BackgroundTumor-associated macrophages (TAMs) play a critical role in modulating the tumor microenvironment and promote tumor metastases. Our studies have demonstrated that ginsenoside Rh2 (G-Rh2), a monomeric compound extracted from ginseng, is a promising anti-tumor agent in lung cancer cells. However, it remains unclear whetherG-Rh2 can modulate the differentiation of TAMs and its interaction with tumor microenvironment. In this study, we investigated how G-Rh2 regulates the phenotype of macrophages and affects the migration of non-small cell lung cancer (NSCLC) cells.MethodsMurine macrophage-like RAW264.7 cells and human THP-1 monocyte were differentiated into M1 and M2 subsets of macrophages with different cytokines combination, which were further identified by flow cytometry with specific biomarkers. M2 macrophages were sorted out to co-culture with NSCLC cell lines, A549 and H1299. Wound healing assay was performed to examine the cell migration. Expression levels of matrix metalloproteinases 2 and 9 (MMP-2, − 9) and vascular endothelial growth factor-C (VEGF-C) were measured by RT-qPCR and western blot, and the release of VEGF in the supernatant was measured by a VEGF ELISA kit. Finally, modulation of TAMs phenotype and VEGF expression by G-Rh2 was examined in vivo.ResultsWe demonstrated that M2 subset of macrophages alternatively differentiated from RAW264.7 or THP-1cells promote migration of NSCLC cells. Further examinations revealed that NSCLC significantly increased the release of VEGF to the media and elevated the expression levels of VEGF at mRNA and protein levels after being co-cultured with M2 macrophages. Similar alterations in MMP-2 and MMP-9 were observed in NSCLC after being co-cultured. Of note,G-Rh2 had a potential to effectively convert M2 phenotype to M1 subset of macrophages. Importantly, G-Rh2 had a preference to decrease the expression levels of VEGF, MMP2, and MMP9 in co-cultured lung cancer cells, over than those in lung cancer cells without co-culturing. Consistently, G-Rh2 reduced M2 macrophage marker CD206 and VEGF expression levels in vivo.ConclusionsAll of these results suggested that M2 subset macrophages drive lung cancer cells with more aggressive phenotypes. G-Rh2 has a potential to convert TAMs from M2 subset to M1 in the microenvironment and prevents lung cancer cell migration, suggesting the therapeutic effects of G-Rh2onlung cancer.

Objective. This study was aimed at investigating the prognostic significance of Baculoviral IAP repeat containing 5 (BIRC5) in lung adenocarcinoma (LAD) lacking EGFR, KRAS, and ALK mutations (triple-negative (TN) adenocarcinomas). Methods. The gene expression profiles were obtained from Gene Expression Omnibus (GEO). The identification of the differentially expressed genes (DEGs) was performed by GeneSpring GX. Gene set enrichment analysis (GSEA) was used to execute gene ontology function and pathway enrichment analysis. The protein interaction network was constructed by Cytoscape. The hub genes were extracted by MCODE and cytoHubba plugin from the network. Then, using BIRC5 as a candidate, the prognostic value in LAD and TN adenocarcinomas was verified by the Kaplan-Meier plotter and The Cancer Genome Atlas (TCGA) database, respectively. Finally, the mechanism of BIRC5 was predicted by a coexpressed network and enrichment analysis. Results. A total of 38 upregulated genes and 121 downregulated genes were identified. 9 hub genes were extracted. Among them, the mRNA expression of 5 genes, namely, BIRC5, MCM4, CDC20, KIAA0101, and TRIP13, were significantly upregulated among TN adenocarcinomas (all P<0.05). Notably, only the overexpression of BIRC5 was associated with unfavorable overall survival (OS) in TN adenocarcinomas (log rank P=0.0037). TN adenocarcinoma patients in the BIRC5 high-expression group suffered from a significantly high risk of distant metastasis (P=0.046), advanced N stage (P=0.033), and tumor-bearing (P=0.031) and deceased status (P=0.003). The mechanism of BIRC5 and coexpressed genes may be linked closely with the cell cycle. Conclusion. Overexpressed in tumors, BIRC5 is associated with unfavorable overall survival in TN adenocarcinomas. BIRC5 is a potential predictor and therapeutic target in TN adenocarcinomas.

IntroductionThe expression of USP22 has been demonstrated to play a pivotal role in solid tumors. However, the prognostic value of USP22 still remains unknown.Materials and methodsA systematic meta-analysis was performed to assess the prognostic value of USP22 in cancers. A literature collection was conducted from inception to June 8, 2017 by searching PubMed, Cochrane Library, Embase, Ovid and Web of Science databases. The pooled hazard ratio (HR) and odds ratio (OR) were used to correlate high expression of USP22 with overall survival (OS) and clinicopathological features.ResultsThe results, pooled by 19 studies with 2,876 cases, indicated that high expression of USP22 predicted poor OS (HR=2.48, 95% CI: 2.11–2.84, p<0.001) and disease-free survival (DFS; HR=2.55, 95% CI: 2.05–3.05, p<0.001) of cancer patients. Furthermore, high expression of USP22 was also significantly associated with advanced clinicopathological parameters, including tumor stage, tumor differentiation, metastasis, nodal status and tumor size.ConclusionOur finding revealed that USP22 might be an indicator of poor prognosis and advanced clinicopathological features of solid tumors and could be served as a novel biomarker.

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