Cellular signalling最新文献

Background: KIF3C serves as a motor protein that facilitates axonal transport in neuronal cells. It belongs to the kinesin superfamily and plays a crucial role in the development of various cancers. However, the role of KIF3C in gastric cancer (GC) the third-highest cause of cancer-related deaths remains unclear. To investigate the regulatory mechanisms and expression patterns of KIF3C in GC and their implications for GC progression, we conducted a series of in vitro and in vivo experiments.

Methods: We employed bioinformatics tools, including GEPIA, Kaplan-Meier plotter, and cBioPortal, to examine the role of KIF3C in GC, with a focus on its prognostic significance and associated signaling pathways. Furthermore, we conducted immunohistochemistry, real-time polymerase chain reaction (RT-PCR), western blot analyses, cell function and signaling pathway experiments. We further assessed the impact of combination therapy with afatinib and MT-DC (ac) phosphoramidite alongside KIF3C knockdown and overexpression in GC cells and a xenograft mouse model experiment.

Results: Kaplan-Meier and Cox regression analyses revealed that high KIF3C expression in GC is significantly associated with poor prognosis. Genomic alteration and immune microenvironment analyses provided insights into the underlying causes of abnormal KIF3C expression. We observed that KIF3C knockdown decreased the proliferation of GC tumor cells. Additionally, KIF3C was overexpressed in GC and elevated expression was significantly correlated with tumor prognosis. We demonstrated that KIF3C knockdown and overexpression could significantly inhibit and promote tumor cell proliferation, respectively, through the combination therapy by modulating PI3K, AKT, and cell cycle signaling pathways. Notably, tumor size and the number of GC nodules were significantly reduced in the Sh-KIF3C group compared to the Sh-ctrl group.

Conclusion: Our findings highlight the potential of KIF3C as a biomarker for tumor progression diagnosis, establishing it as a pivotal therapeutic target for combating tumor advancement in GC.

Background: Metabolic reprogramming, particularly glycolysis, is essential in processes like cancer and immune response. While FGF21's role in hepatocyte glucose metabolism has been linked to glucose transporters and its impact on aerobic glycolysis and cellular growth in HCC remain unclear. In this study, we investigated FGF21-mediated modulation of glucose metabolism in HCC through mTOR and HIF1α axis in HCC.

Methods: The study evaluated the dysregulation of FGF21 and its prognostic impact in HCC using various datasets. The literature review was done to identify glycolysis related genes to find significant interaction with FGF21 using stringdb and their correlation in datasets. The regulation of FGF21 was validated in HepG2 cell lines by transfecting FGF21 and measuring its effects on glycolysis, including glucose uptake, lactate levels, and key glycolytic enzymes using rt-PCR. Additionally, the effect of FGF21 transfection on mTOR and HIF1α was also evaluated using rt-PCR.

Results: The insilico analysis indicates that the FGF21-mTOR-HIF1α signaling axis regulates glucose metabolism, with mTOR as a central integrator of signals from FGF21 and HIF1α. Invitro experiments showed that silencing FGF21 expression via siRNA reduced glycolytic enzyme expression, glucose uptake, lactate levels, and cell proliferation in HepG2 cells. Conversely, recombinant FGF21 treatment has a reverse effect in HepG2 cells. Additionally, FGF21 treatment also affected mTOR and HIF1α expression, highlighting its role in metabolic regulation and disease through the mTOR-HIF1α axis.

Conclusion: The regulation of FGF21 influences glycolysis via the mTOR-HIF1α axis, highlighting its critical role in glucose metabolism and metabolic adaptation in response to energy availability.

Mitophagy serves as a mitochondrial quality control mechanism to maintain the homeostasis of mitochondria and the intracellular environment. Studies have shown that there is a close relationship between mitophagy and apoptosis. Sestrin2 (Sesn2) is a highly conserved class of stress-inducible proteins that play important roles in reducing oxidative stress damage, inflammation, and apoptosis. However, the potential mechanism of how Sesn2 regulates mitophagy and apoptosis in severe acute pancreatitis (SAP) remains unclear. In the study, RAW264.7 (macrophage cell Line) cellular inflammation model established by lipopolysaccharide (LPS) treatment as well as LPS and CAE-induced SAP mouse model (wild-type and Sen2 Knockout mouse) were used. Our study showed that LPS stimulation significantly increased the level of Sesn2 in RAW264.7 cells, Sesn2 increased mitochondrial membrane potential, decreased inflammation levels, mitochondrial superoxide levels and apoptosis, and also promoted monocyte macrophages toward the M2 anti-inflammatory phenotype, suggesting a protective effect of Sesn2 on mitochondria. Further, Sesn2 increased mitophagy and decreased apoptosis via modulating the PINK1-Parkin signaling. Meanwhile, knockout of Sesn2 exacerbated pancreatic, mitochondrial damage and inflammation in a mouse model of SAP. In addition, the protective effect of Sesn2 against SAP was shown to be associated with mitophagy conducted by the PINK1-Parkin pathway via inhibiting apoptosis. These findings reveal that Sesn2 in balancing mitochondrial autophagy and apoptosis by modulating the PINK1-Parkin signaling may present a new therapeutic strategy for the treatment of SAP.

The tumor susceptibility gene 101 (TSG101) was firstly identified as a tumor-inhibiting factor in 1996. Subsequent studies gradually revealed its crucial role in several important cellular processes, including cell survival, vesicle transportation, viral infection, etc. Additionally, TSG101 has been identified as an oncoprotein in certain tumorigenic processes. These conflicting findings suggest that TSG101 might exhibit tumor heterogeneity. Currently, the expression pattern and function of TSG101 in oral squamous cell carcinoma (OSCC) are still untouched. Herein, we reported that TSG101 expression is upregulated and is associated with poorer survival and a higher propensity for lymph node metastasis in OSCC patients. In vivo mouse models confirmed that TSG101 down-regulation effectively inhibited the pulmonary metastases of human OSCC cells. In vitro cell experiments not only proved that TSG101 knockdown significantly disrupted metastasis-related phenotypes in different OSCC cell lines, but also revealed that TSG101 possibly controls the cell cycle through regulating the transcription of Cyclin A/B to play these roles. Additionally, we further validated these findings with a mouse cell line and murine orthotopic OSCC models. Collectively, the oncoprotein function of TSG101 in OSCC is evident from this study. We offer fresh insights into the heterogeneity of TSG101 and highlight new potential targets for OSCC management.

Lung cancer is the primary cause of cancer-related deaths worldwide, particularly for non-small cell lung cancer (NSCLC). However, the exact mechanism underlying tumor formation remains unclear. It is widely acknowledged that inflammation and oxidative stress occur in the tumor microenvironment, promoting cell malignant growth and metastasis. Thioredoxin-1 (TXN), the main regulator of oxidative stress, plays a significant role in the development of NSCLC. However, the specific tumor-promoting mechanism is still being investigated. This study aimed to examine the function and mechanism of TXN in NSCLC. The effects of knockdown or overexpression TXN on cell proliferation, invasion and apoptosis were evaluated by Cell Counting Kit-8, colony formation, wound healing, transwell, TUNEL staining, and flow cytometric assays. Western blotting was performed to analyze the regulation of TXN and downstream proteins suppressed by genes and pharmacology. TXN knockdown significantly suppressed cell proliferation, invasion and promoted apoptosis both in vitro and in vivo, whereas TXN overexpression reversed these malignant phenotypes. We found that TXN regulated c-Myc expression through ERK1/2 and ERK5 signaling pathways. Suppressing ERK1/2 led to the compensatory activation of ERK5, and simultaneously inhibiting ERK1/2 and ERK5 synergistically reduced c-Myc expression, further attenuating cell proliferation, invasion and enhanced apoptosis. Our results indicated tumor promotion of TXN in NSCLC and TXN regulated c-Myc in the interest of tumorigenesis through ERK1/2 and ERK5 signaling pathways. Targeting TXN and blocking the ERK1/2 and ERK5 pathways could potentially offer new therapeutic strategies for NSCLC.

Background: Mitochondrial DNA (mtDNA) and chloroplast DNA (cpDNA) are distinct from nuclear DNA (nuDNA) in a eukaryotic cell. Animal mitochondria transcribe a single primary transcript that carries all genes from a DNA strand; In contrast, plant mitochondria and chloroplasts produce multiple primary transcripts, with each transcript carrying several genes. How primary transcripts of plant mtDNA and cpDNA are processed into mature RNAs is still unknown.

Results: In the present study, we employed PacBio's full-length transcriptome data to characterize the transcription of Arabidopsis thaliana mtDNA, providing a more comprehensive and precise understanding. The primary findings included 20 novel mitochondrial (mt) RNAs of A. thaliana, transcripts carrying single introns or exons, long mt and chloroplast (cp) tRNAs with intricate secondary structures, and the role of tRNA-like structures in RNA processing. The gene of No. 20 novel mt RNA and its paralog on chromosome 2 of A. thaliana were assigned locus IDs ATMG01335 and AT2G07811.

Conclusions: According to our upgraded "mitochondrial cleavage" model, tRNA-like structures serve as "punctuation" marks for RNA processing, akin to the role of tRNAs. Both tRNA-like structures and tRNAs collaborate for RNA processing in plant mitochondria and chloroplasts.

Core1 β1,3-galactosyltransferase (C1GALT1) is an essential glycotransferase controlling the elongation of GalNAc-type O-glycosylation and its altered expression contributes tumor progression in various cancers. However, the mechanism how C1GALT1 influences gliomas remains unclear. Here，our results from The Cancer Genome Atlas (TCGA) database, The Chinese Glioma Genome Atlas (CGGA) database and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database showed that the expression of C1GALT1 was increased in higher grade gliomas namely glioblastoma compared with low grade gliomas or non-tumor tissues and significantly associated with poor survival. Downregulation of C1GALT1 suppressed cell proliferation, invasion, and migration in glioma cell lines. Consistent with the result in vitro, C1GALT1 knockdown distinctly inhibited the weight and tumor growth in nude mice. Mechanistically, C1GALT1 knockdown decreased the level of terminal galactose O-glycosylation and phosphorylation on epidermal growth factor receptor (EGFR). Moreover, The AKT/ERK phosphorylation was attenuated in C1GALT1 knockdown cells. And C1GALT1 knockdown decreased the expression of cyclinD1, matrix metalloproteinase 9 (MMP9) through the AKT/ERK signaling pathway Furthermore, transcription factor SP1 which the expression was found to be associated the C1GALT1 expression could bind to the promoter of C1GALT1 gene and regulated its expression. In conclusion, our data show that C1GALT1 enhances the progression of glioma by regulated the O-glycosylation and phosphorylation of EGFR and the subsequent downstream AKT/ERK signaling pathway. Therefore, C1GALT1 represents a potential target for the diagnosis and treatment of glioma.

Reversing cardiac fibrosis contributes to the restoration of cardiac function in acute myocardial infarction (MI). Exosomes-derived mesenchymal stem cells (MSCs) have been established as potential biomarkers of cardiovascular diseases. While vericiguat has demonstrated promising outcomes in MI via reverse hypertrophy and fibrosis, previous studies about vericiguat pretreatment with MSCs is limited. We aim at exploring whether exosomes derived from vericiguat pretreatment MSCs could augment cardioprotective function and the underlying mechanisms. In our study, exosomes isolated from MSCs (MSC-Exo) and pretreated with vericiguat (MSC^VER-Exo) were administered to cardiac fibroblasts (CFs) in vitro and male infarcted Sprague-Dawley rat hearts in vivo. In vivo, MSC^VER-Exo could significantly improve cardiac function and attenuate cardiac fibrosis and decrease the expression of α-smooth muscle actin (α-SMA), Ι and III collagen (Col Ι and Col III) compared to MSC-Exo treatment. In vitro, MSC^VER-Exo could also restrain proliferation, migration, and the profibrotic genes expression in CFs. miR-1180-3p was enrich in MSC^VER-Exo. Besides, miR-1180-3p could be delivered to CFs via Exo and alleviated TGF-β1-induced fibrosis through inhibiting ETS1 signaling. The elucidation of this mechanism suggested that exosomes derived from vericiguat pretreatment MSCs could improve cardioprotective effects through promoting CFs function. MiR-1180-3p targeting ETS1 played an important role in antifibrosis.