The topoisomerase inhibitor CPT-11 prevents the growth and metastasis of lung cancer cells in nude mice by inhibiting EGFR/MAPK signaling pathway.

Objective: The topoisomerase inhibitor CPT-11 has been applied in treatment of multiple cancer types. Here, we probed into the possible mechanism of CPT-11 in affecting growth and metastasis of lung cancer (LC) cells, with involvement of the EGFR/MAPK pathway. Methods: The target protein of CPT-11 was screened through bioinformatics analysis, and the LC-related microarray datasets GSE29249, GSE32863 and GSE44077 were obtained for differential analysis for identifying the target protein. A subcutaneous xenograft tumor model and a metastatic tumor model were constructed in nude mice for in vivo mechanism verification of the regulatory role of CPT-11 in LC through modulation of EGRF/MAPK pathway. Results: Bioinformatics analysis showed that EGFR was the target protein of CPT-11. In vivo animal experiments confirmed that CPT-11 enhanced LC cell growth and metastasis in nude mice. CPT-11 could inhibit activation of EGFR/MAPK pathway. EGFR promoted LC cell growth and metastasis in nude mice through activation of the MAPK pathway. Conclusion: The topoisomerase inhibitor CPT-11 may prevent LC growth and metastasis by inhibiting activation of EGFR/MAPK pathway.

Development of a 5-Gene Signature to Evaluate Lung Adenocarcinoma Prognosis Based on the Features of Cancer Stem Cells.

Cancer stem cells (CSCs) can induce recurrence and chemotherapy resistance of lung adenocarcinoma (LUAD). Reliable markers identified based on CSC characteristic of LUAD may improve patients' chemotherapy response and prognosis. OCLR was used to calculate mRNA expression-based stemness index (mRNAsi) of LUAD patients' data in TCGA. Association analysis of mRNAsi was performed with clinical features, somatic mutation, and tumor immunity. A prognostic prediction model was established with LASSO Cox regression. Kaplan-Meier Plotter (KM-plotter) and time-dependent ROC were applied to assess signature performance. For LUAD, univariate and multivariate Cox analysis was performed to identify independent prognostic factors. LUAD tissues showed a noticeably higher mRNAsi in than nontumor tissues, and it showed significant differences in T, N, M, AJCC stages, and smoking history. The most frequently mutated gene was TP53, with a higher mRNAsi relating to more frequent mutation of TP53. The mRNAsi was significantly negatively correlated with immune score, stromal score, and ESTIMATE score in LUAD. The blue module was associated with mRNAsi. The 5-gene signature was confirmed as an independent indicator of LUAD prognosis that could promote personalized treatment of LUAD and accurately predict overall survival (OS) of LUAD patients.

Construction of prediction model of inflammation related genes in idiopathic pulmonary fibrosis and its correlation with immune microenvironment.

Background: The role of inflammation in the formation of idiopathic pulmonary fibrosis (IPF) has gained a lot of attention recently. However, the involvement of genes related to inflammation and immune exchange environment status in the prognosis of IPF remains to be further clarified. The objective of this research is to establish a new model for the prediction of the overall survival (OS) rate of inflammation-related IPF. Methods: Gene Expression Omnibus (GEO) was employed to obtain the three expression microarrays of IPF, including two from alveolar lavage fluid cells and one from peripheral blood mononuclear cells. To construct the risk assessment model of inflammation-linked genes, least absolute shrinkage and selection operator (lasso), univariate cox and multivariate stepwise regression, and random forest method were used. The proportion of immune cell infiltration was evaluated by single sample Gene Set Enrichment Analysis (ssGSEA) algorithm. Results: The value of genes linked with inflammation in the prognosis of IPF was analyzed, and a four-genes risk model was constructed, including tpbg, Myc, ffar2, and CCL2. It was highlighted by Kaplan Meier (K-M) survival analysis that patients with high-risk scores had worse overall survival time in all training and validation sets, and univariate and multivariate analysis highlighted that it has the potential to act as an independent risk indicator for poor prognosis. ROC analysis showed that the prediction efficiency of 1-, 3-, and 5-year OS time in the training set reached 0.784, 0.835, and 0.921, respectively. Immune infiltration analysis showed that Myeloid-Derived Suppressor Cells (MDSC), macrophages, regulatory T cells, cd4+ t cells, neutrophils, and dendritic cells were more infiltrated in the high-risk group than in the low-risk group. Conclusion: Inflammation-related genes can be well used to evaluate the IPF prognosis and impart a new idea for the treatment and follow-up management of IPF patients.

Dexamethasone reduces serum level of IL-17 in Bleomycin-A5-induced rats model of pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis is a chronic progressive disease with limited therapeutic options and inflammatory cytokines play important roles in the pathogenesis of pulmonary fibrosis. MATERIAL AND METHOD: Here, we investigated the changes of TGF-ß1, IL-8, and IL-17 in the serum of bleomycin-A5-induced rats model of pulmonary fibrosis. 120 healthy male Wistar rats were randomly divided into three groups, the control group (n = 30), the model group (n = 45) and the dexamethasone (DEX) group (n = 45). The rats of both model group and DEX group were injected with Bleomycin-A5 (5 mg/kg) through tracheofistulization to induce pulmonary fibrosis, while the rats of the control group were injected with equivalent physiological saline. After operation, DEX (4 mg/kg) was given to the DEX group rats intraperitoneally once a day. Equivalent saline was administered to rats of both the control group and the model group. RESULTS: On the 1st, 14th, and 28th day after operation, pathological changes of the lung tissues, and the levels of serum IL-8, TGF-ß1, and IL-17 were measured. The concentrations of serum TGF-ß1, IL-8, and IL-17 were significantly increased after bleomycin-A5 treatment, especially on the 14th day (p < .01). There was no significant difference between model group and DEX group in the serum level of TGF-ß1 and IL-8, but DEX treatment significantly reduce serum IL-17 level (p < .01). CONCLUSIONS: DEX protect bleomycin-A5-induced pulmonary fibrosis in rats through reduced the level of IL-17 in serum.

The association of SERPINE2 gene with COPD in a Chinese Han population.

PURPOSE: Polymorphisms of several candidate genes have been studied and associated with the development of chronic obstructive pulmonary disease (COPD). One such candidate is the SERPINE2 (Serpin peptidase inhibitor, clade E member 2) gene. MATERIALS AND METHODS: To assess whether the SERPINE2 gene is associated with COPD in a Chinese Han population. Samples were collected from a Chinese Han population and analyzed for the association of single nucleotide polymor phisms (SNPs) or haplotypes of SERPINE2 gene with COPD in a case-control study. Three SNPs including rs840088 G/A in intron 1, rs1438831 A/G in 5' upstream sequence and rs3795879 G/A in intron 3 were detected using the polymerase chain reaction (PCR)-based restriction fragment length polymorphism technique in 409 COPD subjects and 411 controls. Genotyping of the SREPINE2 polymorphisms at positions rs840088, rs1438831and rs3795879 was performed. RESULTS: We found that none of the rs840088G/A, rs1438831G/A and rs3795879 G/A polymorphisms were associated with the disease. The p-values were 0.630, 0.208 and 0.398 respectively. CONCLUSION: Our data suggested that there was no significant association between SERPINE2 polymorphism and COPD susceptibility in the Chinese Han population.