Clear cell renal cell carcinoma (ccRCC) are typically situated in a complex inflammatory and immune microenvironment, which has been reported to contribute to the unfavorable prognosis of patients with ccRCC. There would be beneficial clinical implications for elucidating the roles of its molecular characteristics in the inflammatory microenvironment. This is because it would facilitate the development of reliable biomarkers for pre-stratification prior to the designation of individualized treatment strategies. In the present study, RNA-sequencing data from 607 patients were retrospectively analyzed to elucidate the profile of inflammatory molecules. Based on this, an inflammatory prognostic signature (IPS) was developed and further validated using clinical ccRCC samples. Subsequently, the associated mechanisms in terms of the immune microenvironment and molecular pathways were then investigated. This proposed IPS was found to exhibit superior accuracy compared with the criterion of a good prognostic model for the prediction of patient prognosis from ccRCC [area under the receiver operating characteristic curve (AUC)=0.811] in addition to being an independent factor for prognostic risk stratification [hazard ratio: 11.73 (95% CI, 26.98-5.10); log-rank test, P<0.001]. Pathologically, ccRCC cells identified as high-risk according to their IPS presented with a more malignant tumor structure, including voluminous eosinophilic cytoplasm, acinar/lamellar/tubular growth patterns and atypic nuclei. High-risk ccRCC also exhibited higher infiltration levels by four types of immune cells, including T regulatory cells, but lower infiltration levels by mast cells. Pathways associated with immune-inflammation interaction, including the IL-17 pathway, were found to be upregulated in IPS-identified high-risk ccRCC. Furthermore, by combining the IPS with clinical factors, an integrated prognostic index was developed and validated for increasing the accuracy of patient risk-stratification for ccRCC (AUC= 0.911). In conclusion, the complex regulatory mechanisms and molecular characteristics involved in ccRCC-inflammation interaction, coupled with their prognostic potential, were systematically elucidated in the present study. This may have important implications in furthering the understanding into the molecular mechanisms underlying this ccRCC-inflammation interaction, which can in turn be exploited for identifying high-risk patients with ccRCC prior to designing their clinical treatment strategy.
Interleukin-18 (IL-18) is a multifunctional cytokine that exhibits antitumor, anti-infection and immunoregulatory functions. This study aimed to investigate the effects of lentiviral vector-packaged interleukin (IL)-18 gene on the malignant behavior of lung cancer and the potential underlying molecular mechanism of IL-18 anticancer activity. Human lung adenocarcinoma A549 cells transfected with human IL-18 gene-containing lentiviral expression vector were the IL-18 intervention group (group A), cells transfected with the empty lentiviral expression vector were empty vector group (group B), and cells without any intervention were the blank control group (group C). Reverse transcription-quantitative PCR and western blotting were used to determine IL-18 mRNA and protein expression levels. Cell Counting Kit-8, colony-formation, flow cytometry, invasion and wound-healing assays were used to evaluate the malignant behavior of A549 cells transfected with the IL-18 lentiviral vector. The expression levels of the T helper (Th)1 cell cytokine interferon-γ (IFN-γ) and the Th2 cell cytokine IL-4 were tested by ELISA, and western blotting was used to test the expressing of nuclear factor κB (NF-κB). The results demonstrated that IL-18 mRNA and protein expression levels in group A were significantly increased compared with groups B and C; the expression levels of IFN-γ in group A were higher and the expression levels of IL-4 in group A were lower compared with those in groups B and C; and the expression of NF-κB was increased in the cytoplasm and decreased in the nucleus in group A compared with groups B and C. The data indicated that, compared with the control groups, the IL-18 gene lentiviral expression vector increased the expression of IL-18, diminished A549 cell proliferative ability, enhanced apoptosis, decreased the invasive and metastatic capacities of the cells, promoted the secretion of IFN-γ, decreased the production of IL-4, reversed the imbalance of Th1/Th2 cell subsets and inhibited the nuclear activation of NF-κB, which collectively present an anti-lung cancer mechanism and deserve further study.
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