AimAnaplastic thyroid carcinoma (ATC) is the most lethal thyroid malignancy. Identification of novel drug targets is urgently needed.Materials & MethodsWe re-analyzed several GEO datasets by systematic retrieval and data merging. Differentially expressed genes (DEGs) were filtered out. We also performed pathway enrichment analysis to interpret the data. We predicted key genes based on protein–protein interaction networks, weighted gene co-expression network analysis and genes’ cancer/testis expression pattern. We also further characterized these genes using data from the Cancer Genome Atlas (TCGA) project and gene ontology annotation.ResultsCell cycle-related pathways were significantly enriched in upregulated genes in ATC. We identified TRIP13, DLGAP5, HJURP, CDKN3, NEK2, KIF15, TTK, KIF2C, AURKA and TPX2 as cell cycle-related key genes with cancer/testis expression pattern. We further uncovered that most of these putative key genes were critical components during chromosome segregation.ConclusionWe predicted several key genes harboring potential therapeutic value in ATC. Cell cycle-related processes, especially chromosome segregation, may be the key to tumorigenesis and treatment of ATC.
Background: The accumulation of senescent cells promotes hepatic fat accumulation. P16, a proto-typical marker of senescent cells, is closely correlated to hepatic lipid accumulation. PCSK9 (proprotein convertase subtilisin/kexin type 9) plays a critical role in lipid metabolism via PCSK9/LDLR (low-density lipoprotein receptor) axis. This study aimed to explore the mechanism of p16 modulating PCSK9 expression to enhance hepatic lipid accumulation. Methods: All aging mice (12 months old) were randomly assigned two groups: control group with HF (high fat) diet for 6 months, and medicine group with ABT263 (senolytic drug) treatment for 6 months in the presence of HF diet. To induce the senescent cells, cells were treated with bleomycin or adenovirus overexpressing p16 (ad-p16). Cells were treated with cell culture medium containing oleic acid (OA) and palmitic acid (PA) to mimic hepatic steatosis in vivo. The senescent cells were evaluated by SA-β-gal staining. For lipid droplets visualization, Oil red O and Nile red staining were performed. Eventually, the effect of p16 on PCSK9/LDLR axis was determined by Western blot and real-time quantitative polymerase chain reaction (RT-qPCR). Results: We found ABT263 treatment markedly reduced lipid droplets, accompanied with dramatically decreased expression of p16 and PCSK9 in the liver. P16 silencing in senescent HL7702 inhibited lipid droplet accumulation, while p16 overexpression in AML12 remarkably increased lipid droplets, cellular content of total cholesterol and low-density lipoprotein cholesterol. Moreover, total PCSK9 protein level enhanced in p16-overexpressed hepatocytes, while LDLR significantly decreased in membrane and increased in cytoplasm in these cells. Mechanically, we found p16 overexpression inhibited K48-linked polyubiquitination of PCSK9. Conclusions: These results indicate a novel role of p16 in lipid droplet accumulation through aberrant regulation of PCSK9/LDLR axis with PCSK9 ubiquitination in hepatocytes. Lowering p16 expression may be a novel strategy to reduce aberrant lipid metabolism in aging-related diseases.
To the Editor: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease. [1] The hallmark of ankylosing spondylitis (AS) phenotype is sacroiliac joint and spinal damage characterized by the new bone formation and joint fusion, which results in irreversible functional disability and reduced quality of life.Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as a first-line drug for axSpA patients. Failed to NSAIDs therapy, tumor necrosis factor (TNF)-a inhibitor (TNFi) was suggested in the treatment strategy of axSpA. [2] But 30% of axSpA patients still do not respond or respond inadequately to the TNFi therapy. Moreover, TNF-a antagonists are believed to have a weak effect on preventing osteophyte formation and spinal structure damage in axSpA.
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