Previous studies have confirmed that microRNA (miR)-128-3p is expressed at low levels in gastric cancer (GC), and low miR-128-3p expression promotes the growth of GC cells. However, whether the dysregulation of miR-128-3p expression affects tumor-infiltrating lymphocytes (TILs) and leads to immune escape remains unclear. In the present study, predictive bioinformatics approaches showed that miR-128-3p expression was inversely correlated with tumor-infiltrating lymphocyte enrichment. When CD4 + T cells and regulatory T cells (Tregs) were enriched, lower miR-128-3p expression was associated with worse overall survival. However, when numbers of CD8 + T cells were decreased, the upregulation of miR-128-3p expression had a favorable effect on GC prognosis. Dual-luciferase reporter assays and cell biology experiments revealed that interleukin 16 (IL16) was the target of miR-128-3p and was negatively regulated by miR-128-3p. In addition, GC cells were cocultured with T lymphocytes, and the subsequent flow cytometric analysis showed that overexpression of miR-128-3p in tumor cells decreased the percentages of CD4+ CD25+ Foxp3+ Tregs by downregulating IL16 expression in GC, whereas miR-128-3p inhibition had the opposite effect. Moreover, the recombinant IL16 reversed the effects of miR-128-3p overexpression, and a competitive antibody against the IL16 receptor CD4 also reversed the effects of miR-128-3p knockdown. These studies identified the mechanism by which the miR-128-3p/IL16 axis promotes the infiltration of CD4+ Tregs in GC, and this mechanism will be a promising therapeutic target in GC immunotherapy.

The mechanism of colistin-induced neurotoxicity is still unknown. Our recent study (L. Zhang, Y. H. Zhao, W. J. Ding, G. Z. Jiang, Z. Y. Lu, L. Li, J. L. Wang, J. Li, and J. C. Li, Antimicrob Agents Chemother 59:2189–2197, 2015, http://dx.doi.org/10.1128/AAC.04092-14 ; H. Jiang, J. C. Li, T. Zhou, C. H. Wang, H. Zhang, and H. Wang, Int J Mol Med 33:1298–1304, 2014, http://dx.doi.org/10.3892/ijmm.2014.1684 ) indicates that colistin induces autophagy and apoptosis in rat adrenal medulla PC-12 cells, and there is interplay between both cellular events. As an important cellular stress sensor, phosphoprotein p53 can trigger cell cycle arrest and apoptosis and regulate autophagy. The aim of the present study was to investigate the involvement of the p53 pathway in colistin-induced neurotoxicity in PC-12 cells. Specifically, cells were treated with colistin (125 μg/ml) in the absence and presence of a p53 inhibitor, pifithrin-α (PFT-α; 20 nM), for 12 h and 24 h, and the typical hallmarks of autophagy and apoptosis were examined by fluorescence/immunofluorescence microscopy and electron microscopy, real-time PCR, and Western blotting. The results indicate that colistin had a stimulatory effect on the expression levels of the target genes and proteins involved in autophagy and apoptosis, including LC3-II/I, p53, DRAM (damage-regulated autophagy modulator), PUMA (p53 upregulated modulator of apoptosis), Bax, p-AMPK (activated form of AMP-activated protein kinase), and caspase-3. In contrast, colistin appeared to have an inhibitory effect on the expression of p-mTOR (activated form of mammalian target of rapamycin), which is another target protein in autophagy. Importantly, analysis of the levels of p53 in the cells treated with colistin revealed an increase in nuclear p53 at 12 h and cytoplasmic p53 at 24 h. Pretreatment of colistin-treated cells with PFT-α inhibited autophagy and promoted colistin-induced apoptosis. This is the first study to demonstrate that colistin-induced autophagy and apoptosis are associated with the p53-mediated pathway.

Gastric cancer (GC) is a prevalent malignant cancer characterized by a poor survival rate. The C-type lectin domain family 11 member A (CLEC11A) is part of the C-type lectin superfamily, and its dysregulation has been implicated in the progression of several cancers. The specific role of CLEC11A and its association with immune infiltration in GC, however, remains unclear. In this study, we employed The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database, Tumor IMmune Estimation Resource (TIMER) database, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan–Meier plotter databases, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and the CIBERSORT algorithm to investigate CLEC11A expression, its prognostic significance, its association with tumor immune infiltration, and gene function enrichment in GC. We conducted western blotting, Cell Counting Kit-8 (CCK-8), wound healing, and transwell assays to validate CLEC11A's function. We found that CLEC11A expression was significantly elevated in GC when compared to adjacent non-tumor tissues. Elevated CLEC11A expression was strongly associated with poor survival outcomes and advanced clinicopathological stages. Moreover, heightened CLEC11A expression positively correlated with immunomodulators, chemokines, and the infiltration of immune cells, especially M2 macrophages, in GC. Additionally, CLEC11A silencing suppressed GC cells proliferation, migration and invasion in vitro. Our results elucidate the functions of CLEC11A in GC, suggesting its potential as a valuable prognostic biomarker and therapeutic target for GC immunotherapy.

Increasing studies have reported that circular RNAs (circRNAs) play critical roles in tumorigenesis and cancer progression. However, the underlying regulatory mechanisms of circRNA-related competing endogenous RNA (ceRNA) in liver hepatocellular carcinoma (LIHC) are still unclear. In the present study, we discovered dysregulated circRNAs through Gene Expression Omnibus (GEO) analysis and validated the expression of the top seven circRNAs with upregulated expression by qRT–PCR and Sanger sequencing. Then, the Cancer-Specific CircRNA Database (CSCD) was used to predict the downstream miRNAs of seven circRNAs, and expression and survival analyses through The Cancer Genome Atlas (TCGA) were performed to identify the key miRNA in LIHC. Thereafter, the hsa_circ_0017264-hsa-miR-195–5p subnetwork was successfully constructed. Subsequently, we predicted downstream target genes of hsa-miR-195–5p with TargetScan, miRDB, and mirtarbase and overlapped them with differentially expressed mRNAs to obtain 21 target genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to predict the biological and functional roles of these target genes. Finally, with Pearson correlation and prognostic value analysis, a survival-related hsa_circ_0017264-hsa-miR-195-5p-CHEK1/CDC25A/FOXK1 axis was established. Gene set enrichment analysis (GSEA) was performed to determine the function of CHEK1/CDC25A/FOXK1 in the ceRNA network. Moreover, immune infiltration analysis revealed that the ceRNA network was markedly associated with the levels of multiple immune cell infiltrates, immune cell biomarkers and immune checkpoints. Overall, the hsa_circ_0017264-hsa-miR-195-5p-CHEK1/CDC25A/FOXK1 network might provide novel insights into the potential mechanisms underlying LIHC onset and progression.

Liver hepatocellular carcinoma (LIHC) seriously endangers the health and quality of life of individuals worldwide. Increasing evidence has underscored that the copper metabolism MURR1 domain (COMMD) family plays important roles in tumorigenesis. However, the specific role, biological function, mechanism and prognostic value of COMMD2 and its correlation with immune cell infiltration in LIHC remain unknown. In this study, we first determined the expression and prognostic potential of COMMD2 in human tumors using The Cancer Genome Atlas (TCGA) data and identified COMMD2 as a potential oncogene in LIHC. High COMMD2 expression was associated with pathological tumor stage and metastasis. Subsequently, noncoding RNAs (ncRNAs) upregulating COMMD2 expression were identified by performing expression, correlation, and survival analyses in combination. The CRNDE/LINC00511/SNHG17/HCG18-miR-29c-3p axis was identified as the most likely ncRNA-associated pathway upstream of COMMD2 in LIHC. Next, the expression profiles of COMMD2 and ncRNAs were validated in LIHC tissues and adjacent normal tissues. Furthermore, COMMD2 was significantly positively correlated with tumor immune cell infiltration, immune cell biomarkers, and immune checkpoint molecule expression. Importantly, COMMD2 potentially influenced prognosis by regulating immune cell infiltration in LIHC. Finally, COMMD2 was knocked down in LIHC cell lines using siRNAs for functional assays in vitro, resulting in suppressed cell proliferation and migration. In summary, our findings showed that the ncRNA-mediated upregulation of COMMD2 was associated with an unfavorable prognosis correlated with immune cell infiltration in LIHC.