Circular RNA (circRNA) is a class of noncoding RNA whose functions remain mostly unknown. Recent studies indicate circRNA may be involved in disease pathogenesis, but direct evidence is scarce. Here, ...we characterize the functional role of a novel circRNA, circCCDC66, in colorectal cancer. RNA-Seq data from matched normal and tumor colon tissue samples identified numerous circRNAs specifically elevated in cancer cells, several of which were verified by quantitative RT-PCR. CircCCDC66 expression was elevated in polyps and colon cancer and was associated with poor prognosis. Gain-of-function and loss-of-function studies in colorectal cancer cell lines demonstrated that circCCDC66 controlled multiple pathological processes, including cell proliferation, migration, invasion, and anchorage-independent growth. In-depth characterization revealed that circCCDC66 exerts its function via regulation of a subset of oncogenes, and knockdown of circCCDC66 inhibited tumor growth and cancer invasion in xenograft and orthotopic mouse models, respectively. Taken together, these findings highlight a novel oncogenic function of circRNA in cancer progression and metastasis.
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A growing body of evidence indicates that circular RNAs are not simply a side product of splicing but a new class of noncoding RNAs in higher eukaryotes. The progression for the studies of circular ...RNAs is accelerated by combination of several advanced technologies such as next generation sequencing, gene silencing (small interfering RNAs) and editing (CRISPR/Cas9). More and more studies showed that dysregulated expression of circular RNAs plays critical roles during the development of several human diseases. Herein, we review the current advance of circular RNAs for their biosynthesis, molecular functions, and implications in human diseases.
Impact statement
The accumulating evidence indicate that circular RNA (circRNA) is a novel class of noncoding RNA with diverse molecular functions. Our review summarizes the current hypotheses for the models of circRNA biosynthesis including the direct interaction between upstream and downstream introns and lariat-driven circularization. In addition, molecular functions such as a decoy of microRNA (miRNA) termed miRNA sponge, transcriptional regulator, and protein-like modulator are also discussed. Finally, we reviewed the potential roles of circRNAs in neural system, cardiovascular system as well as cancers. These should provide insightful information for studying the regulation and functions of circRNA in other model of human diseases.
Abstract
Psychosocial and behavioral interventions have been shown to significantly reduce depressive and anxiety symptoms in different populations. Recent evidence suggests that the mental health of ...the general population has deteriorated significantly since the start of Coronavirus Disease 2019 (COVID-19) pandemic. We conducted a systematic review and meta-analysis of studies on the therapeutic effects of psychosocial and behavioral interventions on depression and anxiety during the COVID-19 pandemic. We systematically searched six electronic databases between December 2019 and February 2022 including PubMed, PsycINFO, Scopus, Web of Science, CNKI, and Wanfang Data. We included randomized clinical trials of psychosocial and behavioral interventions in individuals with depressive or anxiety symptoms during the COVID-19 outbreak compared to various control conditions. A total of 35 eligible studies with 5457 participants were included. The meta-analysis results showed that psychosocial and behavioral interventions had statistically significant moderate effects on depression SMD = − 0.73, 95% CI (− 1.01, − 0.45),
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= 90% and large effects on anxiety SMD = − 0.90, 95% CI (− 1.19, − 0.60),
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= 92%, especially in the general population and COVID-19 survivors. Exercise and cognitive behavioral therapy were found to be the most effective treatments with moderate-to-large effect size for depression and anxiety during the outbreak of COVID-19. We also found the internet-based approach could also achieve almost equally significant effects on depression and anxiety compared with face-to-face traditional approach. Our findings suggest that cognitive behavioral therapy and physical exercise intervention are significantly effective for depression and anxiety related to the COVID-19 pandemic regardless of the delivery modes, and gender differences should be taken into consideration for better implementation of interventions in clinical and community practice.
Hypoxia occurs in a wide variety of physiological and pathological conditions, including tumorigenesis. Tumor cells have to adapt to hypoxia by altering their gene expression and protein synthesis. ...Here, we showed that hypoxia inhibits translation through activation of PERK and inactivation of mTOR in human colon cancer HCT116 cells. Prolonged hypoxia (1% O2, 16 h) dramatically inhibits general translation in HCT116 cells, yet selected mRNAs remain efficiently translated under such a condition. Using microarray analysis of polysome- associated mRNAs, we identified a large number of hypoxia-regulated genes at the translational level. Efficiently translated mRNAs during hypoxia were validated by polysome profiling and quantitative real-time RT-PCR. Pathway enrichment analysis showed that many of the up-regulated genes are involved in lysosome, glycan and lipid metabolism, antigen presentation, cell adhesion, and remodeling of the extracellular matrix and cytoskeleton. The majority of down-regulated genes are involved in apoptosis, ubiquitin-mediated proteolysis, and oxidative phosphorylation. Further investigation showed that hypoxia induces lysosomal autophagy and mitochondrial dysfunction through translational regulation in HCT116 cells. The abundance of several translation factors and the mTOR kinase activity are involved in hypoxia-induced mitochondrial autophagy in HCT116 cells. Our studies highlight the importance of translational regulation for tumor cell adaptation to hypoxia.
Cancer development is a complex and heterogeneous process. It is estimated that 5-10% of human genes probably contribute to oncogenesis, whereas current experimentally validated cancer genes only ...cover 1% of the human genome. Thus hundreds of cancer genes may still remain to be identified. To search for new genes that play roles in carcinogenesis and facilitate cancer research, we developed a systematic workflow to use information saved in a previously established tumor-associated gene (TAG) database.
By exploiting the information of conserved protein domains from the TAG, we identified 183 potential new TAGs. As a proof-of-concept, one predicted oncogene, fyn-related kinase (FRK), which shows an aberrant digital expression pattern in liver cancer cells, was selected for further investigation. Using 68 paired hepatocellular carcinoma samples, we found that FRK was up-regulated in 52% of cases (P < 0.001). Tumorigenic assays performed in Hep3B and HepG2 cell lines revealed a significant correlation between the level of FRK expression and invasiveness, suggesting that FRK is a positive regulator of invasiveness in liver cancer cells.
These findings implied that FRK is a multitalented signal transduction molecule that produces diverse biological responses in different cell types in various microenvironments. In addition, our data demonstrated the accuracy of computational prediction and suggested that other predicted TAGs can be potential targets for future cancer research.
The TAG database is available online at the Bioinformatics Center website: http://www.binfo.ncku.edu.tw/TAG/.
Conspecific male animals fight for resources such as food and mating opportunities but typically stop fighting after assessing their relative fighting abilities to avoid serious injuries. ...Physiologically, how the fighting behavior is controlled remains unknown. Using the fighting fish Betta splendens, we studied behavioral and brain-transcriptomic changes during the fight between the two opponents. At the behavioral level, surface-breathing, and biting/striking occurred only during intervals between mouth-locking. Eventually, the behaviors of the two opponents became synchronized, with each pair showing a unique behavioral pattern. At the physiological level, we examined the expression patterns of 23,306 brain transcripts using RNA-sequencing data from brains of fighting pairs after a 20-min (D20) and a 60-min (D60) fight. The two opponents in each D60 fighting pair showed a strong gene expression correlation, whereas those in D20 fighting pairs showed a weak correlation. Moreover, each fighting pair in the D60 group showed pair-specific gene expression patterns in a grade of membership analysis (GoM) and were grouped as a pair in the heatmap clustering. The observed pair-specific individualization in brain-transcriptomic synchronization (PIBS) suggested that this synchronization provides a physiological basis for the behavioral synchronization. An analysis using the synchronized genes in fighting pairs of the D60 group found genes enriched for ion transport, synaptic function, and learning and memory. Brain-transcriptomic synchronization could be a general phenomenon and may provide a new cornerstone with which to investigate coordinating and sustaining social interactions between two interacting partners of vertebrates.
•ApoE-4 impacts molecular and neurocognitive indices in individuals with a ADFH.•ADFH individuals with ApoE-4 show deviant task-set and memory updating processes.•Cardiorespiratory fitness levels ...were correlated with levels of Aβ1–42 in ADFH.
The present study examined whether the ɛ4 allele of the apolipoprotein E (ApoE) gene impacts molecular biomarkers and neurocognitive performance among individuals at genetic risk for developing Alzheimer's disease (AD). The correlations between physical fitness and molecular/neurocognitive indices were also explored.
Fasting blood samples were collected from 162 individuals with a family history of AD (ADFH). There were twenty-two carriers of the ApoE-4 variant (ApoE-4 group). For comparison purposes we randomly selected 22 non-ɛ4 carriers (non-ApoE-4 group) from the ADFH individuals. Circulating inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IL-8, and IL-15), neuroprotective growth factors (e.g., BDNF, IGF-1, IGF-2, VEGF, and FGF-2), and Amyloid-β peptides (e.g., Aβ1–40 and Aβ1–42), neurocognitive performance e.g., behavior and brain even-related potentials (ERP) during a task-switching paradigm, as well as physical fitness scores were measured.
The ApoE-4 group relative to the non-ApoE-4 group was similar with respect to molecular biomarkers, physical fitness, and most measures of neurocognitive performance. However, ADFH individuals that were ɛ4 carriers exhibited significantly higher local switching accuracy costs, worse accuracy as well as smaller ERP P3 amplitudes for the memory-switching condition. Importantly, cardiorespiratory fitness levels were significantly correlated with accuracy for most task-switching conditions, and levels of BDNF, Aβ1–40, and Aβ1–42 collapsed across the two groups even when controlling for the age co-variable, while the ApoE-4 group revealed similar pattern of results.
These data suggest that individuals with ADFH that were carriers of the ApoE-4 variant performed worse on the task-switching paradigm and that this could be due to compromised task-set and memory updating processes. Physical exercise interventions aimed to enhance cardiorespiratory fitness levels could be a potential AD prevention strategy for ameliorating cognitive function and reducing the accumulation of the Aβ peptides in this high risk group.
The cytosolic DNA sensor cGMP-AMP synthase (cGAS) synthesizes the noncanonical cyclic dinucleotide 2′3′-cGAMP to activate the adaptor protein stimulator of IFN genes (STING), thus awakening host ...immunity in response to DNA pathogen infection. However, dengue virus (DENV), an RNA virus without a DNA stage in its life cycle, also manipulates cGAS-STING–mediated innate immunity by proteolytic degradation of STING. Here, we found that the sensitivity of STING to DENV protease varied with different human STING haplotypes. Exogenous DNA further enhanced DENV protease’s ability to interact and cleave protease-sensitive STING. DNA-enhanced STING cleavage was reduced in cGAS-knockdown cells and triggered by the cGAS product 2′3′-cGAMP. The source of DNA may not be endogenous mitochondrial DNA but rather exogenous reactivated viral DNA. Cells producing 2′3′-cGAMP by overexpressing cGAS or with DNA virus reactivation enhanced STING cleavage in neighboring cells harboring DENV protease. DENV infection reduced host innate immunity in cells with the protease-sensitive STING haplotype, whose homozygote genotype frequency was found significantly reduced in Taiwanese people with dengue fever. Therefore, the human STING genetic background and DNA pathogen coinfection may be the missing links contributing to DENV pathogenesis.
Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. ...Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2-derived prostaglandin E
, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE
biosynthesis or signal transduction ameliorated loss-of-DUSP2-induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia-induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens.
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