Background Tumor‐educated platelets (TEPs) may enable blood‐based cancer diagnosis. This study aimed to identify diagnostic TEPs genes involved in carcinogenesis. Materials and Methods The TEPs differentially expressed genes (DEGs) between healthy samples and early/advanced cancer samples were obtained using bioinformatics. Gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were used to identify the pathways and functional annotation of TEPs DEGs. Protein‐protein interaction of these TEPs DEGs was analyzed based on the STRING database and visualized by Cytoscape software. The correlation analysis and diagnostic analysis were performed to evaluate the diagnostic value of TEPs mRNAs expression for early/advanced cancers. Quantitative real‐time PCR (qRT‐PCR) was applied to validate the role of DEGs in cancers. Results TEPs mRNAs were mostly involved in protein binding, extracellular matrix, and cellular protein metabolic process. RSL24D1 was negatively correlated to early‐stage cancers compared to healthy controls and may be potentially used for early cancer diagnosis. In addition, HPSE, IFI27, LGALS3BP, CRYM, HBD, COL6A3, LAMB2, and IFITM3 showed an upward trend in the expression from early to advanced cancer stages. Moreover, ARL2, FCGR2A, and KLHDC8B were positively associated with advanced, metastatic cancers compared to healthy controls. Among the 12 selected DEGs, the expression of 7 DEGs, including RSL24D1, IFI27, CRYM, HBD, IFITM3, FCGR2A, and KLHDC8B, were verified by the qRT‐PCR method. Conclusion This study suggests that the 7‐gene TEPs liquid‐biopsy biomarkers may be used for cancer diagnosis and monitoring.
Accumulating evidence has demonstrated the roles of circular RNAs (circRNAs) in hepatocellular carcinoma (HCC); however, their roles in HCC need to be further studied. Through high-throughput human circRNA microarray analysis of HCC and adjacent normal tissues, we identified hsa_circ_0051040 as a novel candidate circRNA for the diagnosis and treatment of HCC. In this study, we found that hsa_circ_0051040 was overexpressed in HCC tissues and cell lines and that its expression was correlated with poor prognosis. Knockdown of hsa_circ_0051040 inhibited the migration, invasion, and proliferation of HCC cells in vitro and in vivo, whereas overexpression of hsa_circ_0051040 had the opposite effects. Moreover, our data demonstrated that hsa_circ_0051040 acted as a sponge for miR-569 to regulate ITGAV expression and induce EMT progression. Our findings indicated that hsa_circ_0051040 promotes HCC development and progression by sponging miR-569 to increase ITGAV expression. Thus, hsa_circ_0051040 is a good candidate as a therapeutic target.
Platelets are generated from the cytoplasm of megakaryocytes (MKs) via actin cytoskeleton reorganization. Zyxin is a focal adhesion protein and wildly expressed in eukaryotes to regulate actin remodeling. Zyxin is upregulated during megakaryocytic differentiation; however, the role of zyxin in thrombopoiesis is unknown. Here we show that zyxin ablation results in profound macrothrombocytopenia. Platelet lifespan and thrombopoietin level were comparable between wild-type and zyxin-deficient mice, but MK maturation, demarcation membrane system formation, and proplatelet generation were obviously impaired in the absence of zyxin. Differential proteomic analysis of proteins associated with macrothrombocytopenia revealed that glycoprotein (GP) Ib-IX was significantly reduced in zyxin-deficient platelets. Moreover, GPIb-IX surface level was decreased in zyxin-deficient MKs. Knockdown of zyxin in a human megakaryocytic cell line resulted in GPIbα degradation by lysosomes leading to the reduction of GPIb-IX surface level. We further found that zyxin was colocalized with vasodilator-stimulated phosphoprotein (VASP), and loss of zyxin caused diffuse distribution of VASP and actin cytoskeleton disorganization in both platelets and MKs. Reconstitution of zyxin with VASP binding site in zyxin-deficient hematopoietic progenitor cell-derived MKs restored GPIb-IX surface expression and proplatelet generation. Taken together, our findings identify zyxin as a regulator of platelet biogenesis and GPIb-IX surface expression through VASP-mediated cytoskeleton reorganization, suggesting possible pathogenesis of macrothrombocytopenia.
Cancer is a disturbing disease with high morbidity and mortality. Although medical technology has been developed rapidly, diagnosis of cancer is still complicated, difficult, as well as expensive. Furthermore, cancers are mostly diagnosed at an advanced stage. Platelets mRNA profiles are altered after educated by tumors. Thereby, tumor-educated platelets (TEPs) mRNA profiles have the potentially diagnostic value for cancers currently. We downloaded and analyzed the next-generation sequencing datasets, GSE68086 and GSE89843, by integrated bioinformatics. A total of 43 biomarker genes were selected for further pathway enrichment analysis and correlation analysis, as well as diagnostic analysis. Gene ontology (GO) analysis showed these 43 TEPs mRNAs were mostly involved in protein binding, extracellular matrix and cellular protein metabolic process. Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis revealed that genes were mainly enriched in metabolic process. Eventually, after taking these 43 genes into spearman correlation analysis and receiving operating characteristic (ROC) curve analysis, we identified: 1) TEPs RSL24D1 mRNA was negatively related to early pan cancer as compared to healthy controls, and potential for early pan cancer diagnosis with a sensitivity of 71.8%, and a specificity of 64.3%; 2) HPSE, IFI27, LGALS3BP, CRYM, HBD, COL6A3, LAMB2, and IFITM3 showed an upward trend in the expression from early to more advanced pan cancer stages. The sensitivity of the diagnostic value for pan cancer of these genes was 60.9%, 59.1%, 56.5%, 57.8%, 54.3%, 55.2%, 55.2%, 60.9%, and a specificity of 94.5%, 90.9%, 87.3%, 89.1%, 72.7%, 85.5%, 89.1%, 94.5% respectively; 3) ARL2, FCGR2A, and KLHDC8B were positively associated with advanced, metastatic pan cancer as compared to healthy controls and could be diagnostic indicators for advanced pan cancer with a sensitivity of 59.2%, 61.8%, 59.7%, and a specificity of 80%, 89.1%, 83.6%, respectively. In summary, our findings identified that the 12-gene TEP liquid-biopsy biomarkers will not only facilitate early diagnosis of pan cancer, but also be beneficial to pan cancer staging.
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