SETDB1 promotes glioblastoma growth via CSF-1-dependent macrophage recruitment by activating the AKT/mTOR signaling pathway.

BACKGROUND: Glioblastoma is a common disease of the central nervous system (CNS), with high morbidity and mortality. In the infiltrate in the tumor microenvironment, tumor-associated macrophages (TAMs) are abundant, which are important factors in glioblastoma progression. However, the exact details of TAMs in glioblastoma progression have yet to be determined. METHODS: The clinical relevance of SET domain bifurcated 1 (SETDB1) was analyzed by immunohistochemistry, real-time PCR and Western blotting of glioblastoma tissues. SETDB1-induced cell proliferation, migration and invasion were investigated by CCK-8 assay, colony formation assay, wound healing and Transwell assay. The relationship between SETDB1 and colony stimulating factor 1 (CSF-1), as well as TAMs recruitment was examined by Western blotting, real-time PCR and syngeneic mouse model. RESULTS: Our findings showed that SETDB1 upregulated in glioblastoma and relative to poor progression. Gain and loss of function approaches showed the SETDB1 overexpression promotes cell proliferation, migration and invasion in glioblastoma cells. However, knockdown SETDB1 exerted opposite effects in vitro. Moreover, SETDB1 promotes AKT/mTOR-dependent CSF-1 induction and secretion, which leads to macrophage recruitment in the tumor, resulted in tumor growth. CONCLUSION: Our research clarified that SETDB1 regulates of tumor microenvironment and hence presents a potential therapeutic target for treating glioblastoma.

BET degrader inhibits tumor progression and stem-like cell growth via Wnt/ß-catenin signaling repression in glioma cells.

Based on their histological appearance, gliomas are a very common primary tumor type of the brain and are classified into grades, Grade I to Grade IV, of the World Health Organization. Treatment failure is due to the cancer stem cells (CSC) phenotype maintenance and self-renewal. BET degraders such as ZBC260 represents a novel class of BET inhibitors that act by inducing BET proteins degradation. This study explores the mode of action and effects of ZBC260 in vivo and in vitro against glioma. By inhibiting cell proliferation and inducting cell cycle arrest, the fact that glioma cell lines show sensitivity to ZBC260. Notably, ZBC260 targeted glioma without side effects in vivo. In addition, the stem cell-like properties of glioma cells were inhibited upon ZBC260 treatment. When the mechanism was examined, our findings indicated that Wnt/ß-catenin pathway repression is required for ZBC260-induced stem cell-like properties and tumor growth suppression. In conclusion, the growth of tumors and stem cell-like properties were inhibited by ZBC260 via Wnt/ß-catenin repression, which suggests ZBC260 as a potential therapeutic agent for glioma.

Lysophosphatidic acid enhances neointimal hyperplasia following vascular injury through modulating proliferation, autophagy, inflammation and oxidative stress.

Lysophosphatidic acid (LPA), which is one of the intermediate products of membrane phospholipid metabolism, is a bioactive phospholipid that possesses diverse activities. In the present study, the effects of LPA on neointimal formation following vascular injury were investigated. A carotid artery balloon injury model was employed in the present study, and following vascular injury, rats received an intraperitoneal injection of 1 mg/kg LPA. Subsequently, histopathological alterations were assessed by hematoxylin and eosin staining, the expression levels of proliferating cell nuclear antigen (PCNA) were detected by immunohistochemistry, apoptosis was assessed via a terminal deoxynucleotidyl transferase­mediated dUTP nick end labeling assay, and the expression levels of apoptosis­associated and autophagy­associated proteins were detected by western blotting. In addition, inflammatory and oxidative stress­associated factors were assessed by reverse transcription­quantitative polymerase chain reaction or corresponding kits. The results of the present study demonstrated that LPA enhanced vascular injury­induced neointimal hyperplasia. LPA further elevated the expression levels of PCNA in the injured carotid artery tissues. LPA exhibited no effect on apoptosis in carotid artery tissues, whereas it modulated autophagy in the injured carotid artery tissues. Furthermore, LPA enhanced vascular injury­induced inflammation and oxidative stress. The present study demonstrated that LPA may enhance neointimal hyperplasia following vascular injury by modulating proliferation, autophagy, inflammation and oxidative stress, but not apoptosis. Furthermore LPA may contribute to the pathology of atherosclerosis and may be considered a promising therapeutic target for the treatment of atherosclerosis.