.
Article in English | MEDLINE | ID: mdl-33481017

ABSTRACT

Most genetic variants for colorectal cancer (CRC) identified in genome-wide association studies (GWAS) are located in intergenic regions, implying pathogenic dysregulations of gene expression. However, comprehensive assessments of target genes in CRC remain to be explored. We conducted a multi-omics analysis using transcriptome and/or DNA methylation data from the Genotype-Tissue Expression, The Cancer Genome Atlas and the Colonomics projects. We identified 116 putative target genes for 45 GWAS-identified variants. Using summary-data-based Mendelian randomization approach (SMR), we demonstrated that the CRC susceptibility for 29 out of the 45 CRC variants may be mediated by cis-effects on gene regulation. At a cutoff of the Bonferroni-corrected PSMR < 0.05, we determined 66 putative susceptibility genes, including 39 genes that have not been previously reported. We further performed in vitro assays for two selected genes, DIP2B and SFMBT1, and provide functional evidence that they play a vital role in colorectal carcinogenesis via disrupting cell behavior, including migration, invasion and epithelial-mesenchymal transition. Our study reveals a large number of putative novel susceptibility genes and provides additional insight into the underlying mechanisms for CRC genetic risk loci.


Subject(s)
Carcinogenesis/genetics , Colorectal Neoplasms/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Nerve Tissue Proteins/genetics , Repressor Proteins/genetics , Transcriptome , Cell Line, Tumor , Cell Proliferation , DNA Methylation , Gene Expression Regulation, Neoplastic , Genome , Genome-Wide Association Study , Humans , Polymorphism, Single Nucleotide , Risk Factors
7.
PLoS Biol ; 18(2): e3000603, 2020 02.
Article in English | MEDLINE | ID: mdl-32092075

ABSTRACT

Type 2 diabetes (T2D) is characterized by insulin resistance along with pancreatic ß cell failure. ß cell factors are traditionally thought to control glucose homeostasis by modulating insulin levels, not insulin sensitivity. Exosomes are emerging as new regulators of intercellular communication. However, the role of ß-cell-derived exosomes in metabolic homeostasis is poorly understood. Here, we report that microRNA-26a (miR-26a) in ß cells not only modulates insulin secretion and ß cell replication in an autocrine manner but also regulates peripheral insulin sensitivity in a paracrine manner through circulating exosomes. MiR-26a is reduced in serum exosomes of overweight humans and is inversely correlated with clinical features of T2D. Moreover, miR-26a is down-regulated in serum exosomes and islets of obese mice. Using miR-26a knockin and knockout mouse models, we showed that miR-26a in ß cells alleviates obesity-induced insulin resistance and hyperinsulinemia. Mechanistically, miR-26a in ß cells enhances peripheral insulin sensitivity via exosomes. Meanwhile, miR-26a prevents hyperinsulinemia through targeting several critical regulators of insulin secretion and ß cell proliferation. These findings provide a new paradigm for the far-reaching systemic functions of ß cells and offer opportunities for the treatment of T2D.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Insulin Resistance , Insulin-Secreting Cells/metabolism , MicroRNAs/metabolism , Animals , Cell Proliferation , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/genetics , Exosomes/metabolism , Gene Expression , Gene Expression Regulation , Glucose/metabolism , Humans , Hyperinsulinism/prevention & control , Hyperplasia/prevention & control , Insulin/metabolism , Insulin-Secreting Cells/pathology , Male , Mice , Mice, Obese , Mice, Transgenic , MicroRNAs/blood , MicroRNAs/genetics , Paracrine Communication , Signal Transduction
8.
Mol Ther ; 30(4): 1754-1774, 2022 04 06.
Article in English | MEDLINE | ID: mdl-35077860

ABSTRACT

Acute pancreatitis (AP) is a common digestive disease without specific treatment, and its pathogenesis features multiple deleterious amplification loops dependent on translation, triggered by cytosolic Ca2+ ([Ca2+]i) overload; however, the underlying mechanisms in Ca2+ overload of AP remains incompletely understood. Here we show that microRNA-26a (miR-26a) inhibits pancreatic acinar cell (PAC) store-operated Ca2+ entry (SOCE) channel expression, Ca2+ overload, and AP. We find that major SOCE channels are post-transcriptionally induced in PACs during AP, whereas miR-26a expression is reduced in experimental and human AP and correlated with AP severity. Mechanistically, miR-26a simultaneously targets Trpc3 and Trpc6 SOCE channels and attenuates physiological oscillations and pathological elevations of [Ca2+]i in PACs. MiR-26a deficiency increases SOCE channel expression and [Ca2+]i overload, and significantly exacerbates AP. Conversely, global or PAC-specific overexpression of miR-26a in mice ameliorates pancreatic edema, neutrophil infiltration, acinar necrosis, and systemic inflammation, accompanied with remarkable improvements on pathological determinants related with [Ca2+]i overload. Moreover, pancreatic or systemic administration of an miR-26a mimic to mice significantly alleviates experimental AP. These findings reveal a previously unknown mechanism underlying AP pathogenesis, establish a critical role for miR-26a in Ca2+ signaling in the exocrine pancreas, and identify a potential target for the treatment of AP.


Subject(s)
MicroRNAs , Pancreatitis , Acinar Cells/metabolism , Acute Disease , Animals , Calcium/metabolism , Calcium Signaling , Humans , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Pancreatitis/genetics , Pancreatitis/metabolism , Pancreatitis/pathology
9.
Int J Med Sci ; 20(12): 1644-1661, 2023.
Article in English | MEDLINE | ID: mdl-37859703

ABSTRACT

Numerous preclinical models have been developed to advance biomedical research in type 1 diabetes mellitus (T1DM). They are essential for improving our knowledge of T1DM development and progression, allowing researchers to identify potential therapeutic targets and evaluate the effectiveness of new medications. A deeper comprehension of these models themselves is critical not only to determine the optimal strategies for their utilization but also to fully unlock their potential applications in both basic and translational research. Here, we will comprehensively summarize and discuss the applications, advantages, and limitations of the commonly used animal models for human T1DM and also overview the up-to-date human tissue bioengineering models for the investigation of T1DM. By combining these models with a better understanding of the pathophysiology of T1DM, we can enhance our insights into disease initiation and development, ultimately leading to improved therapeutic responses and outcomes.


Subject(s)
Biomedical Research , Diabetes Mellitus, Type 1 , Animals , Humans , Diabetes Mellitus, Type 1/drug therapy , Models, Animal
10.
Gut ; 71(2): 322-332, 2022 02.
Article in English | MEDLINE | ID: mdl-33632712

ABSTRACT

OBJECTIVE: The systemic spread of colorectal cancer (CRC) is dominated by the portal system and exhibits diverse patterns of metastasis without systematical genomic investigation. Here, we evaluated the genomic evolution of CRC with multiorgan metastases using multiregion sequencing. DESIGN: Whole-exome sequencing was performed on multiple regions (n=74) of matched primary tumour, adjacent non-cancerous mucosa, liver metastasis and lung metastasis from six patients with CRC. Phylogenetic reconstruction and evolutionary analyses were used to investigate the metastatic seeding pattern and clonal origin. Recurrent driver gene mutations were analysed across patients and validated in two independent cohorts. Metastatic assays were performed to examine the effect of the novel driver gene on the malignant behaviour of CRC cells. RESULTS: Based on the migration patterns and clonal origins, three models were revealed (sequential, branch-off and diaspora), which not only supported the anatomic assumption that CRC cells spread to lung after clonally expanding in the liver, but also illustrated the direct seeding of extrahepatic metastases from primary tumours independently. Unlike other cancer types, polyphyletic seeding occurs in CRC, which may result in late metastases with intermetastatic driver gene heterogeneity. In cases with rapid dissemination, we found recurrent trunk loss-of-function mutations in ZFP36L2, which is enriched in metastatic CRC and associated with poor overall survival. CRISPR/Cas9-mediated knockout of ZFP36L2 enhances the metastatic potential of CRC cells. CONCLUSION: Our results provide genomic evidence for metastatic evolution and indicate that biopsy/sequencing of metastases may be considered for patients with CRC with multiorgan or late postoperative metastasis.


Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/secondary , Liver Neoplasms/secondary , Lung Neoplasms/secondary , Mutation/genetics , Transcription Factors/genetics , China , Cohort Studies , Evolution, Molecular , Humans , Liver Neoplasms/genetics , Lung Neoplasms/genetics , Models, Genetic , Exome Sequencing
11.
Hepatology ; 73(4): 1327-1345, 2021 04.
Article in English | MEDLINE | ID: mdl-32567701

ABSTRACT

BACKGROUND AND AIMS: Endoplasmic reticulum (ER) stress is an adaptive response to excessive ER demand and contributes to the development of numerous diseases, including nonalcoholic fatty liver disease (NAFLD), which is hallmarked by the accumulation of lipid within hepatocytes. However, the underlying mechanisms remain elusive. MicroRNAs (miRNAs) play an indispensable role in various stress responses, but their implications in ER stress have not yet been systemically investigated. In this study, we identify a negative feedback loop consisting of hepatic ER stress and miR-26a in NAFLD pathogenesis. APPROACH AND RESULTS: Combining miRNA dot blot array and quantitative PCR, we find that miR-26a is specifically induced by ER stress in liver cells. This induction of miR-26a is critical for cells to cope with ER stress. In human hepatoma cells and murine primary hepatocytes, overexpression of miR-26a markedly alleviates chemical-induced ER stress, as well as palmitate-triggered ER stress and lipid accumulation. Conversely, deficiency of miR-26a exhibits opposite effects. Mechanistically, miR-26a directly targets the eukaryotic initiation factor 2α, a core ER stress effector controlling cellular translation. Intriguingly, miR-26a is reduced in the livers of patients with NAFLD. Hepatocyte-specific restoration of miR-26a in mice significantly mitigates high-fat diet-induced ER stress and hepatic steatosis. In contrast, deficiency of miR-26a in mice exacerbates high-fat diet-induced ER stress, lipid accumulation, inflammation and hepatic steatosis. CONCLUSIONS: Our findings suggest ER stress-induced miR-26a up-regulation as a regulator for hepatic ER stress resolution, and highlight the ER stress/miR-26a/eukaryotic initiation factor 2α cascade as a promising therapeutic strategy for NAFLD.


Subject(s)
Endoplasmic Reticulum Stress , MicroRNAs , Non-alcoholic Fatty Liver Disease , Animals , Cells, Cultured , Diet, High-Fat/adverse effects , Disease Models, Animal , Endoplasmic Reticulum Stress/drug effects , Endoplasmic Reticulum Stress/genetics , Endoplasmic Reticulum Stress/physiology , Eukaryotic Initiation Factor-2/metabolism , Feedback, Physiological/physiology , Hepatocytes/metabolism , Hepatocytes/physiology , Humans , Lipogenesis/physiology , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Mice, Transgenic , MicroRNAs/biosynthesis , MicroRNAs/genetics , MicroRNAs/metabolism , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/physiopathology , Obesity/complications , Obesity/metabolism , Obesity/physiopathology , Up-Regulation
12.
Dig Dis Sci ; 67(5): 1879-1889, 2022 05.
Article in English | MEDLINE | ID: mdl-33939149

ABSTRACT

BACKGROUND/AIMS: Stress hyperglycemia is common in critical illness but it has not been clearly studied in patients with acute pancreatitis (AP). This study aimed to investigate the specific blood glucose (BG) level that defines stress hyperglycemia and to determine the impact of stress hyperglycemia on clinical outcomes in AP patients. METHODS: AP patients admitted ≤ 48 h after abdominal pain onset were retrospectively analyzed. Patients were stratified by pre-existing diabetes and stress hyperglycemia was defined using stratified BG levels for non-diabetes and diabetes with clinical outcomes compared. RESULTS: There were 967 non-diabetic and 114 diabetic (10.5%) patients met the inclusion criteria and the clinical outcomes between these two groups were not significantly different. In non-diabetes, the cut-off BG level of ≥ 180 mg/dl was selected to define stress hyperglycemia with an 8.8-fold higher odds ratio for persistent organ failure (POF) (95% CI 5.4-14.3; P < 0.001). For diabetes, ≥ 300 mg/dl was selected with a 7.5-fold higher odds ratio for POF (95% CI 1.7-34.3; P = 0.009). In multivariable logistic regression, stress hyperglycemia was independently associated with POF, acute necrotic collection, major infection and mortality. The combination of BG and systemic inflammatory response syndrome (SIRS) score in predicting POF was better than SIRS or Glasgow score alone. CONCLUSIONS: This study identifies a cut-off BG level of ≥ 180 mg/dl and ≥ 300 mg/dl was optimal to define stress hyperglycemia for non-diabetic and diabetic AP patients, respectively. There was a significant relationship between stress hyperglycemia and adverse clinical outcomes.


Subject(s)
Diabetes Mellitus , Hyperglycemia , Pancreatitis , Acute Disease , Blood Glucose , Humans , Hyperglycemia/complications , Hyperglycemia/epidemiology , Pancreatitis/complications , Retrospective Studies , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/epidemiology
13.
Trends Biochem Sci ; 41(10): 818-821, 2016 10.
Article in English | MEDLINE | ID: mdl-27503842

ABSTRACT

Translation is a crucial step in transmitting genetic information from mRNA to functional protein. Four recent papers provide novel imaging approaches to directly observe translation of single mRNAs in real time in live cells, and represent a powerful toolkit to dissect the molecular mechanisms of translation regulation.


Subject(s)
Molecular Imaging/methods , Protein Biosynthesis , RNA, Messenger/genetics , Ribosomes/chemistry , Cell Line, Tumor , Fluorescent Dyes/chemistry , HEK293 Cells , Humans , Immunoglobulin Fab Fragments/chemistry , RNA, Messenger/metabolism , Staining and Labeling/methods , Time-Lapse Imaging
14.
Mol Cancer ; 19(1): 149, 2020 10 14.
Article in English | MEDLINE | ID: mdl-33054773

ABSTRACT

Renal cell carcinoma (RCC) is the most common malignant kidney tumor and has a high incidence rate. Circular RNAs (circRNAs) are noncoding RNAs with widespread distribution and diverse cellular functions. They are highly stable and have organ- and tissue-specific expression patterns. CircRNAs have essential functions as microRNA sponges, RNA-binding protein- and transcriptional regulators, and protein translation templates. Recent reports have shown that circRNAs are abnormally expressed in RCC and act as important regulators of RCC carcinogenesis and progression. Moreover, circRNAs have emerged as potential biomarkers for RCC diagnosis and prognosis and targets for developing new treatments. However, further studies are needed to better understand the functions of circRNAs in RCC. In this review, we summarize and discuss the recent research progress on RCC-associated circRNAs, with a focus on their potential for RCC diagnosis and targeted therapy.


Subject(s)
Biomarkers, Tumor/genetics , Carcinogenesis/pathology , Carcinoma, Renal Cell/pathology , Gene Expression Regulation, Neoplastic , Kidney Neoplasms/pathology , RNA, Circular/genetics , Carcinogenesis/genetics , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/therapy , Disease Progression , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/therapy
15.
Mol Cancer ; 19(1): 145, 2020 09 24.
Article in English | MEDLINE | ID: mdl-32972405

ABSTRACT

As a point of convergence for numerous oncogenic signaling pathways, signal transducer and activator of transcription 3 (STAT3) is central in regulating the anti-tumor immune response. STAT3 is broadly hyperactivated both in cancer and non-cancerous cells within the tumor ecosystem and plays important roles in inhibiting the expression of crucial immune activation regulators and promoting the production of immunosuppressive factors. Therefore, targeting the STAT3 signaling pathway has emerged as a promising therapeutic strategy for numerous cancers. In this review, we outline the importance of STAT3 signaling pathway in tumorigenesis and its immune regulation, and highlight the current status for the development of STAT3-targeting therapeutic approaches. We also summarize and discuss recent advances in STAT3-based combination immunotherapy in detail. These endeavors provide new insights into the translational application of STAT3 in cancer and may contribute to the promotion of more effective treatments toward malignancies.


Subject(s)
Immunotherapy , Molecular Targeted Therapy , Neoplasms/therapy , STAT3 Transcription Factor/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Humans , Immunity/drug effects , Immunity/immunology , Neoplasms/genetics , Neoplasms/immunology , STAT3 Transcription Factor/immunology , Signal Transduction/drug effects , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology
16.
J Hepatol ; 73(2): 371-382, 2020 08.
Article in English | MEDLINE | ID: mdl-32165252

ABSTRACT

BACKGROUND & AIMS: RNA G-quadruplexes (RG4s) appear to be important in post-transcriptional gene regulation, but their pathophysiological functions remain unknown. MicroRNA-26a (miR-26a) is emerging as a therapeutic target for various human diseases, however the mechanisms underlying endogenous miR-26a regulation are poorly understood. Herein, we study the role of RG4 in miR-26a expression and function in vitro and in vivo. METHODS: Putative RG4s within liver-enriched miRNAs were predicted by bioinformatic analysis, and the presence of an RG4 structure in the miR-26a-1 precursor (pre-miR-26a-1) was further analyzed by biophysical and biochemical methods. RG4 stabilizers, pre-miR-26a-1 overexpression plasmids, and luciferase reporter assays were used to assess the effect of RG4 on pre-miR-26a-1 maturation. Both miR-26a knock-in and knockout mouse models were employed to investigate the influence of this RG4 on miR-26a expression and function. Moreover, the interaction between RG4 in pre-miR-26a-1 and DEAH-box helicase 36 (DHX36) was determined by biophysical and molecular methods. Finally, miR-26a processing and DHX36 expression were quantified in the livers of obese mice. RESULTS: We identify a guanine-rich sequence in pre-miR-26a-1 that can fold into an RG4 structure. This RG4 impairs pre-miR-26a-1 maturation, resulting in a decrease in miR-26a expression and subsequently an increase in miR-26a cognate targets. In line with known miR-26a functions, this RG4 can regulate hepatic insulin sensitivity and lipid metabolism in vitro and in vivo. Furthermore, we reveal that DHX36 can bind and unwind this RG4 structure, thereby enhancing miR-26a maturation. Intriguingly, there is a concordant decrease of miR-26a maturation and DHX36 expression in obese mouse livers. CONCLUSIONS: Our findings define a dynamic DHX36/RG4/miR-26a regulatory axis during obesity, highlighting an important role of RG4 in physiology and pathology. LAY SUMMARY: Specific RNA sequences called G-quadruplexes (or RG4) appear to be important in post-transcriptional gene regulation. Obesity leads to the formation of these RG4 structures in pre-miR-26a-1 molecules, impairing the maturation and function of miR-26a, which has emerged as a therapeutic target in several diseases. This contributes to hepatic insulin resistance and the dysregulation of liver metabolism.


Subject(s)
DEAD-box RNA Helicases/metabolism , G-Quadruplexes , Liver/metabolism , MicroRNAs/metabolism , Obesity/metabolism , Animals , Computational Biology/methods , Drug Discovery/methods , Gene Expression Regulation , Gene Knock-In Techniques/methods , Gene Knockout Techniques/methods , Insulin Resistance/genetics , Mice , Models, Animal , Molecular Structure
17.
Hepatology ; 70(1): 215-230, 2019 07.
Article in English | MEDLINE | ID: mdl-30839115

ABSTRACT

Metastasis is the main cause of cancer-related death, yet the underlying mechanisms are still poorly understood. Long noncoding RNAs (lncRNAs) are emerging as crucial regulators of malignancies; however, their functions in tumor metastasis remain largely unexplored. In this study, we identify a lncRNA, termed metabolism-induced tumor activator 1 (MITA1), which is up-regulated in hepatocellular carcinoma (HCC) and contributes to metastasis. MITA1, a chromatin-enriched lncRNA discovered by our nuclear RNA sequencing, is significantly induced by energy stress. This induction of MITA1 is governed by the liver kinase B1-adenosine monophosphate-activated protein kinase (LKB1-AMPK) pathway and DNA methylation. Knockdown of MITA1 dramatically inhibits the migration and invasion of liver cancer cells in vitro and HCC metastasis in vivo. Mechanistically, MITA1 promotes the epithelial-mesenchymal transition, an early and central step of metastasis, which may partly attribute to an increase in Slug (snail family zinc finger 2) transcription. MITA1 deficiency reduces the expression of the mesenchymal cell markers, especially Slug, whereas Slug overexpression greatly impairs the effects of MITA1 deficiency on HCC migration and invasion. Correspondingly, there is a positive correlation between the levels of MITA1 and Slug precursors in HCC tissues. Conclusion: Our data reveal MITA1 as a crucial driver of HCC metastasis, and highlight the identified AMPK-MITA1-Slug axis as a potential therapeutic strategy for HCC.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Epithelial-Mesenchymal Transition , Liver Neoplasms/metabolism , Neoplasm Metastasis , RNA, Long Noncoding/metabolism , A549 Cells , AMP-Activated Protein Kinase Kinases , Adenylate Kinase/metabolism , DNA Methylation , Energy Metabolism , Hep G2 Cells , Humans , Protein Serine-Threonine Kinases/metabolism , Snail Family Transcription Factors/metabolism
18.
Kidney Blood Press Res ; 44(3): 287-297, 2019.
Article in English | MEDLINE | ID: mdl-31163420

ABSTRACT

MicroRNAs (miRNAs) are short, single-stranded, noncoding RNAs that modulate many key biological processes by simultaneously suppressing multiple target genes. Among them, miR-26a, a conserved miRNA among vertebrates, is highly expressed in various tissues. Accumulating evidence demonstrates that miR-26a plays pivotal roles in cellular differentiation, cell growth, apoptosis, and metastasis, thereby participating in the initiation and development of various human diseases, such as metabolic disease and cancer. More recently, miR-26a was found as a versatile regulator of renal biology and disease. miR-26a is intensively involved in the maintenance of podocyte homeostasis and the actin cytoskeleton. It is also able to modulate the homeostasis and function of mesangial cells. In addition, miR-26a affects the expansion of regulatory T cells in the context of ischemia-reperfusion injury and autoimmune diabetes and thus protects the renal system from immune attack. These available data strongly suggest that renal miR-26a possesses critical pathological functions and represents a potential target for renal disease therapies. This review summarizes current knowledge of miR-26a in renal biology and disease, laying the foundation for exploring its previously unknown functions and mechanisms in the renal system.


Subject(s)
Kidney Diseases/pathology , Kidney/physiology , MicroRNAs/physiology , Animals , Homeostasis , Humans , Mesangial Cells , Podocytes , T-Lymphocytes, Regulatory
20.
Proc Natl Acad Sci U S A ; 110(44): 17892-7, 2013 Oct 29.
Article in English | MEDLINE | ID: mdl-24114270

ABSTRACT

Ten eleven translocation (TET) enzymes (TET1/TET2/TET3) and thymine DNA glycosylase (TDG) play crucial roles in early embryonic and germ cell development by mediating DNA demethylation. However, the molecular mechanisms that regulate TETs/TDG expression and their role in cellular differentiation, including that of the pancreas, are not known. Here, we report that (i) TET1/2/3 and TDG can be direct targets of the microRNA miR-26a, (ii) murine TETs, especially TET2 and TDG, are down-regulated in islets during postnatal differentiation, whereas miR-26a is up-regulated, (iii) changes in 5-hydroxymethylcytosine accompany changes in TET mRNA levels, (iv) these changes in mRNA and 5-hydroxymethylcytosine are also seen in an in vitro differentiation system initiated with FACS-sorted adult ductal progenitor-like cells, and (v) overexpression of miR-26a in mice increases postnatal islet cell number in vivo and endocrine/acinar colonies in vitro. These results establish a previously unknown link between miRNAs and TET expression levels, and suggest a potential role for miR-26a and TET family proteins in pancreatic cell differentiation.


Subject(s)
Cell Differentiation/physiology , DNA-Binding Proteins/metabolism , Epigenesis, Genetic/physiology , Gene Expression Regulation, Developmental/physiology , Islets of Langerhans/physiology , MicroRNAs/metabolism , Proto-Oncogene Proteins/metabolism , Thymine DNA Glycosylase/metabolism , 5-Methylcytosine/analogs & derivatives , Animals , Cytosine/analogs & derivatives , Dioxygenases , Flow Cytometry , Islets of Langerhans/enzymology , Luciferases , Mice , Mice, Transgenic , Microfluidics , Real-Time Polymerase Chain Reaction
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