Effect of ubiquitin-specific proteinase 43 on ovarian serous adenocarcinoma and its clinical significance.

BACKGROUND: Ovarian cancer stands as a highly aggressive malignancy. The core aim of this investigation is to uncover genes pivotal to the progression and prognosis of ovarian cancer, while delving deep into the intricate mechanisms that govern their impact. METHODS: The study entailed the retrieval of RNA-seq data and survival data from the XENA database. Outliers were meticulously excluded in accordance with TCGA guidelines and through principal components analysis. The R package 'deseq2' was harnessed to extract differentially expressed genes. WGCNA was employed to prioritise these genes, and Cox regression analysis and survival analysis based on disease-specific time were conducted to identify significant genes. Immunohistochemistry validation was undertaken to confirm the distinct expression of USP43. Furthermore, the influence of USP43 on the biological functions of ovarian cancer cells was explored using techniques such as RNA interference, western blotting, scratch assays, and matrigel invasion assays. The examination of immune infiltration was facilitated via CIBERSORT. RESULTS: The study unearthed 5195 differentially expressed genes between ovarian cancer and normal tissue, comprising 3416 up-regulated and 1779 down-regulated genes. WGCNA pinpointed 204 genes most intimately tied to tumorigenesis. The previously undisclosed gene USP43 exhibited heightened expression in tumour tissues and exhibited associations with overall survival and disease-specific survival. USP43 emerged as a driver of cell migration (43.27 ± 3.91% vs 19.69 ± 1.94%) and invasion ability (314 ± 32 vs 131 ± 12) through the mechanism of epithelial mesenchymal transition, potentially mediated by the KRAS pathway. USP43 was also identified as a booster of CD4+ T memory resting cell infiltration, while concurrently reducing M1 macrophages within cancer, thereby fostering a milieu with relatively immune suppressive traits. Interestingly, USP43 demonstrated connections with epigenetically regulated-mRNAsi, although not with mRNAsi. CONCLUSION: This study underscores the role of USP43 in facilitating tumour migration and invasion. It postulates USP43 as a novel therapeutic target for ovarian cancer treatment.

Ovarian cancer is the most deadly tumour among all gynecological tumours. Thus we tried to explore the relevant mechanism of ovarian cancer because its occurrence and development mechanism has not been fully elucidated. We used bioinformatics methods to perform differential gene analysis on ovarian cancer tissues and normal tissues, and used methods such as WGCNA and COX regression analysis to find the gene USP43 related to tumour development and prognosis. USP43 is a gene that has not been studied in ovarian cancer before. Through RNA interference technology, we found that it can promote the migration and invasion ability of ovarian cancer and promote epithelial-mesenchymal transition of ovarian cancer cells. In addition, this gene has also been proven to be related to tumour immunity and tumour stemness. These results indicate that USP43 can promote the tumorigenesis of ovarian cancer and can be used as a drug target.

Resveratrol attenuates inflammation and fibrosis in rheumatoid arthritis-associated interstitial lung disease via the AKT/TMEM175 pathway.

BACKGROUND AND PURPOSE: Interstitial lung disease (ILD) represents a significant complication of rheumatoid arthritis (RA) that lacks effective treatment options. This study aimed to investigate the intrinsic mechanism by which resveratrol attenuates rheumatoid arthritis complicated with interstitial lung disease through the AKT/TMEM175 pathway. METHODS: We established an arthritis model by combining chicken type II collagen and complete Freund's adjuvant. Resveratrol treatment was administered via tube feeding for 10 days. Pathological changes in both the joints and lungs were evaluated using HE and Masson staining techniques. Protein expression of TGF-ß1, AKT, and TMEM175 was examined in lung tissue. MRC-5 cells were stimulated using IL-1ß in combination with TGF-ß1 as an in vitro model of RA-ILD, and agonists of AKT, metabolic inhibitors, and SiRNA of TMEM175 were used to explore the regulation and mechanism of action of resveratrol RA-ILD. RESULTS: Resveratrol mitigates fibrosis in rheumatoid arthritis-associated interstitial lung disease and reduces oxidative stress and inflammation in RA-ILD. Furthermore, resveratrol restored cellular autophagy. When combined with the in vitro model, it was further demonstrated that resveratrol could suppress TGF-ß1 expression, and reduce AKT metamorphic activation, consequently inhibiting the opening of AKT/MEM175 ion channels. This, in turn, lowers lysosomal pH and enhances the fusion of autophagosomes with lysosomes, ultimately ameliorating the progression of RA-ILD. CONCLUSION: In this study, we demonstrated that resveratrol restores autophagic flux through the AKT/MEM175 pathway to attenuate inflammation as well as fibrosis in RA-ILD by combining in vivo and in vitro experiments. It further provides a theoretical basis for the selection of therapeutic targets for RA-ILD.