To investigate the mechanism of lncRNA SNHG1 in the immune escape of breast cancer (BC).
SNHG1, miR-448 and IL-10 levels were evaluated by qRT-PCR. The protein levels of IDO and Foxp3 were measured ...by Western blot. SNHG1 and miR-448 interaction was tested by RIP assay and RNA pull-down assay. MiR-448 and IDO interaction was observed by luciferase reporter assay.
Compared with CD4+T cells, miR-448 expression in CD4+ TIL cells was decreased, while the expression of SNHG1, IDO, IL-10 and Foxp3 were increased. Moreover, SNHG1 directly contacted with miR-448, which could negatively regulate IDO. In cells treated with siRNA-SNHG and miR-448 inhibitor, interference SNHG1 up-regulated miR-448 expression and down-regulated IDO expression, while miR-448 inhibitor reversed this effect. In addition, miR-448 inhibitor reversed the inhibitory effect of siRNA-SNHG1 on Treg cell differentiation, and siRNA-SNHG1 could reduce tumor volume and down-regulated the expressions of SNHG1, IL-10, IDO and Foxp3.
Interference SNHG1 could inhibit the differentiation of Treg cells by promoting miR-448 expression and reducing IDO level, thereby impeding the immune escape of BC.
Cancer-associated fibroblasts (CAFs) are an essential component in the tumor microenvironment and have been reported to contribute to tumor progression through many mechanisms; however, the detailed ...mechanism underlying the immune-suppression effect of CAFs is not clearly defined. In this study, human breast cancer-derived CAFs were cultured, and CAF-derived exosomes in a culture medium were isolated. Using a miRNA profiles assay, we identify a significantly higher level of microRNA-92 isolated in CAFs exosomes. After treatment by CAF-derived exosomes, breast cancer cells express higher programmed cell death receptor ligand 1 (PD-L1), accompanied with increased miR-92 expression. Increased PD-L1 expression, which was induced by CAF-derived exosomes, significantly promotes apoptosis and impaired proliferation of T cells. The underlying mechanism of this effect was studied, proliferation and migration of breast cancer cells were increased after the transfection of miR-92, LATS2 was recognized as a target gene of miR-92, and further confirmed by a luciferase assay. Immunoprecipitation showed that LATS2 can interact with YAP1, chromatin immunoprecipitation confirmed that after nuclear translocation YAP1 could bind to the enhancer region of PD-L1 to promotes transcription activity. Furthermore, the animal study confirmed that CAFs significantly promoted tumor progression and impaired the function of tumor-infiltrated immune cells
. Our data revealed a novel mechanism that can induce immune suppression in the tumor microenvironment.
Mitochondria are the main source of reactive oxygen species (ROS) in cells. Early studies have shown that mitochondrial reactive oxygen species (mROS) are related to the occurrence and adverse ...outcomes of many diseases, and are thus regarded as an important risk factor that threaten human health. Recently, increasing evidence has shown that mROS are very important for an organism's homeostasis. mROS can regulate a variety of signaling pathways and activate the adaptation and protection behaviors of an organism under stress. In addition, mROS also regulate important physiological processes, such as cell proliferation, differentiation, aging, and apoptosis. Herein, we review the mechanisms of production, transformation, and clearance of mROS and their biological roles in different physiological processes.
Development of the acquired resistance is one major obstacle during chemotherapy for cancer patients. Exosomes mediate intercellular communication and cause environmental changes in tumor progression ...by transmitting active molecules. In this study, the role of long noncoding RNA H19 within exosomes is elucidated in terms of regulating doxorubicin (DOX) resistance of breast cancer. As a result, increased H19 expression was observed in DOX‐resistant breast cancer cells in comparison with the corresponding parental cells. Suppression of H19 significantly lowered DOX resistance by decreasing cell viability, lowering colony‐forming ability, and inducing apoptosis. Moreover, extracellular H19 could be moved to sensitive cells via being incorporated into exosomes. Treating sensitive cells with exosomes from resistant cells increased the chemoresistance of DOX, while downregulation of H19 in sensitive cells abated this effect. Taken together, H19 could be delivered by exosomes to sensitive cells, leading to the dissemination of DOX resistance. Our finding highlights the potential of exosomal H19 as a molecular target to reduce DOX resistance.
H19 knockdown induces DOX sensitivity in DOX‐resistant breast cancer cells. (A) qRT‐PCR analysis was performed to examine the knockdown efficiency of three siRNAs in MCF‐7/DOX and MDA‐MB‐231/DOX. (B and C) CCK‐8 assay was used to determine the effects of H19 depletion on cell viability and IC50 values in MCF‐7/DOX and MDA‐MB‐231/DOX cells after treatment with various concentrations of DOX. (D and E) Colony forming ability was detected in si‐NC‐ and or si‐H19#2‐transfected MCF‐7/DOX and MDA‐MB‐231/DOX cells upon DOX treatment. (F and G) MCF‐7/DOX and MDA‐MB‐231/DOX cells transfected with si‐NC or si‐H19#2 were treated with DOX for 48 hr, followed by flow cytometry analysis of apoptotic rate.
The dorsal striatum has emerged as a key region in sensory-guided, reward-driven decision making. A posterior sub-region of the dorsal striatum, the auditory striatum, receives convergent projections ...from both auditory thalamus and auditory cortex. How these pathways contribute to auditory striatal activity and function remains largely unknown. Here we show that chemogenetic inhibition of the projections from either the medial geniculate body (MGB) or primary auditory cortex (ACx) to auditory striatum in mice impairs performance in an auditory frequency discrimination task. While recording striatal sound responses, we find that transiently silencing the MGB projection reduced sound responses across a wide-range of frequencies in striatal medium spiny neurons. In contrast, transiently silencing the primary ACx projection diminish sound responses preferentially at the best frequencies in striatal medium spiny neurons. Together, our findings reveal that the MGB projection mainly functions as a gain controller, whereas the primary ACx projection provides tuning information for striatal sound representations.
Selective synthesis of higher oxygenates (linear α‐alcohols and α‐aldehydes, C2+
OH) from syngas is highly attractive but remains challenging owing to the low C2+
OH selectivity and low catalytic ...stability. Herein we introduce a multifunctional catalyst composed of CoMn and CuZnAlZr oxides that dramatically increased the oxygenates selectivity to 58.1 wt %, where more than 92.0 wt % of the produced oxygenates are C2+
OH. Notably, the total selectivity to value‐added chemicals including oxygenates and olefins reached 80.6 wt % at CO conversion of 29.0 % with high stability. The appropriate component proximity can effectively suppress the formation of the undesired C1 products, and the selectively propulsion of reaction network by synergetic effect of different components contributes to the enhanced selectivity to higher oxygenates. This work provides an alternative strategy for the rational design of new catalysts for direct conversion of syngas into higher oxygenates with co‐production of olefins.
A stable multifunctional catalyst composed of CoMn oxides and CuZnAlZr oxides was developed for direct conversion of syngas to higher oxygenates and olefins with a total selectivity of 80.6 wt % at a CO conversion of 29.0 %. The interaction manner of the two components plays a crucial role in suppressing C1 products formation and enhancing the selectivity to higher oxygenates.
Epigenetic mechanisms such as DNA methylation have the potential to affect organism acclimatization and adaptation to environmental changes by influencing their phenotypic plasticity; however, little ...is known about the role of methylation in the adaptive phenotypic divergence of marine invertebrates. Therefore, in this study, a typical intertidal species, the Pacific oyster (Crassostrea gigas), was selected to investigate the epigenetic mechanism of phenotypic plasticity in marine invertebrates. Intertidal and subtidal oysters subjected to one-generation common garden experiments and exhibited phenotypic divergence were used. The methylation landscape of both groups of oysters was investigated under temperate and high temperature. The two tidal oysters exhibited divergent methylation patterns, regardless of the temperature, which was mainly original environment-induced. Intertidal samples exhibited significant hypomethylation and more plasticity of methylation in response to heat shock, while subtidal samples showed hypermethylation and less plasticity. Combined with RNA-seq data, a positive relationship between methylation and expression in gene bodies was detected on a genome-wide scale. In addition, approximately 11% and 7% of differentially expressed genes showed significant methylation variation under high temperatures in intertidal and subtidal samples, respectively. Genes related to apoptosis and organism development may be regulated by methylation in response to high temperature in intertidal oysters, whereas oxidation-reduction and ion homeostasis-related genes were involved in subtidal oysters. The results also suggest that DNA methylation mediates phenotypic divergence in oysters adapting to different environments. This study provides new insight into the epigenetic mechanisms underlying phenotypic plasticity in adaptation to rapid climate change in marine organisms.
Revealing the mechanical role of long non-coding RNAs (lncRNAs) in tumorigenesis can contribute to novel therapeutic target for cancers. The regulatory role of linc01134 in hepatocellular carcinoma ...(HCC) has not been studied yet.
qRT-PCR and western blot were conducted to measure relevant RNA and protein expressions. CCK-8, colony formation, EdU, flow cytometry, wound-healing, transwell assays and xenograft experiments were performed to determine the role of linc01134 in HCC. ChIP and luciferase reporter assays were performed to analyze the effects of Yin Yang-1 (YY1) on linc01134 transcription activity. Relevant mechanical experiments were performed to verify interaction between relative genes.
YY1 enhanced linc01134 transcription by interacting with linc01134 promoter. Knockdown of linc01134 inhibited proliferation, migration and epithelial-mesenchymal transition (EMT), yet promoting apoptosis in HCC cells. Mechanically, linc01134 acted as miR-324-5p sponge and interacted with insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to increase the stability of YY1 mRNA expression. Up-regulated YY1 continuously stimulated linc01134 expression by enhancing linc01134 promoter activity, forming a positive feedback loop.
Linc01134/miR-324-5p/IGF2BP1/YY1 feedback loop mediates HCC progression, which possibly provide prognosis and treatment target of HCC.
Microglia are important for brain homeostasis and immunity, but their role in regulating vigilance remains unclear. We employed genetic, physiological, and metabolomic methods to examine microglial ...involvement in the regulation of wakefulness and sleep. Microglial depletion decreased stable nighttime wakefulness in mice by increasing transitions between wakefulness and non-rapid eye movement (NREM) sleep. Metabolomic analysis revealed that the sleep-wake behavior closely correlated with diurnal variation of the brain ceramide, which disappeared in microglia-depleted mice. Ceramide preferentially influenced microglia in the thalamic reticular nucleus (TRN), and local depletion of TRN microglia produced similar impaired wakefulness. Chemogenetic manipulations of anterior TRN neurons showed that they regulated transitions between wakefulness and NREM sleep. Their firing capacity was suppressed by both microglial depletion and added ceramide. In microglia-depleted mice, activating anterior TRN neurons or inhibiting ceramide production both restored stable wakefulness. These findings demonstrate that microglia can modulate stable wakefulness through anterior TRN neurons via ceramide signaling.
Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with a bad prognosis. Chemotherapy is still the standard of care for TNBC treatment. Circular RNAs (CircRNAs) ...have been recently discovered to be closely involved in the initiation and development of human cancers. Herein, we focus our attention on the functions and underlying mechanisms of circUBE2D2 in TNBC progression and chemoresistance.
The expression of circUBE2D2, miR-512-3p, and cell division cycle associated 3 (CDCA3) mRNA were determined by qRT-PCR. CCK-8, colony formation, transwell and flow cytometry assays were performed to detect cell proliferation, migration, invasion and apoptosis. Western blot assay was utilized to measure the protein level of CDCA3. RNA pull-down, luciferase reporter and RIP experiments were employed to examine the possible regulatory mechanism of circUBE2D2.
CircUBE2D2 expression was elevated in TNBC tissues and cells. TNBC patients with high circUBE2D2 expression are inclined to present advanced TNM stage, lymph node metastasis and adverse prognosis. Knockdown of circUBE2D2 repressed cell proliferation, migration and invasion in vitro, and impeded tumor growth in vivo. Moreover, silencing of circUBE2D2 reduced doxorubicin resistance of TNBC cells. In-depth mechanism analysis revealed that circUBE2D2 served as a miRNA sponge to protect CDCA3 from the attack of miR-512-3p. Additionally, the tumor-suppressive effect induced by circUBE2D2 depletion was greatly impaired upon miR512-3p down-regulation or CDCA3 overexpression. Also, depletion of circUBE2D2 decreased the resistance to doxorubicin through regulating miR-512-3p/CDCA3 axis.
CircUBE2D2 promoted TNBC progression and doxorubicin resistance through acting as a sponge of miR-512-3p to up-regulate CDCA3 expression. Targeting circUBE2D2 combine with doxorubicin might be exploited as a novel therapy for TNBC.
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