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Background: Lung cancer is the most prevalent cancer worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of all cases. Circular RNAs(circRNA) play crucial roles in regulating the progression of lung cancer. Despite the identification of a large number of circRNAs, their expression patterns, functions, and mechanisms of action in NSCLC development remain unclear.This study aims to investigate the transcriptional expressions, functions, and potential mechanisms of circRNA hsa_circ_0050386 in NSCLC. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized for the analysis of hsa_circ_0050386 expression. Cell proliferation was detected using the IncuCyte Live Cell Analysis System and clone formation assays. Migration and invasion of NSCLC cells were evaluated through Transwell assays. Flow cytometry was performed to assay cell cycle and apoptosis. Western blot was used to investigate protein expression. Protein binding analysis was conducted by employing pull-down assays, RNA immunoprecipitation (RIP), and mass spectrometry. The role of hsa_circ_0050386 in vivo was evaluated through the use of a xenograft model. Results: The study discovered that hsa_circ_0050386 displayed lower expression levels in NSCLC tissues when compared to adjacent normal tissues. Patients exhibiting lower levels of hsa_circ_0050386 expression exhibited an inverse correlation with the Clinical Stage, T-stage, and M-stage of NSCLC. Functionally, hsa_circ_0050386 suppressed the proliferation and invasion of NSCLC cells both in vitro and in vivo. A comprehensive examination exposed the interaction between hsa_circ_0050386 and RNA binding protein Serine and arginine-rich splicing factor 3 (SRSF3), resulting in the down-regulation of Fibronectin 1 (FN1) expression, which inhibits the progression of NSCLC. Conclusions: Our study shows that hsa_circ_0050386 suppresses the malignant biological behavior of NSCLC cells by down-regulating the expression of FN1, and may serve as a potential biomarker and therapeutic target for NSCLC treatment. [ABSTRACT FROM AUTHOR]

Background: The epithelial-mesenchymal transition (EMT) plays an indispensable role in the development and progression of Endometrial cancer (EC). Nevertheless, little evidence is reported to uncover the functionality and application of EMT-related molecules in the prognosis of EC. This study aims to develop novel molecular markers for prognosis prediction in patients with EC. Methods: RNA sequencing profiles of EC patients obtained from The Cancer Genome Atlas (TCGA) database were used to screen differential expression genes (DEGs) between tumors and normal tissues. The Cox regression model with the LASSO method was utilized to identify survival-related DEGs and to establish a prognostic signature whose performance was evaluated by Kaplan–Meier curve, receiver operating characteristic (ROC) and calibration curve. Eventually, functional enrichment analysis and cellular experiments were performed to reveal the roles of prognosis-related genes in EC progression. Results: A total of 540 EMT-related DEGs in EC were screened, and subsequently a four-gene risk signature comprising SIRT2, SIX1, CDKN2A and PGR was established to predict overall survival of EC. This risk signature could serve as a meaningfully independent indicator for EC prognosis via multivariate Cox regression (HR = 2.002, 95%CI = 1.433–2.798; P < 0.001). The nomogram integrating the risk signature and clinical characteristics exhibited robust validity and performance at predicting EC overall survival indicated by ROC and calibration curve. Functional enrichment analysis revealed that the EMT-related genes risk signature was associated with extracellular matrix organization, mesenchymal development and cellular component morphogenesis, suggesting its possible relevance to epithelial-mesenchymal transition and cancer progression. Functionally, we demonstrated that the silencing of SIX1, SIRT2 and CDKN2A expression could accelerate the migratory and invasive capacities of tumor cells, whereas the downregulation of PGR dramatically inhibited cancer cells migration and invasion. Conclusions: Altogether, a novel four-EMT-related genes signature was a potential biomarker for EC prognosis. These findings might help to ameliorate the individualized prognostication and therapeutic treatment of EC patients. [ABSTRACT FROM AUTHOR]

Background: The miRNA profile is changed after burn or sepsis and is involved in regulating inflammatory reactions. However, the function and molecular mechanism of miRNAs in regulating burn sepsis-induced acute kidney injury (AKI) are still unclear. Methods: In this study, animal and cell sepsis models were established after burned rats were injected with lipopolysaccharide (LPS) or NRK-52E cells treated with LPS, respectively. Cytokine expression, inflammatory cell infiltration, serum creatinine (Scr) and kidney injury molecule-1 (KIM-1) levels were analysed after the indicated treatments. Results: Burn sepsis increased the expression of inflammatory factors (TNF-α and IL-1β) and chemokines (MIP-1α, MIP-2 and MCP-1). Moreover, burn sepsis promoted macrophage and neutrophil infiltration into the kidney and upregulated the levels of Scr and KIM-1 in the kidney and urine. Ectopic expression of miR-181c significantly reduced LPS-induced TLR4 protein expression, suppressed KIM-1 mRNA levels and subsequently inhibited the activation of inflammatory genes (TNF-α and IL-1β) and chemokine genes (MIP-1α, MIP-2 and MCP-1). Conclusions: Our results demonstrated that miR-181c could suppress TLR4 expression, reduce inflammatory factor and chemokine secretion, mitigate inflammatory cell infiltration into the kidney and downregulate KIM-1 expression, which might ultimately attenuate burn sepsis-induced AKI. [ABSTRACT FROM AUTHOR]

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Background: Severe burns are a common and highly lethal trauma. The key step for severe burn therapy is to promote the wound healing as early as possible, and reports indicate that mesenchymal stem cell (MSC) therapy contributes to facilitate wound healing. In this study, we investigated effect of human umbilical cord MSCs (hUC-MSCs) could on wound healing in a rat model of severe burn and its potential mechanism. Methods: Adult male Wistar rats were randomly divided into sham, burn, and burn transplanted hUC-MSCs. GFP labeled hUC-MSCs or PBS was intravenous injected into respective groups. The rate of wound closure was evaluated by Image Pro Plus. GFP-labeled hUC-MSCs were tracked by in vivo bioluminescence imaging (BLI), and human-specific DNA expression in wounds was detected by PCR. Inflammatory cells, neutrophils, macrophages, capillaries and collagen types I/III in wounds were evaluated by histochemical staining. Wound blood flow was evaluated by laser Doppler blood flow meter. The levels of proinflammatory and anti-inflammatory factors, VEGF, collagen types I/III in wounds were analyzed using an ELISA. Results: We found that wound healing was significantly accelerated in the hUC-MSC therapy group. The hUC-MSCs migrated into wound and remarkably decreased the quantity of infiltrated inflammatory cells and levels of IL-1, IL-6, TNF-α and increased levels of IL-10 and TSG-6 in wounds. Additionally, the neovascularization and levels of VEGF in wounds in the hUC-MSC therapy group were markedly higher than those in other control groups. The ratio of collagen types I and III in the hUC-MSC therapy group were markedly higher than that in the burn group at indicated time after transplantation. Conclusion: The study suggests that hUC-MSCs transplantation can effectively improve wound healing in severe burned rat model. Moreover, these data might provide the theoretical foundation for the further clinical application of hUC-MSC in burn areas. [ABSTRACT FROM AUTHOR]

Growth arrest and DNA damage (GADD) 45α is a member of GADD inducible gene family, and is inducible in cell response to oxidative stress. GADD45α upregulation induces MKK4/JNK activation in some published experimental systems. However, we found here that the depletion of GADD45α (GADD45α−/−) in mouse embryonic fibroblasts (MEFs) resulted in an increase in the phosphorylation of MKK4/7, MKK3/6 and consequently specific up-regulated the activation of JNK/p38 and their downstream transcription factors, such as c-Jun and ATF2, in comparison to those in GADD45α+/+ MEFs cell following nickel exposure. This up-regulation of MKK-JNK/p38 pathway in GADD45α−/− cell could be rescued by the reconstitutional expression of HA-GADD45α in GADD45α−/− MEFs, GADD45α−/−(HA-GADD45α). Subsequent studies indicated that GADD45α deletion repressed expression of PP2Cα, the phosphotase of MKK3/6 and MKK4/7, whereas ectopic expression of HA-PP2Cα in GADD45α−/− cells attenuated activation of MKK3/6-p38 and MKK4/7-JNK pathways. Collectively, our results demonstrate a novel function and mechanism responsible for GADD45α regulation of MKK/MAPK pathway, further provides insight into understanding the big picture of GADD45α in the regulation of cellular responses to oxidative stress and environmental carcinogens. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-1α (HIF-1α) has been reported to regulate over 100 gene expressions in response to hypoxia and other stress conditions. In the present study, we found that arsenite could induce HIF-1α protein accumulation in both mouse epidermal Cl41 cells and mouse embryonic fibroblasts (MEFs). Knockout of p85α, a regulatory subunit of PI-3K, in MEFs (p85α) dramatically decreased the arsenite-induced HIF-1α accumulation, indicating that p85α is crucial for arsenite effects on the stabilization of HIF-1α protein. Our further studies suggest that arsenite could induce inducible Hsp70 expression, and transfection of inducible Hsp70 into p85α MEFs could restore HIF-1α protein accumulation. Moreover, the results using EMSA and Supershift assays indicate that p85α is crucial for arsenite-induced activation of the heat-shock transcription factor 1 (HSF-1), which is responsible for transcription of inducible Hsp70. Taken together, p85α-mediated HIF-1α stabilization upon arsenite exposure is specifically through HSF-1 activation and subsequent up-regulation of the inducible Hsp70 expression. [ABSTRACT FROM AUTHOR]

The WW and C2 domain containing (WWC) protein family functions as scaffolds regulating cell proliferation and organ growth control through the Hippo signaling pathway. However, their pan-cancer dysregulation and mechanistic roles in signaling transduction have remained unclear. We performed integrated pan-cancer analyses of WWC family gene expression using data from The Cancer Genome Atlas (TCGA) across 33 different cancer types. Prognostic relevance was evaluated by survival analyses. WWC genetic alterations, DNA methylation, pathway activities, drug response, and tumor immunology were analyzed using online databases. Furthermore, we examined the functional roles of WWCs in lung cancer cells. We observed aberrant WWC expression in various cancers, which associated with patient prognosis. WWC hypermethylation occurred in many cancers and exhibited negative correlation with expression, alongside mutations linked to poor outcomes. Pathway analysis implicated WWCs as Hippo pathway scaffolds, while drug sensitivity analysis suggested associations with diverse chemotherapies. Additionally, pan-cancer analyses elucidated vital immunomodulatory roles for WWC through heterogeneous correlations with immune cell infiltrates, checkpoint molecules, tumor mutation burden, microsatellite instability, and chemokine pathways across cancers. Experimentally, WWCs suppressed lung cancer cell proliferation, migration, and invasion while enhancing apoptosis and paclitaxel chemosensitivity. Mechanistically, WWCs bound large tumor suppressor 1 and 2 (LATS1/2) kinases to stimulate phosphorylation cascades, thereby inhibiting nuclear translocation of the Yes-associated protein (YAP) oncoprotein. Taken together, our multi-omics characterization provides comprehensive evidence for WWCs as putative tumor suppressors across cancers via Hippo pathway modulation. WWCs may serve as prognostic markers and therapeutic targets in lung cancer. • WWC genes exhibit abnormal expression patterns across cancers and correlate with prognosis. • WWC mutations link to poor prognosis; WWC methylation elevated and negatively correlates with WWC expression. • WWC overexpression in lung cancer reduces proliferation, migration, invasion, and promotes chemotherapy drug sensitivity. • WWC genes bind LATS1/2 kinases to stimulate phosphorylation cascades, inhibiting YAP oncoprotein nuclear translocation. [ABSTRACT FROM AUTHOR]