BackgroundTumor recurrence, the chief reason for poor prognosis of glioma, is largely attributed to glioma stem cells (GSCs) and epithelial-mesenchymal transition (EMT). However, the mechanisms among them remain unknown. Here, we determined whether leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), known as a stem cell marker for colon cancer and gastric cancer, can serve as a novel GSC marker involved in EMT and a therapeutic target in glioma.MethodsStemness properties were examined in FACS-isolated LGR5+/LGR5− cells. Reported stem cell markers, EMT and the Wnt/β-catenin pathway were examined in stable LGR5 knockdown or overexpressed GSCs by Western Blot. The treatment experiment was performed in an intracranial orthotopic xenograft model by knockdown of LGR5 or by using the Wnt/β-catenin pathway inhibitor Wnt-C59. LGR5 expression was determined in 268 glioma specimens by immunohistochemistry.ResultsLGR5+ cells possessed stronger stemness properties compared to LGR5− cells. The expression of SOX2, Nanog, CD133, CD44, CD24 and EpCAM was modulated by LGR5. Both LGR5 knockdown and Wnt-C59 reduced tumor invasion and migration and blocked EMT by inhibiting the Wnt/β-catenin pathway in vitro and suppressed the intracranial orthotopic xenograft growth and prolonged the survival of xenograft mice in vivo. Moreover, LGR5 was positively correlated with Ki67, N-cadherin and WHO grade and negatively correlated with IDH1. Glioma patients with high expression of LGR5 showed significantly poorer prognosis.ConclusionsLGR5 is a new functional GSC marker and prognostic indicator that can promote EMT by activating the Wnt/β-catenin pathway and would thus be a novel therapeutic target for glioma.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0864-6) contains supplementary material, which is available to authorized users.

Recent studies suggest that inflammation response biomarkers are prognostic indicators of solid tumor outcomes. Here, we quantify the prognostic value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in glioblastomas (GBMs), taking into consideration the role of the isocitrate dehydrogenase (IDH) mutation status. We examined 141 primary glioblastomas (pGBMs) and 25 secondary glioblastomas (sGBMs). NLRs, PLRs, and LMRs were calculated before surgery. IDH mutations were detected immunohistochemically after tumor resection, and patients' clinical outcomes were analyzed after classification into GBM, pGBM, and IDH-wild type glioblastoma (IDH-wt GBM) groups. To make comparisons, we set cutoffs for NLR, PLR and LMR of 4.0, 175.0, and 3.7, respectively. In a multivariate analysis, both NLR (HR=1.712, 95% CI 1.026-2.858, p=0.040) and PLR (HR=2.051, 95% CI 1.288-3.267, p=0.002) had independent prognostic value. While a low NLR was associated with a better prognosis only in the IDH-wt GBM group, PLR was predictive of patient survival in the GBM, pGBM, and IDH-wt GBM groups. By contrast, LMR exhibited no prognostic value for any of the 3 types of GBM.

BackgroundANXA2 (Annexin A2) is a pleiotropic calcium-dependent phospholipid binding protein that is abnormally expressed in various cancers. We previously found that ANXA2 is upregulated in esophageal squamous cell carcinoma (ESCC). This study was designed to investigate the functional significance of ANXA2 dysregulation and underlying mechanism in ESCC.MethodsProliferation, migration, invasion and metastasis assay were performed to examine the functional roles of ANXA2 in ESCC cells in vitro and in vivo. Real-time RT-PCR, immunoblotting, ChIP, reporter assay, confocal-immunofluorescence staining, co-immunoprecipitation and ubiquitination assay were used to explore the molecular mechanism underlying the actions of deregulated ANXA2 in ESCC cells.ResultsOverexpression of ANXA2 promoted ESCC cells migration and invasion in vitro and metastasis in vivo through activation of the MYC-HIF1A-VEGF cascade. Notably, ANXA2 phosphorylation at Tyr23 by SRC led to its translocation into the nucleus and enhanced the metastatic potential of ESCC cells. Phosphorylated ANXA2 (Tyr23) interacted with MYC and inhibited ubiquitin-dependent proteasomal degradation of MYC protein. Accumulated MYC directly potentiated HIF1A transcription and then activated VEGF expression. Correlation between these molecules were also found in ESCC tissues. Moreover, dasatinib in combination with bevacizumab or ANXA2-siRNA produced potent inhibitory effects on the growth of ESCC xenograft tumors in vivo.ConclusionsThis study provides evidence that highly expressed p-ANXA2 (Tyr23) contributes to ESCC progression by promoting migration, invasion and metastasis, and suggests that targeting the SRC-ANXA2-MYC-HIF1A-MYC axis may be an efficient strategy for ESCC treatment.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0851-y) contains supplementary material, which is available to authorized users.

No abstract

The prognosis of patients with glioblastoma (GBM) is dismal. It has been reported that Insulin-like growth factor (IGF) binding protein 2 (IGFBP2) is associated with the mobility and invasion of tumor cells. We investigated the expression of IGFBP2 mRNA in GBMs and its clinical relevance, using tissue microarrays and RNAscope in situ hybridization in 180 GBMs and 13 normal or edematous tissues. The correlations between the expression and clinical pathological parameters as well as some other biomarkers were analyzed. Overexpression of IGFBP2 mRNA was observed in 23.9% of tumors tested. No expression of IGFBP2 mRNA was detected in normal or edematous tissues. Kaplan–Meier survival analysis showed that the survival time of all the patients with high IGFBP2 tumors had shorter survival than those with low IGFBP2 (P<0.01). Univariate regression and multivariate regression both indicated that the expression of IGFBP2 transcript level was an independent prognostic factor (P=0.008 and 0.007, respectively). Furthermore, expression of IGFBP2 mRNA was related to the occurrence of isocitrate dehydrogenase 1 (IDH1) mutation, high heat shock protein 27 (Hsp27) expression and telomerase reverse transcriptase (TERT) promoter mutation (TERTp+) (P=0.013, 0.015 and 0.016, respectively), and patients with TERTp+/IGFBP2high showed the shortest survival. In conclusion, IGFBP2 mRNA expression status is an independent prognostic biomarker in GBMs, and the combination of IGFBP2 mRNA and TERTp status might serve as a prognostic indicator in patients with GBM.