Because of the early onset of local invasion and distant metastasis, pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a 5-year survival rate of less than 5%. In this study, we investigated the role of fascin, a prometastasis actin-bundling protein, in PDAC progression, invasion, and the molecular mechanisms underlying fascin overexpression in PDAC. Our data showed that the expression levels of fascin were higher in cancer tissues than in normal tissues, and fascin overexpression correlated with the PDAC differentiation and prognosis. Fascin overexpression promoted PDAC cell migration and invasion by elevating matrix metalloproteinase-2 (MMP-2) expression. Fascin regulated MMP-2 expression through protein kinase C and extracellular signal-regulated kinase. Importantly, our data showed that hypoxia induced fascin overexpression in PDAC cells by promoting the binding of hypoxia-inducible factor-1 (HIF-1) to a hypoxia response element on the fascin promoter and transactivating fascin mRNA transcription. Intriguingly, HIF-1a expression levels in PDAC patient specimens significantly correlated with fascin expression. Moreover, immunohistochemistry staining of consecutive sections demonstrated colocalization between HIF-1a and fascin in PDAC specimens, suggesting that hypoxia and HIF-1a were responsible for fascin overexpression in PDAC. When ectopically expressed, fascin was able to rescue PDAC cell invasion after HIF-1a knockdown. Our results demonstrated that fascin is a direct target gene of HIF-1. Our data suggested that the hypoxic tumor microenvironment in PDAC might promote invasion and metastasis by inducing fascin overexpression, and fascin might be targeted to block PDAC progression. Cancer Res; 74(9);
Objectives: Intervertebral disc degeneration is a progressive and chronic disease, usually manifesting as low back pain. This study aimed to screen effective biomarkers for medical practice as well as figuring out immune infiltration situations between circulation and intervertebral discs.Methods: Gene expression profiles of GSE124272 was included for differentially analysis, WGCNA and immune infiltration analysis from GEO database, and other GSE series were used as validation datasets. A series of validation methods were conducted to verify the robustness of hub genes, such as principal component analysis, machine learning models, and expression verification. Lastly, nomogram was established for medical practice.Results: 10 genes were commonly screened via combination of DEGs, WGCNA analysis and lipid metabolism related genes. Furthermore, 3 hub gens CYP27A1, FAR2, CYP1B1 were chosen for subsequent analysis based on validation of different methods. GSEA analysis discovered that neutrophil extracellular traps formation and NOD-like receptor signaling pathway was activated during IDD. Immune infiltration analysis demonstrated that the imbalance of neutrophils and γδT cells were significantly correlated with IDD progression. Nomogram was established based on CYP27A1, FAR2, CYP1B1 and age, the calibration plot confirmed the stability of our model.Conclusion: CYP27A1, FAR2, CYP1B1 were considered as hub lipid metabolism related genes (LMRGs) in the development of IDD, which were regarded as candidate diagnostic biomarkers especially in circulation. The effects are worth expected in the early diagnosis of IDD through detecting these genes in blood.
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