DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in glioma.

BACKGROUND: DNA damage repair (DDR) alterations are important events in cancer initiation, progression, and therapeutic resistance. However, the involvement of DDR alterations in glioma malignancy needs further investigation. This study aims to characterize the clinical and molecular features of gliomas with DDR alterations and elucidate the biological process of DDR alterations that regulate the cross talk between gliomas and the tumor microenvironment. METHODS: Integrated transcriptomic and genomic analyses were undertaken to conduct a comprehensive investigation of the role of DDR alterations in glioma. The prognostic DDR-related cytokines were identified from multiple datasets. In vivo and in vitro experiments validated the role of p53, the key molecule of DDR, regulating M2 polarization of microglia in glioma. FINDINGS: DDR alterations are associated with clinical and molecular characteristics of glioma. Gliomas with DDR alterations exhibit distinct immune phenotypes, and immune cell types and cytokine processes. DDR-related cytokines have an unfavorable prognostic implication for GBM patients and are synergistic with DDR alterations. Overexpression of MDK mediated by p53, the key transcriptional factor in DDR pathways, remodels the GBM immunosuppressive microenvironment by promoting M2 polarization of microglia, suggesting a potential role of DDR in regulating the glioma microenvironment. INTERPRETATION: Our work suggests that DDR alterations significantly contribute to remodeling the glioma microenvironment via regulating the immune response and cytokine pathways. FUND: This study was supported by: 1. The National Key Research and Development Plan (No. 2016YFC0902500); 2. National Natural Science Foundation of China (No. 81702972, No. 81874204, No. 81572701, No. 81772666); 3. China Postdoctoral Science Foundation (2018M640305); 4. Special Fund Project of Translational Medicine in the Chinese-Russian Medical Research Center (No. CR201812); 5. The Research Project of the Chinese Society of Neuro-oncology, CACA (CSNO-2016-MSD12); 6. The Research Project of the Health and Family Planning Commission of Heilongjiang Province (2017-201); and 7. Harbin Medical University Innovation Fund (2017LCZX37, 2017RWZX03).

MicroRNA-365 suppressed cell proliferation and migration via targeting PAX6 in glioblastoma.

MicroRNAs (miRNAs) act an important role in the progression of tumor. In this study, we showed that the serum expression of miR-365 was downregulated in the glioblastoma compared with in the healthy controls. We also demonstrated that miR-365 expression was downregulated in glioblastoma tissues compared with the adjacent normal tissues. Overexpression of miR-365 suppressed the glioblastoma cell proliferation and migration. Moreover, ectopic expression of miR-365 promoted the expression of Ecadherin while inhibited the expression of N-cadherin and Vimentin in U87 cell. Furthermore, we identified PAX6 as a direct target gene of miR-365 in U87 cell. Overexpression of miR-365 suppressed glioblastoma cell proliferation and migration and epithelial-to-mesenchymal transition through inhibiting PAX6 expression. These results suggested that miR-365 played a tumor suppressor in glioblastoma.

Pep-1 peptide-functionalized liposome to enhance the anticancer efficacy of cilengitide in glioma treatment.

In this study, we have established an effective and novel nanocarrier system for the effective treatment of glioma. We have established the glioma tissue penetrating nanocarrier system by conjugating Pep-1 as a targeting ligand on the liposome surface to enhance the anticancer efficacy of cilengitide (CGL). The particles were nanosized and exhibited a controlled release of drug in both the pH conditions. The cellular uptake assay showed that conjugation of Pep-1 on the liposome surface remarkably increased the cellular uptake. The uptake of CGT-loaded Pep-1 peptide-conjugated liposome (PeCNL) increased to 89.8% compared to 47.5% for CNL indicating the efficient internalization of the nanocarriers. Consistently, PeCNL exhibited a significantly higher cytotoxic effect in cancer cells compared to that of non-targeted CGT-loaded liposome (CNL). PeCNL exhibited a higher apoptosis of cancer cells (∼35%) compared to that of CNL. Most importantly, PeCNL exhibited a significantly superior anticancer effect with tumor volume as low as ∼350mm3 indicating the superior anticancer potential of targeted formulations. Similarly, PeCNL showed the lowest staining for Ki67 indicating that the targeted NP has the maximum effect in controlling the proliferation of cancer cells. Taken together, Pep-1 conjugated liposome could exhibit better antitumor efficacy when applied to IL-13R2 receptor overexpressed specific brain glioma.

miR-590-3p suppresses cancer cell migration, invasion and epithelial-mesenchymal transition in glioblastoma multiforme by targeting ZEB1 and ZEB2.

Invasion and migration of glioblastoma multiforme (GBM) is a multistep process and an important phenotype that causes this disease to invade surrounding tissues in the brain. The purpose of this study was to determine the role of miR-590-3p in regulation of epithelial mesenchymal transition (EMT) and metastasis of GBM cells. Expression levels of miR-590-3p in 15 GBM specimens with adjacent tissues and five GBM cell lines were assessed by quantitative RT-PCR. We found that miR-590-3p was down-regulated in detected GBM tissue samples and all of the GBM cell lines. In addition, Ectopic expression of miR-590-3p suppressed and miR-590-3p-in promoted EMT, migration, and invasion in U87MG and A172 cells. Bioinformatics coupled with luciferase and Western blot assays also revealed that miR-590-3p inhibited expression of ZEB1 and ZEB2, which are master regulators of tumor metastasis. Our study first indicates that miR-590-3p functions as a suppressor of GBM EMT and metastasis by targeting ZEB1 and ZEB2, and it may be a therapeutic target for metastatic GBM.

Treatment of malignant glioma using hyperthermia.

Thirty pathologically diagnosed patients with grade III-IV primary or recurrent malignant glioma (tumor diameter 3-7 cm) were randomly divided into two groups. The control group underwent conventional radiotherapy and chemotherapy. In the hyperthermia group, primary cases received hyperthermia treatment, and patients with recurrent tumors were treated with hyperthermia in com-bination with radiotherapy and chemotherapy. Hyperthermia treatment was administered using a 13.56-MHz radio frequency hyperthermia device. Electrodes were inserted into the tumor with the aid of a CT-guided stereotactic apparatus and heat was applied for 1 hour. During 3 months after hyperthermia, patients were evaluated with head CT or MRI every month. Gliomas in the hyper-thermia group exhibited growth retardation or growth termination. Necrosis was evident in 80% of the heated tumor tissue and there was a decrease in tumor diameter. Our findings indicate that ra-dio frequency hyperthermia has a beneficial effect in the treatment of malignant glioma.