Diagnostic Value of GDF10 for the Tumorigenesis and Immune Infiltration in Lung Squamous Cell Carcinoma.

OBJECTIVE: Lung squamous cell carcinoma (LUSC) is associated with a low survival rate. Evidence suggests that bone morphogenetic proteins (BMPs) and their receptors (BMPRs) play crucial roles in tumorigenesis and progression. However, a comprehensive analysis of their role in LUSC is lacking. Our study aimed to explore the relationship between BMPs/BMPRs expression levels and the tumorigenesis and prognosis of LUSC. METHODS: The "R/Limma" package was utilized to analyze the differential expression characteristics of BMPs/BMPRs in LUSC, using data from TCGA, GTEx, and GEO databases. Concurrently, the "survminer" packages were employed to investigate their prognostic value and correlation with clinical features in LUSC. The core gene associated with LUSC progression was further explored through weighted gene correlation network analysis (WGCNA). LASSO analysis was conducted to construct a prognostic risk model for LUSC. Clinical specimens were examined by immunohistochemical analysis to confirm the diagnostic value in LUSC. Furthermore, based on the tumor immune estimation resource database and tumor-immune system interaction database, the role of the core gene in the tumor microenvironment of LUSC was explored. RESULTS: GDF10 had a significant correlation only with the pathological T stage of LUSC, and the protein expression level of GDF10 decreased with the tumorigenesis of LUSC. A prognostic risk model was constructed with GDF10 as the core gene and 5 hub genes (HRASLS, HIST1H2BH, FLRT3, CHEK2, and ALPL) for LUSC. GDF10 showed a significant positive correlation with immune cell infiltration and immune checkpoint expression. CONCLUSION: GDF10 might serve as a diagnostic biomarker reflecting the tumorigenesis of LUSC and regulating the tumor immune microenvironment to guide more effective treatment for LUSC.

Identification and validation of DPY30 as a prognostic biomarker and tumor immune microenvironment infiltration characterization in esophageal cancer.

Esophageal cancer (ESCA) is a lethal malignancy and is associated with the alterations of various genes and epigenetic modifications. The protein dpy-30 homolog (DPY30) is a core member of histone H3K4 methylation catalase and its dysfunction is associated with the occurrence and development of cancer. Therefore, the present study investigated the role of DPY30 in ESCA and evaluated the association between the expression of DPY30, the clinicopathological characteristics of ESCA and the tumor immune microenvironment. It conducted a comprehensive analysis of DPY30 in patients with ESCA using The Cancer Genome Atlas (TCGA) database and clinical tissue microarray specimens of ESCA. Immunohistochemistry was performed to assess the expression levels of DPY30 in tissues. Receiver operating curve analysis, Kaplan-Meier survival analysis and Cox regression analysis were performed to identify the diagnostic and prognostic value of DPY30. Gene Set Enrichment Analysis, protein-protein interaction network and Estimation of Stromal and Immune cells in Malignant Tumor tissues using the Expression data were used to screen DPY30-associated genes and evaluate the immune score of the TCGA samples. The results demonstrated that the expression of mRNA and protein levels of DPY30 were significantly upregulated in tumor tissues compared with normal tissue samples. The expression of DPY30 was closely associated with the poor prognosis of patients with ESCA. The present study also found that DPY30 expression and the pathological characteristics of ESCA were significantly correlated. Additionally, the expression of DPY30 demonstrated a significant positive correlation with various immune cells infiltration. The results suggested that DPY30 might influence tumor immune infiltration. In conclusion, the findings suggested that DPY30 might be a potential prognostic biomarker and an immunotherapeutic target in ESCA.

Downregulation of T-cell cytotoxic marker IL18R1 promotes cancer proliferation and migration and is associated with dismal prognosis and immunity in lung squamous cell carcinoma.

Immunotherapy can improve the survival of patients with advanced lung squamous cell carcinoma (LUSC). T cytotoxic cells are one of the main members of the immune microenvironment. Herein, we aimed to identify the roles of T-cell cytotoxic markers interleukin 18 (IL18) receptor 1 (IL18R1) in the LUSC progression using bioinformatics, clinical tissue specimen, and cell experiment. We assessed the association between the IL18R1 expression and immune infiltration and IL18R1-related competing RNA network. The IL18R1 expression was downregulated in the LUSC tissues. The IL18R1 expression downregulation was associated with diagnosis and short overall survival and disease-specific survival, and it was also an independent risk factor for dismal survival time in LUSC. IL18R1-related nomograms predicted the survival time of patients with LUSC. IL18R1 overexpression inhibited the proliferation, migration, and invasion of LUSC cells. The IL18R1 expression was significantly associated with the microenvironment (stromal, immune, and estimate scores), immune cells (such as the T cells, cytotoxic cells, CD8 T cells), and immune cell markers (such as the CD8A, PD-1, and CTLA4) in LUSC. AC091563.1 and RBPMS-AS1 downregulation was positively associated with the IL18R1 expression, negatively associated with the miR-128-3p expression, and associated with short disease-specific survival and progression in LUSC. In conclusion, IL18R1 was significantly downregulated and associated with the prognosis and immune microenvironment. IL18R1 overexpression inhibits the growth and migration of cancer cells in LUSC. Furthermore, AC091563.1 and RBPMS-AS1 might compete with IL18R1 to bind miR-128-3p for participating in LUSC progression. These results showed that IL18R1 is a biomarker for evaluating the prognosis of patients with LUSC.

MiRNA-122 Promotes Ischemia-Reperfusion Injury after Lung Transplantation via the Toll-like Receptor Signaling Pathway.

OBJECTIVE: MiRNAs have been recently implicated in the pathogenesis of ischemia-reperfusion (IR) injury. This study aimed to investigate the miRNA expression profiles in the early stages after lung transplantation (LT) and to study the involvement of the Toll-like receptor (TLR) signaling pathway in lung IR injury following LT. METHODS: We established the left LT model in mice and selected the miRNA-122 as a research target. The mice were injected with a miRNA-122-specific inhibitor, following which pathological changes in the lung tissue were studied using different lung injury indicators. In addition, we performed deep sequencing of transplanted lung tissues to identify differentially expressed (DE) miRNAs and their target genes. These target genes were used to further perform gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RESULTS: A total of 12 DE miRNAs were selected, and 2476 target genes were identified. The GO enrichment analysis predicted 6063 terms, and the KEGG analysis predicted 1554 biological pathways. Compared with the control group, inhibiting the expression of miRNA-122 significantly reduced the lung injury and lung wet/dry ratio (P<0.05). In addition, the activity of myeloperoxidase and the expression levels of tumor necrosis factor-alpha and TLR2/4 were decreased (P<0.05); whereas the expression of interleukin-10 was increased (P<0.05). Furthermore, the inhibition of miRNA-122 suppressed the IR injury-induced activation of the TLR signaling pathway. CONCLUSION: Our findings showed the differential expression of several miRNAs in the early inflammatory response following LT. Of these, miRNA-122 promoted IR injury following LT, whereas its inhibition prevented IR injury in a TLR-dependent manner.

Monocytes promote pyroptosis of endothelial cells during lung ischemia-reperfusion via IL-1R/NF-κB/NLRP3 signaling.

In our previous study, we observed that donor pulmonary intravascular nonclassical monocytes play a major role in early PGF, but the specific mechanism remained unclear. In this study, we investigated the mechanistic role of monocytes in inducing pyroptosis of human pulmonary microvascular endothelial cells (HPMECs) during IRI. A murine hilar ligation model of IRI was utilized whereby left lungs underwent 1 h of ischemia and 23 h of reperfusion. Monocyte depletion by intraperitoneal clodronate-liposome treatment on pulmonary edema and pyroptosis activation were determined. In vitro experiments, we performed the co-culture experiments under hypoxia-reoxygenation (H/R) conditions to mimic the IRI environment. We monitored the expression of NLRP3, caspase-1 and IL-1ß in co-cultures of monocytes (U937 cells) and HPMECs under H/R conditions. NLRP3, IL-1ß and IL-1R siRNA knockdown, caspase-1 and NF-κB pathway inhibitors were employed to elucidate the mechanism modulating HPMEC pyroptosis during H/R. Treatment of mice with clodronate-liposome attenuated IR-induced pulmonary edema, cytokine production and pyroptosis activation. In vitro, NLRP3 knockdown in monocytes reduced caspase-1 and IL-1ß secretion in co-cultures of monocytes and HPMECs. Reduced HPMEC pyroptosis was also observed either containing HPMECs with genetically engineered IL-1R knockdown or in co-culture treated with a Triplotide inhibitor that disrupts NF-κB signaling. Monocytes play a vital role in the development of transplant-associated ischemia-reperfusion injury. A potential role is that monocytes secrete IL-1ß to induce HPMEC pyroptosis via the IL-1R/NF-κB/NLRP3 pathway.