ABSTRACT
The tumor microenvironment is a complex network of cells, extracellular matrix, and signaling molecules that plays a critical role in tumor progression and metastasis. Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits. However, recent studies have shown that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) also play multifaceted roles in the tumor microenvironment beyond their structural functions, particularly in hepatocellular carcinoma (HCC). This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC, including their involvement in angiogenesis, immune modulation, lymphangiogenesis, and metastasis. By providing a detailed account of the complex interplay between LECs, BECs, and tumor cells, this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.
ABSTRACT
BACKGROUND: Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-editing enzyme that significantly impacts cancer progression and various biological processes. The expression of ADAR1 mRNA has been examined in multiple cancer types using The Cancer Genome Atlas (TCGA) dataset, revealing distinct patterns in kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and liver hepatocellular carcinoma (LIHC) compared to normal controls. However, the reasons for these differential expressions remain unclear. METHODS: In this study, we performed RT-PCR and western blotting (WB) to validate ADAR1 expression patterns in clinical tissue samples. Survival analysis and immune microenvironment analysis (including immune score and stromal score) were conducted using TCGA data to determine the specific cell types associated with ADAR1, as well as the key genes in those cell types. The relationship between ADAR1 and specific cell types' key genes was verified by immunohistochemistry (IHC), using clinical liver and kidney cancer samples. RESULTS: Our validation analysis revealed that ADAR1 expression was downregulated in KICH, KIRC, and KIRP, while upregulated in LIHC compared to normal tissues. Notably, a significant correlation was found between ADAR1 mRNA expression and patient prognosis, particularly in KIRC, KIRP, and LIHC. Interestingly, we observed a positive correlation between ADAR1 expression and stromal scores in KIRC, whereas a negative correlation was observed in LIHC. Cell type analysis highlighted distinct relationships between ADAR1 expression and the two stromal cell types, blood endothelial cells (BECs) and lymphatic endothelial cells (LECs), and further determined the signature gene claudin-5 (CLDN5), in KIRC and LIHC. Moreover, ADAR1 was inversely related with CLDN5 in KIRC (n = 26) and LIHC (n = 30) samples, verified via IHC. CONCLUSIONS: ADAR1 plays contrasting roles in LIHC and KIRC, associated with the enrichment of BECs and LECs within tumors. This study sheds light on the significant roles of stromal cells within the complex tumor microenvironment (TME) and provides new insights for future research in tumor immunotherapy and precision medicine.
Subject(s)
Adenosine Deaminase , Carcinoma, Hepatocellular , Carcinoma, Renal Cell , Gene Expression Regulation, Neoplastic , Kidney Neoplasms , Liver Neoplasms , RNA-Binding Proteins , Tumor Microenvironment , Adenosine Deaminase/genetics , Adenosine Deaminase/metabolism , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/mortality , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/metabolism , Kidney Neoplasms/mortality , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Prognosis , Female , Male , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Middle AgedABSTRACT
The SiO2 @SiO2 :Tb(1,2-BDC)3 phen microspheres with monodispersed core-shell structure, are kind of fluorescent particles, which are prepared by a seeded growth method under the catalysis of glacial acetic acid (1,2-BDC, 1,2-benzenedicarboxylic acid; phen, 1,10-phenanthroline). Firstly, silica seed was fabricated by the hydrolysis of ethyl orthosilicate, and the Tb(1,2-BDC)3 phen was prepared by using 1,2-BDC and phen. Then, a thin mesoporous silica shell doped with Tb(1,2-BDC)3 phen was grown on the prepared monodisperse silica colloids. The prepared phosphor was analyzed by Fourier-transform infrared spectroscopy, X-ray diffraction analysis, scanning electron microscopy, transmission electron microscopy, thermogravimetric and fluorescence spectroscopy. The experimental results showed that the diameter of the SiO2 @SiO2 :Tb((1,2-BDC)3 phen microsphere was about 200 nm with a typical core-shell structure, among which the diameter of the silica core was 180 nm, and that of the mesoporous silicon shell doped with terbium complex was about 10 nm. The fluorescence intensity of SiO2 @SiO2 :Tb((1,2-BDC)3 phen microsphere is nearly three times higher than that of Tb((1,2-BDC)3 phen complexes. The prepared microspheres could be widely used in bio-imaging, optoelectronic appliances and medical diagnosis.
Subject(s)
Silicon Dioxide , Terbium , Microscopy, Electron, Transmission , Microspheres , Spectroscopy, Fourier Transform InfraredABSTRACT
Invasion and metastasis are the main causes of colorectal cancer (CRC)-related death. Accumulating evidence suggested that sphingosine kinase 1 (SphK1) promoted the metastasis of CRC and autophagy played an important role in SphK1 promoting the metastasis of malignancy. However, the mechanism by which SphK1-driven autophagy promotes invasion and metastasis in CRC remains to be clarified. In the present study, immunohistochemical detection showed the expression of SphK1 and paxillin was higher in human CRC tissues than those of normal colorectal mucosal tissues, they were both associated with TNM staging, lymphatic, and distance metastasis. In addition, study of in situ tumor transplantation model in nude mice showed that the suppression of SphK1 inhibited the growth of colonic orthotopic implantation tumors and the expression of paxillin, p-paxillin, LC3 in the tumor. So, SphK1 may promote CRC metastasis via inducing the expression of paxillin expression and its phosphorylation, in vivo. Furthermore, results of CCK8 assay, transwell and wound healing assays showed that SphK1 promoted the viability, invasion, and metastasis of CRC cells. Transmission electron microscopy detection showed that SphK1 is the key factor in autophagy induction in CRC cells. Moreover, western blot examination indicated that the expression of LC3â ¡/â , paxillin, p-paxillin, MMP-2, and vimentin was enhanced in SphK1-overexpressed CRC cells and suppressed in SphK1 knockdown CRC cells, meanwhile, the expression of E-cadherin was suppressed in SphK1-overexpressed CRC cells and enhanced in SphK1 knockdown CRC cells. Suppression of autophagy by 3MA reversed the expression of paxillin and its phosphorylation in SphK1-overexpressed CRC cells, indicated that SphK1-driven autophagy induced the expression of paxillin and its phosphorylation in CRC cells. Together, these findings reveal that SphK1-driven autophagy may promote the invasion and metastasis of CRC via promoting the expression of focal adhesion paxillin and its phosphorylation.
Subject(s)
Autophagy/genetics , Focal Adhesions/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Adult , Aged , Aged, 80 and over , Animals , Colorectal Neoplasms/genetics , Female , Humans , Male , Mice , Mice, Nude , Middle Aged , Neoplasm MetastasisABSTRACT
Systematic chemotherapy is indispensable for gastric cancer patients with advanced stage disease, but the occurrence of chemoresistance drastically limits treatment effectiveness. There is a tremendous need for identifying the underlying mechanism of chemoresistance. NIK and IKKßbinding protein (NIBP) (also known as TRAPPC9, trafficking protein particle complex 9) is a regulator of the cytokineinduced NFκB signaling pathway which has been proven to play pivotal roles in the progression of various malignancies. Nevertheless, it is still ambiguous whether NIBP is involved in the chemoresistance of gastric cancer. The aim of the present study was to investigate the effect of NIBP on chemotherapy resistance of gastric cancer (GC) and to research the mechanisms of Ginkgo biloba extract 761 (EGb 761®) on reversing chemoresistence which has been confirmed in our previous study. In the present study, the results of immumohistochemisty revealed that the positive staining rates of NIBP, NFκB p65 and NFκB pp65 in gastric cancer tissues were obviously higher than those in normal tissues. Furthermore, a close correlation was found to exist between the expression of NIBP and NFκB p65 (pp65) in gastric cancer tissues. Moreover, the overexpression of NIBP was closely related to tumor differentiation, depth of invasion, clinical stage and lymphatic metastasis in gastric cancer. Western blot analysis, realtime PCR, MTT assay and flow cytometric analysis were performed and the results demonstrated that compared with the gastric cancer SGC7901 cells, the expression of NIBP, NFκB p65, NFκB pp65 and mesenchymal marker vimentin were significantly increased in gastric cancer multidrugresistant SGC7901/CDDP cells, and the epithelial cell marker ZO1 was significantly decreased. Meanwhile, it was found that SGC7901/CDDP cells were accompanied by spindlelike mesenchymal appearance and upregulation of stem cell marker CD133 which has been verified to be an upstream regulatory gene of epithelialmesenchymal transition (EMT). Further research confirmed that downregulation of NIBP by Ginkgo biloba extract (EGb) 761 EGb 761 suppressed the cisdiamminedichloroplatinum(II) (CDDP)induced NFκB signaling pathway, EMT and the expression of CD133 in SGC7901 and SGC7901/CDDP cells. Altogether, these data indicate that the NIBPregulated NFκB signaling pathway plays a pivotal role in the chemoresistance of gastric cancer by promoting CD133induced EMT.
Subject(s)
Carrier Proteins/metabolism , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition , Signal Transduction , Stomach Neoplasms/metabolism , Up-Regulation , Adult , Aged , Carrier Proteins/genetics , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , Epithelial-Mesenchymal Transition/drug effects , Female , Ginkgo biloba , Humans , Intercellular Signaling Peptides and Proteins , Male , Middle Aged , NF-kappa B/metabolism , Plant Extracts/pharmacology , Signal Transduction/drug effects , Stomach Neoplasms/genetics , Up-Regulation/drug effectsABSTRACT
OBJECTIVE: To explore the score criteria of severe hand, foot and mouth disease (HFMD) cases and to provide evidence for unified criteria and treatment on severe HFMD cases. METHODS: All severe cases and partial mild cases reported by two designated hospitals of HFMD in Fuyang during March to June, 2008 were scored by the methods of criteria constructed in advance. ROC curve was adopted to evaluate the score criteria and the gold standard was defined according to ICU, intubation and clinical outcomes, etc. Sensitivity, specificity and Youden's index were used to determine the division scores on critical, severe and mild cases. RESULTS: 97% of the cases (34 cases) were scored less than 6 points. 88% of cases (24 cases) who were intubated or mechanical ventilated had the scores of 6 points or higher. 79% of deaths (11 cases) were scored 10 points or higher. The area of receiver operation characteristic (ROC) curve was 0.90 (95%CI: 0.83 - 0.98) between severe and mild cases and the area of ROC curve was 0.95 (95%CI: 0.92 - 0.98) between critical and severe, mild cases. When comprehensively considering the sensitivity and specificity, severe cases were best judged when score was 4 points (sensitivity, specificity and Youden's index were 0.94, 0.68 and 0.62 respectively). When score was 6 points, critical cases were judged very well (sensitivity, specificity and Youden's index were 0.92, 0.84 and 0.76 respectively). CONCLUSION: Score criteria could be quantified to determine the degree of seriousness and with high-value for diagnosis on HFMD.