Pan-cancer analysis of NUP155 and validation of its role in breast cancer cell proliferation, migration, and apoptosis.

NUP155 is reported to be correlated with tumor development. However, the role of NUP155 in tumor physiology and the tumor immune microenvironment (TIME) has not been previously examined. This study comprehensively investigated the expression, immunological function, and prognostic significance of NUP155 in different cancer types. Bioinformatics analysis revealed that NUP155 was upregulated in 26 types of cancer. Additionally, NUP155 upregulation was strongly correlated with advanced pathological or clinical stages and poor prognosis in several cancers. Furthermore, NUP155 was significantly and positively correlated with DNA methylation, tumor mutational burden, microsatellite instability, and stemness score in most cancers. Additionally, NUP155 was also found to be involved in TIME and closely associated with tumor infiltrating immune cells and immunoregulation-related genes. Functional enrichment analysis revealed a strong correlation between NUP155 and immunomodulatory pathways, especially antigen processing and presentation. The role of NUP155 in breast cancer has not been examined. This study, for the first time, demonstrated that NUP155 was upregulated in breast invasive carcinoma (BRCA) cells and revealed its oncogenic role in BRCA using molecular biology experiments. Thus, our study highlights the potential value of NUP155 as a biomarker in the assessment of prognostic prediction, tumor microenvironment and immunotherapeutic response in pan-cancer.

Electroacupuncture Promotes Skeletal Muscle Myogenic Differentiation and Protein Synthesis by Reducing Let-7c-5p Levels.

Objective: Acupuncture with low-frequency electrical stimulation (Acu-LFES) can attenuate muscle atrophy. Previous studies have found that Acu-LFES reduces the let-7 family in serum exosomes. This study explored the effects of let-7c-5p in chronic kidney disease (CKD) muscle atrophy. Methods: A total of 24 mice were randomly divided into control group, Acu-LFES group, CKD group, and CKD/Acu-LFES group (n = 6/group). The 5/6 nephrectomy was performed to establish the CKD model in mice. After 20 weeks, the Acu-LFES group and CKD/Acu-LFES group were treated with electroacupuncture at the "Zu San Li" and "Yang Ling Quan" bilaterally points for 15 minutes once. Surface sensing of translation (SUnSET), Reverse Transcription-quantitative PCR(RT-qPCR), immunofluorescence staining, and Western blot were performed to examine each group's state of protein production and myogenic differentiation. we knocked down or exogenously expressed let-7c-5p in C2C12 myoblast, RT-qPCR, and Western blot were performed to examine protein synthesis and myogenic differentiation. Results: The protein expressions of MyoD and Myogenin (MyoG) were decreased in the CKD group (P = .029 and P = .026) concomitant with a decrease in the muscle fiber cross-sectional area. Acu-LFES prevented muscle atrophy in CKD mice. The protein expressions of MyoD and MyoG were increased in the CKD/Acu-LFES group (P = .006 and P = .001). In muscle of CKD mice, IGF1, IGF1R, IRS1, phosphorylated mTOR and P70S6K proteins were decreased compared with control muscle (P = .001, P = .007, P < .001, P < .001 and P < .001), whereas atrogin-1/MAFbx and MuRF1 were dramatically increased (P < .001). Acu-LFES reversed these phenomena, indicating IGF1/mTOR signaling pathway was induced to promote muscle protein synthesis and myogenic differentiation. Meanwhile, Acu-LFES caused a decrease of let-7c-5p in skeletal muscle of CKD mice (P = .034). Inhibiting let-7c-5p promoted C2C12 myogenic differentiation (P = .002 and P = .001) and increased IGF1, IGF1R, IRS1 levels while upregulating mTOR and P70S6K phosphorylation (P < .001, P = .002, P = .009, P < .001 and P = .007). It is interesting to observe that the abundance of atrogin-1/MAFbx and MuRF-1 was unaffected by let-7c-5p (P > .05). Conclusions: Acu-LFES-reduced expression of let-7c-5p can ameliorate CKD-induced skeletal muscle atrophy by upregulating the IGF1/mTOR signaling pathway, which enhances skeletal muscle protein synthesis and myogenic differentiation. Let-7c-5p may be a potential regulator for the treatment of muscle atrophy.

TcpC inhibits neutrophil extracellular trap formation by enhancing ubiquitination mediated degradation of peptidylarginine deiminase 4.

TcpC is a multifunctional virulence factor of uropathogenic E. coli (UPEC). Neutrophil extracellular trap formation (NETosis) is a crucial anti-infection mechanism of neutrophils. Here we show the influence of TcpC on NETosis and related mechanisms. We show NETosis in the context of a pyelonephritis mouse model induced by TcpC-secreting wild-type E. coli CFT073 (CFT073wt) and LPS-induced in vitro NETosis with CFT073wt or recombinant TcpC (rTcpC)-treated neutrophils are inhibited. rTcpC enters neutrophils through caveolin-mediated endocytosis and inhibits LPS-induced production of ROS, proinflammatory cytokines and protein but not mRNA levels of peptidylarginine deiminase 4 (PAD4). rTcpC treatment enhances PAD4 ubiquitination and accumulation in proteasomes. Moreover, in vitro ubiquitination kit analyses show that TcpC is a PAD4-targetd E3 ubiquitin-ligase. These data suggest that TcpC inhibits NETosis primarily by serving as an E3 ligase that promotes degradation of PAD4. Our findings provide a novel mechanism underlying TcpC-mediated innate immune evasion.