Journal of Environmental Pathology Toxicology and Oncology最新文献

Technological advancement to enhance tumor cells (TC) has allowed discovery of various cellular bio-markers: cancer stem cells (CSC), circulating tumor cells (CTC), and endothelial progenitor cells (EPC). These are responsible for resistance, metastasis, and premetastatic conditions of cancer. Detection of CSC, CTC, and EPC assists in early diagnosis, recurrence prediction, and treatment efficacy. This review describes various methods to detect TC subpopulations such as in vivo assays (sphere-forming, serial dilution, and serial transplantation), in vitro assays (colony-forming cells, microsphere, side-population, surface antigen staining, aldehyde dehydrogenase activity, and Paul Karl Horan label-retaining cells, surface markers, nonenriched and enriched detection), reporter systems, and other analytical methods (flow cytometry, fluorescence microscopy/spectroscopy, etc.). The detailed information on methods to detect CSC, CTC, and EPC in this review will assist investigators in successful prognosis, diagnosis, and cancer treatment with greater ease.

Lung cancer is the most common type of cancer in the world and about 1 million people die from lung cancer every year in the world. Inflammation is an important factor in the onset, progression and metastasis of lung cancer. The most important regulators of inflammation are chemokines and chemokine receptors. Chemokines induce the proliferation of cancer cells and prevent their apoptosis. Chemokines may indirectly affect tumor growth by inducing growth and release of angiogenic factors from cells in the tumor microenvironment. CXCL12/CXCR4 are chemokine and chemokine receptors predicted to be involved in lung cancer pathogenesis. This study aimed to determine the relationship between CXCL12/CXCR4 gene variations and CXCL12 serum levels in disease pathogenesis in lung cancer. For this purpose, DNA samples isolated from 90 lung cancer patients (36 squamous cell carcinomas, 18 small cell carcinomas and 36 adenocarcinomas) and 90 control individuals were genotyped by PCR-RFLP method for CXCL12 (rs1801157) and CXCR4 (rs2228014). CXCL12 protein levels were determined from serum samples by the enzyme-linked immuno-sorbent assay (ELISA) method. Results were evaluated using IBM SPSS Statistics 21 software and FINNETI program. As a result, there was no significant difference between the genotype frequencies of the CXCL12 rs1801157 variant and the risk of lung cancer (P = 0.396). CXCR4 rs2228014 genotypes were significantly associated with lung cancer risk (P < 0.001). Lung cancer patients had significantly elevated serum CXCL12 levels than controls (P < 0.001). In conclusion, the rs2228014 variants localized on the chemokine receptors CXCR4 gene was found to be closely related to lung cancer risk.

Aberrant expression of the SRY-related HMG-box (SOX) genes contributes to tumor development and progression. This research aimed to identify the regulation of the SOX genes in stomach adenocarcinoma (STAD). Expression profiles downloaded from The Cancer Genome Atlas (TCGA) were conducted to analyze the expression and function of the SOX genes. A competing endogenous RNAs (ceRNA) network mediated by the SOX genes was effectively constructed consisting of 64 lncRNAs, 29 miRNAs, and 11 SOX genes based on predicted miRNAs shared by lncRNAs and mRNAs using miRDB, TargetScan, miRTarBase, miRcode, and starBase v2.0. SOX9 was identified as a prognostic signature, which showed the usefulness of diagnosis and prognosis of STAD by the receiver operating characteristic (ROC) and Kaplan-Meier curves. SOX9 was also shown specifically in STAD and identified as highly expressed in the gastrointestinal tract. Gene Ontology (GO) enrichment analysis showed that SOX9 might influence the genes related to the pattern specification process, sodium ion homeostasis, and potassium ion transport, mainly including FEZF1, HOXC13, HOXC10, HOXC9, HOXA11, DPP6, ATP4B, CASQ2, KCNA1, ATP4A, and SFRP1. Furthermore, HOTAIR knockdown, miR-206-mimic transfection, the Cell Count Kit-8 (CCK-8) assay were performed to verify the function of HOTAIR/miR-206/SOX9 axis, which was identified in the ceRNA network analysis. HOTAIR could induce proliferation potentially by competitively binding miR-206/SOX9 axis in STAD. These findings provide new clues with prognostic and therapeutic implications in STAD and suggest that HOTAIR/miR-206/SOX9 might be a potential new strategy for therapeutic targeting of gastric cancer.

Hepatocellular carcinoma (HCC) is the predominant pathological type of liver cancer. Several therapeutic treatments, including sorafenib and regorafenib, have only modestly improved survival in patients with HCC. The aim of this study was to investigate the expression profiles and the regulation of competitive endogenous RNAs (ceRNAs) of the sorafenib-related target genes in HCC. Based on clinical information and expression profiles of HCC clinical samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, shared differentially expressed genes (DEGs) were analyzed and identified. Sorafenib-associated DEGs (SADs) were obtained by intersecting the DEGs with the sorafenib target genes from SuperTarget database. The expression patterns of SADs were verified in the Oncomine database. The biological functions of the SADs were annotated by gene set enrichment analysis (GSEA). In addition, a ceRNA network associated with SADs was constructed. Long non-coding RNAs (lncRNAs) in network that were significantly associated with overall survival were identified as prognosis of patients by Cox regression analysis. Finally, the expression levels of prognostic genes in HCC tissues and cell lines were verified using qRT-PCR. Gene expression differential analysis yielded a total of 146 common DEGs were obtained, including 21 upregulated and 125 downregulated DEGs. Among them, ten SADs were detected to be differentially expressed between tumor and normal tissues, including AXL, CYP2C19, CYP2C8, CYP2C9, CYP3A4, FGFR2, GMNN, PDGFRA, and TTK. GSEA analysis grouped them into three categories by function. The first category (CYP2C19, CYP2C8, CYP2C9 and CYP3A4) and second category (GMNN, TTK and EGER2) had the opposite roles in the enriched terms and pathways, while the third class (AXL and PDGFRA) has enrichment terms and pathways that intersect with those of the first and second categories. A ceRNA network associated with SADs was also constructed including 49 lncRNAs, 14 miRNAs, and 8 mRNAs. Three of these lncRNAs, SNHG7, GAS5 and HCP5, were found upregulated in HCC tissues and to be independent predictors in HCC patients. Significant correlations were found in expression between the prognostic lncRNAs and SADs. Ten SADs were systematically identified using expression data from HCC and normal tissues from TCGA and GEO datasets. GSEA analysis provided us with insight into the function of SADs. In the future, we will continue to explore the mechanisms of coordinated regulation of SADs-related prognostic lncRNAs and SADs at the ceRNA axis level and their potential functions in the development of HCC.

Oral squamous cell carcinoma (OSCC) still threatens people's daily life. METTL14 is a newly discovered methyltransferase that catalyzes m6A methylation. Hence, this research was carried out to investigate the action mechanism of METTL14 in OSCC. The SCC-4 and UM2 cells, and tumorigenicity assay were utilized to investigate METTL14 roles in vitro and in vivo. Bioinformatic analysis was carried out with the UCSC, TCGA database and The Human Protein Atlas. The gene expression at mRNA and protein levels were measured by qRT-PCR and Western blot. In addition, cell growth and metastasis was analyzed by colony formation and transwell assays. MeRIP assay was performed to test the m6A levels of CALD1. The METTL14 and CALD1 levels were prominently expressed in OSCC cells. METTL14 silencing depleted the cell growth and metastasis. Furthermore, METTL14 silencing depleted the tumor growth in vivo. Additionally, the mRNA and m6A levels of CALD1 were depleted after METTL14 silencing. Overexpressed CALD1 neutralized the si-METTL14 effects in OSCC cells. In conclusion, METTL14 participated in the OSCC progression through modulating the mRNA and m6A levels of CALD1.

Leukemia threatens children's health, and leukemia cell proliferation and apoptosis participate in the regulation of leukemia. The current study aims to probe into the miR-125b-5p biological function in regulating leukemia cell proliferation and apoptosis by myeloid cell leukemia 1 (MCL1). Quantitative real-time polymerase chain reaction was conducted to quantify miR-125b-5p expression in leukemia cells. Cell transfection, cell-counting assay 8, Western blot, and flow cytometry assays were applied to assess the miR-125b-5p function in leukemia. A dual-luciferase reporter gene assay was applied to investigate the mechanism. miR-125b-5p was lessened in leukemia cells, and the increased miR-125b-5p repressed leukemia cell proliferation and boosted apoptosis. Further, miR-125b-5p could bound with the MCL1 3'-untranslated region and regulated its expression. Furthermore, the elevated expression of miR-125b-5p repressed leukemia cell proliferation and boosted apoptosis through downregulating MCL1. miR-125b-5p inhibited leukemia cell proliferation and boosted apoptosis through decreasing MCL1.

As an important element in regulating the tumor microenvironment (TME), integrin plays a key role in tumor progression. This study aimed to establish prognostic signatures to predict the overall survival and identify the immune landscape of patients with lung adenocarcinoma based on integrins. The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA-LUAD) and Gene Expression Omnibus datasets were used to obtain information on mRNA levels and clinical factors (GSE72094). The least absolute shrinkage and selection operator (LASSO) model was used to create a prediction model that included six integrin genes. The nomogram, risk score, and time-dependent receiver operating characteristic analysis all revealed that the signatures had a good prognostic value. The gene signatures may be linked to carcinogenesis and TME, according to a gene set enrichment analysis. The immunological and stromal scores were computed using the ESTIMATE algorithm, and the data revealed, the low-risk group had a higher score. We discovered that the B lymphocytes, plasma, CD4+ T, dendritic, and mast cells were much higher in the group with low-risk using the CiberSort. Inflammatory processes and several HLA family genes were upregulated in the low-risk group. The low-risk group with a better prognosis is more sensitive to immune checkpoint inhibitor medication, according to immunophenoscore (IPS) research. We found that the patients in the high-risk group were more susceptible to chemotherapy than other group patients, according to the prophetic algorithm. The gene signatures could accurately predict the prognosis, identify the immune status of patients with lung adenocarcinoma, and provide guidance for therapy.

Methyltransferase like 3 (METTL3) has been reported to be dysregulated in glioma. However, its role in aerobic glycolysis of glioma remains unknown. This study was conducted to explore the molecular mechanism by which METTL3 regulates aerobic glycolysis of glioma and provide novel targets for the treatment of glioma. The expression levels of METTL3, microRNA (miR)-27b-3p, and pyruvate dehydrogenase kinase 1 (PDK1) were determined in glioma cell lines and normal human astrocytes. Cell proliferation and aerobic glycolysis were evaluated by cell counting kit-8 and colony formation assays and measurements of glucose uptake, lactate production, adenosine triphosphate, Hexokinase activity, oxygen consumption rate, and extracellular acidification rate. After m6A quantification analysis, methylated RNA immunoprecipitation, and the dual-luciferase assay, the rescue experiments were performed using miR-27b-3p inhibitor or pcDNA3.1-PDK1 with pcDNA3.1-METTL3. METTL3 was lower in glioma cells and METTL3 overexpression reduced aerobic glycolysis. METTL3 increased m6A modification to promote the processing of pri-miR-27b by DGCR8 and the expression of mature miR-27b-3p, and miR-27b-3p targeted and inhibited PDK1 expression. miR-27b-3p inhibition or PDK1 overexpression both neutralized the inhibitory role of METTL3 overexpression in aerobic glycolysis. Overall, METTL3 overexpression increased the expression of mature miR-27b-3p via m6A modification and inhibited PDK1 expression, thus suppressing aerobic glycolysis of glioma.

Gastric cancer (GC) ranks third for cancer-related fatalities worldwide. It is still unclear what causes GC to progress. Using integrated bioinformatics analysis, COL5A2 has been proved to be related to GC development, which may identify the likely pathogenic mechanism. Data from GC patients were gathered using The Cancer Gene Atlas (TCGA) and the gene expression omnibus (GEO). The level of COL5A2 expression was compared between paired GC and normal tissues. The differentially expressed genes (DEGs) in GC patients with high and low COL5A2 expression were identified using functional enrichment analysis to identify the signature pathways linked to the DEGs. The clinical pathologic traits connected to overall survival (OS) of GC patients were examined utilizing Cox regression and the Kaplan-Meier method. To assess the prognostic significance of COL5A2, receiver operating characteristic (ROC) curves was drawn. How the immune system infiltrate both normal gastric and GC tumor tissues was investigated. Using the human protein atlas (HPA) database, regression, and the Kaplan-Meier method, immunohistochemical analysis of DEG COL5A2 expression in GC tissues was carried out. The correlation between COL5A2 expression and the GC grouping was found to be highly significant. Functional annotations revealed that COL5A2 participates in extracellular matrix structure, collagen metabolism, and other biological processes (BPs). High COL5A2 expression was associated with poor prognostic and clinical features, such as clinical T, N, and M stages. ROC curves exhibited that COL5A2 might predict the occurrence of gastric cancer. The infiltration degree of 21 immune cell subsets, including activated dendritic cells (aDCs), CD8+ T cells, and cytotoxic cells, was found to be dramatically relevant to COL5A2. Immunohistochemical analysis indicated that the expression of COL5A2 in tumor tissues is higher than that in normal tissues. The COL5A2 gene may offer fresh perspectives on the pathogenic mechanism underlying GC, as well as potential biomarkers for estimating GC patient prognosis. As a result, COL5A2 may be a useful biomarker for predicting patient survival.