USP9X inhibits metastasis in pulmonary sarcomatoid carcinoma by regulating epithelial-mesenchymal transition, angiogenesis and immune infiltration.

BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a highly invasive pulmonary malignancy with an extremely poor prognosis. The results of previous studies suggest that ubiquitin-specific peptidase 9X (USP9X) contributes to the progression of numerous types of cancer. Nevertheless, there is little knowledge about the molecular mechanisms and functions of USP9X in the metastasis of PSC. METHODS: Immunohistochemistry and western blotting were used to detect USP9X expression levels in PSC tissues and cells. Wound healing, transwell, enzyme-linked immunosorbent assay (ELISA), tube formation, and aortic ring assays were used to examine the function and mechanism of USP9X in the metastasis of PSC. RESULTS: Expression of USP9X was markedly decreased and significantly correlated with metastasis and prognosis of patients with PSC. Then we revealed that USP9X protein levels were negatively associated with the levels of epithelial-mesenchymal transition (EMT) markers and the migration of PSC cells. It was confirmed that USP9X in PSC cells reduced VEGF secretion and inhibited tubule formation of human umbilical vein endothelial cells (HUVEC) in vitro. USP9X was detected to downregulate MMP9. Meanwhile, MMP9 was positively related to EMT, angiogenesis and was negatively related to immune infiltration in the public databases. USP9X was significantly negatively associated with the expression of MMP9, EMT markers, CD31, and positively associated with CD4, and CD8 in PSC tissues. CONCLUSION: The present study reveals the vital role of USP9X in regulating EMT, angiogenesis and immune infiltration and inhibiting metastasis of PSC via downregulating MMP9, which provides a new effective therapeutic target for PSC.

The Deubiquitinating Enzyme UCHL1 Induces Resistance to Doxorubicin in HER2+ Breast Cancer by Promoting Free Fatty Acid Synthesis.

Ubiquitin C-terminal hydrolase L1 (UCHL1), which is a deubiquitinating enzyme, is known to play a role in chemoresistance in cancers. However, its potential roles and mechanisms in the chemoresistance of breast cancer (BC) remain unclear. In this study, we examined its expression in patients with BC and employed Kaplan-Meier analysis and the log-rank test for survival analyses. It was found that up-regulated UCHL1 expression was positively associated with both chemoresistance and poor prognosis, especially in patients with HER2+ BC. Moreover, UCHL1 expression was elevated in HER2+ BC cells (SK-BR-3 and BT474). Similarly, doxorubicin (DOX)-resistant BC cells (MCF-7/DOX) had higher UCHL1 levels than MCF-7 cells. CCK-8 assay showed that BC cells with higher UCHL1 levels were more resistant to DOX. Furthermore, by inhibiting UCHL1 in BC cells with elevated UCHL1 expression, we demonstrated that UCHL1 promoted DOX-resistance in BC. Mechanistically, UCHL1 probably promoted DOX-resistance of BC by up-regulating free fatty acid (FFA) synthesis, as exhibited by reduced FFA synthase expression and resurrected DOX-sensitivity upon UCHL1 inhibition. Overall, UCHL1 up-regulation is associated with DOX-resistance and poor prognosis in patients with HER2+ BC. UCHL1 induces DOX-resistance by up-regulating FFA synthesis in HER2+ BC cells. Thus, UCHL1 might be a potential clinical target for overcoming DOX resistance in patients with HER2+ BC.

Cable-car measurements of vertical aerosol profiles impacted by mountain-valley breezes in Lushan Mountain, East China.

In-situ field observations of vertical aerosol profiles for one month in complex terrain (Lushan Mountain, China) were carried out using a cable car, which resolved detailed vertical distributions of mountain aerosols with low-cost operation. Cable-car observations were conducted during the early morning and late afternoon, when mountain and valley winds dominated, respectively. The diurnal aerosol variations at the top and foot of Lushan Mountain were analyzed based on environmental and meteorological stations. The observations indicated that the mountain-valley breezes notably impacted the mountain-area aerosol distribution under weak weather conditions. More uniform aerosol profiles for the afternoon than the morning, with their decreasing rates of PM2.5 (particles with diameters less than 2.5 µm) were 1.64 and 2.28 µg m-3/100 m, respectively. The PM2.5/PM10 ratio at the mountain top increased from 0.69 to 0.81, and that at the mountain base decreased from 0.75 to 0.70 from morning to afternoon. The PM2.5 concentration decreased in and around Lushan Mountain from daytime to nighttime, with the impacted diameter of the 300-m topography line being smaller than ~5 km, while the concentration increased in Jiujiang City. The relative decreasing rate of PM2.5 was higher at the mountain top site (~20%) than at the base site (~2%) from daytime to nighttime. Moreover, uniform aerosol profiles could have been caused by regional transport through a relatively strong low-level synoptic flow (~5 m s-1) and the mountain's dynamic lifting effect.

USP5 Promotes Metastasis in Non-Small Cell Lung Cancer by Inducing Epithelial-Mesenchymal Transition via Wnt/ß-Catenin Pathway.

Ubiquitin-specific protease 5 (USP5) is a deubiquitinating enzyme that functions as an oncoprotein in a variety of human cancers. However, the expression and role of USP5 in the metastasis of non-small cell lung cancer (NSCLC) have not been addressed. In this study, we examined the expression and prognostic significance of USP5 in NSCLC. The results revealed that USP5 was overexpressed and correlated with metastasis and overall survival in NSCLC tissues. A further in vitro study revealed that the levels of USP5 protein in NSCLC cells were associated with epithelial-mesenchymal transition (EMT) markers. Furthermore, USP5 overexpression significantly enhanced, whereas USP5 silencing significantly decreased the expression of EMT proteins and migration and invasion of NSCLC cells. In addition, the results from western blotting demonstrated that USP5 regulated EMT via the Wnt/ß-catenin signaling pathway. Further immunohistochemical analysis revealed that USP5 was significantly associated with the expression of ß-catenin and EMT markers in NSCLC tissues. Overall, USP5 upregulation is associated with tumor metastasis and poor prognosis in patients with NSCLC. USP5 promotes EMT and the invasion and migration of NSCLC cells. Therefore, USP5 may serve as a novel prognostic biomarker and provide a potential target for the treatment of metastasis in NSCLC.

Corrigendum: USP5 Promotes Metastasis in Non-Small Cell Lung Cancer by Inducing Epithelial-Mesenchymal Transition via Wnt/ß-Catenin Pathway.

[This corrects the article DOI: 10.3389/fphar.2020.00668.].

Aircraft measurement campaign on summer cloud microphysical properties over the Tibetan Plateau.

We reported the first aircraft campaign on summer cloud microphysical properties conducted in July of 2014 over the Tibetan Plateau during the third Tibetan Plateau Atmospheric Sciences Experiment (TIPEX-III), and demonstrated that the summer clouds over the Tibetan Plateau were primarily characterized as mixed-phase cumulus clouds induced by strong solar radiation heating. Moreover, the characteristic number concentration of cloud droplets (2~50 µm in diameter) in developing cumuli was around 10 cm-3, which was about 1~2 orders of magnitudes lower than other continent and ocean regions, and that for large drops (>50 µm in diameter) was around 10-3 cm-3, which was also lower than other regions. The droplet spectrum distributions (DSDs) of cloud drops were much wider than other regions, indicating that the cumulus clouds over the plateau could form precipitation easier than that in other regions. Ice microphysics was characterized as very active glaciation and riming processes with high supercooled water content, which caused the formation of high concentration of graupel particles in clouds. The findings of this study suggest that these unique cloud microphysical properties formed by the high topography and clean environment of the Tibetan Plateau could induce higher precipitation efficiency when airflow passed over the plateau, so that the plateau could act as a regional "water tower".

MicroRNA-17-5p contributes to osteoarthritis progression by binding p62/SQSTM1.

Autophagy has been reported to be widely involved in the pathogenesis of osteoarthritis (OA). Increasing evidence suggested the important role of microRNAs (miRs) in the progression of OA. However, the functional role of miR-17-5p in OA development has remained to be fully elucidated. First, a mouse model of OA was established and the relative level of miR-17-5p was determined using PCR. Safranin O-fast green staining was applied to determine cartilage degeneration. TargetScan software and a dual luciferase reporter assay were applied to determine potential target genes of miR-17-5P. Autophagy measurement was performed using green fluorescent protein-microtubule-associated protein 1 light chain 3 (LC3) dot analysis. The results demonstrated that the relative expression of miR-17-5p was significantly decreased in OA model mice. In addition, the level of miR-17-5p was decreased in SW1353 human chondrosarcoma cells treated with interleukin-1ß. Furthermore, autophagy was found to be suppressed in the knee joints of experimental OA model mice. The dual luciferase reporter assay confirmed that p62/sequestosome 1 was a target gene of miR-17-5p. Of note, miR-17-5p inhibitor-induced reduction of LC3 dots was markedly reversed by knockdown of p62 in SW1353 cells. In conclusion, decreased miR-17-5p expression in chondrocytes induced autophagy mainly through suppressing the expression of p62, thereby contributing to OA progression.

Neuronal Nitric Oxide Synthase in Neural Stem Cells Induces Neuronal Fate Commitment via the Inhibition of Histone Deacetylase 2.

Active adult neurogenesis produces new functional neurons, which replace the lost ones and contribute to brain repair. Promoting neurogenesis may offer a therapeutic strategy for human diseases associated with neurodegeneration. Here, we report that endogenous neuronal nitric oxide synthase (nNOS) for neural stem cells (NSCs) or progenitors positively regulates neurogenesis. nNOS repression exhibits significantly decreased neuronal differentiation and nNOS upregulation promotes neurons production from NSCs. Using a quantitative approach, we show that instructive effect, that is instruction of NSCs to adopt a neuronal fate, contributes to the favorable effect of endogenous nNOS on neurogenesis. Furthermore, nNOS-mediated instruction of neuronal fate commitment is predominantly due to the reduction of histone deacetylase 2 (HDAC2) expression and enzymatic activity. Further investigation will be needed to test whether HDAC2 can serve as a new target for therapeutic intervention of neurodegenerative disorders.