Background: Neuroblastoma (NB) is one of the deadliest paediatric solid tumours due to its rapid proliferative characteristics. Amplified copies of MYCN are considered the most important marker for the prediction of tumour relapse and progression in NB, but they were only detected in 20–30% of NB patients, indicating there might be other oncogenes in the development of NB. The far upstream element binding protein 1 (FUBP1) was first identified as a transcriptional regulator of the proto-oncogene MYC. However, the expression and role of FUBP1 in NB have not been documented.Methods: FUBP1 expression was analysed from GEO database and verified by immunohistochemistry (IHC) and western blotting (WB) in NB tissues and cell lines. Cell proliferation and apoptosis were detected by Cell Counting Kit-8, Colony formation assay, EDU, TUNEL staining and flow cytometric analysis. Several glycolytic metabolites production was confirmed by ELISA and oxygen consuming rate (OCR). Luciferase assay, WB, chromatin immunoprecipitation (CHIP) were used to explore the mechanisms of the effect of FUBP1 on NB.Results: FUBP1 mRNA levels were increased along with the increase in International Neuroblastoma Staging System (INSS) stages. High expression of FUBP1 with low N-Myc expression accounted for 44.6% of NB patient samples (n = 65). In addition, FUBP1 protein levels were remarkably increased with NB malignancy in the NB tissue microarray (NB: n = 65; ganglioneuroblastoma:n = 31; ganglioneuroma:n = 27). Furthermore, FUBP1 expression was negatively correlated with patient survival rate but positively correlated with ki67 content. In vitro experiments showed that FUBP1 promotes NB cell proliferation and inhibits cell apoptosis via enhancing glycolysis and ATP production. Mechanistically, FUBP1 inhibited the degradation of HIF1α via downregulation of Von Hippel-Lindau (VHL), the E3 ligase for HIF1α, resulting in upregulation of lactate dehydrogenase isoform B (LDHB) expression to enhance glycolysis. Overexpressed or silenced N-Myc could not regulate FUBP1 or LDHB levels.Conclusions: Taken together, our findings demonstrate for the first time that elevated FUBP1 promotes NB glycolysis and growth by targeting HIF1α rather than N-Myc, suggesting that FUBP1 is a novel and powerful oncogene in the development of NB independent of N-Myc and may have potential in the diagnosis and treatment of NB.

Objectives: Due to lack of effective biomarkers for non-small cell lung cancer (NSCLC), many patients are diagnosed at an advanced stage, which leads to poor prognosis. Dysregulation of N6-methyladenosine (m⁶A) RNA contributes significantly to tumorigenesis and tumor progression. However, the diagnostic value of m⁶A RNA status in peripheral blood to screen NSCLC remains unclear. Methods: Peripheral blood samples from 152 NSCLC patients and 64 normal controls (NCs) were applied to assess the m⁶A RNA levels. Bioinformatics and qRT-PCR analysis were performed to identify the specific immune cells in peripheral blood cells and investigate the mechanism of the alteration of m⁶A RNA levels. Results: Robust elevation of m⁶A RNA levels of peripheral blood cells was exhibited in the NSCLC group. Moreover, the m⁶A levels increased as NSCLC progressed, and reduced after treatment. The m⁶A levels contained area under the curve (AUC) was 0.912, which was remarkably greater than the AUCs for CEA (0.740), CA125 (0.743), SCC (0.654), and Cyfra21-1 (0.730). Furthermore, the combination of these traditional biomarkers with m⁶A levels elevated the AUC to 0.970. Further analysis established that the expression of m⁶A erasers FTO and ALKBH5 were both markedly reduced and negatively correlated with m⁶A levels in peripheral blood of NSCLC. Additionally, GEO database and flow cytometry analysis implied that FTO and ALKBH5 attributes to peripheral CD4⁺ T cells proportion and activated the immune functions of T cells. Conclusions: These findings unraveled that m⁶A RNA of peripheral blood immune cells was a prospective biomarker for the diagnosis of NSCLC.

Gastric cancer (GC) exhibits molecular heterogeneity and diverse immune cell infiltration patterns closely associated with patient prognosis. However, a comprehensive understanding of the variations in immune cell phenotypes among different patient subgroups still needs to be improved. In this study, we performed a detailed analysis of the tumor microenvironment in GC by integrating 200,466 single cells from 72 patients across six datasets. We classified patients into immune-deserted, B, T, and myeloid cell subtypes. Using genomic and clinical data from TCGA samples, we identified cellular components associated with tumor histology and genotypes. GC patients were stratified into immune-deserted, B cell, T cell, and myeloid cell subtypes, and we described the pathway and transcription factor activity characteristics of different microenvironment subtypes. Integration of bulk RNA-seq data reveals that fibroblasts and endothelial cells were associated with adverse patient outcomes whereas NK and T cells were notably correlated with improved prognosis. Subsequently, we focused on characterizing cancer-associated fibroblasts (CAFs) and discovered that they acquire new functional properties within the tissue microenvironment, providing evidence of CAF plasticity. We constructed a novel four-gene CAF signature including SPARC, EFEMP1, RGS5 and SERPINE1 which may enhance patient stratification and prognostic prediction of GC patients. qPCR analysis revealed that the significant expressions of SPARC, EFEMP1, RGS5 and SERPINE1 were significantly upregulated in gastric cancer tissues compared to the normal tissues. Our study provides insights into the composition of the tumor microenvironment and construction of a four-gene CAF signature associated with clinical prognosis, offering new perspectives for the clinical management of gastric cancer.

Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer’s disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular mechanism is uncertain. Here, the present investigation identified significantly elevated serum Kallistatin levels in AD patients concomitant with hyperglycemia and hypertriglyceridemia, suggesting potential crosstalk between neuroendocrine regulation and metabolic dysregulation in AD pathophysiology. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower long-term potentiation in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by downregulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, the experiments clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD.

Accumulation of amyloid β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer’s disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular is uncertain. Here, we reported that serum Kallistatin concentrations were meaningfully higher in AD patients, with a higher concentration of fasting blood glucose and triglyceride. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower LTP in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by down-regulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, our data clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD.

Accumulation of amyloid β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer’s disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular is uncertain. Here, we reported that serum Kallistatin concentrations were meaningfully higher in AD patients, with a higher concentration of fasting blood glucose and triglyceride. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower LTP in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by down-regulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, our data clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD. Highlights Kallistatin-transgenic(KAL-TG) mice defined its cognitive memory impairment phenotype accompanied by increased Aβ deposition and tau phosphorylation. Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling. Fenofibrate could alleviate cognitive memory impairment and down-regulate the serum Kallistatin level.