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Transforming growth factor beta (TGF-β)-regulated long-non-coding RNAs (lncRNAs) modulate several aspects of tumor development such as proliferation, invasion, metastasis, epithelial to mesenchymal transition (EMT), and drug resistance in various cancers, including Glioblastoma multiforme (GBM). We identified several novel differentially expressed lncRNAs upon TGF-β treatment in glioma cells using genome-wide microarray screening. We show that TGF-β induces lncRNA-MUF in glioma cells, and its expression is significantly upregulated in glioma tissues and is associated with poor overall survival of GBM patients. Knockdown of lncRNA-MUF reduces proliferation, migration, and invasion in glioma cells and sensitizes them to temozolomide (TMZ)-induced apoptosis. In addition, lncRNA-MUF downregulation impairs TGF-β-induced smad2/3 phosphorylation. In line with its role in regulating invasion, lncRNA-MUF functions as a competing endogenous RNA (ceRNA) for miR-34a and promotes Snail1 expression. Collectively, our findings suggest lncRNA-MUF as an attractive therapeutic target for GBM.

Growing evidence suggests an essential role of neuroinflammation in behavioral abnormalities associated with hepatic encephalopathy (HE). Here, we report the involvement of autotaxin−lysophosphatidic acid (LPA) signaling in HE's pathogenesis. We demonstrate that the autotaxin (ATX) inhibitor PF-8380 attenuates neuroinflammation and improves neurological dysfunction in the mouse model of HE. In the thioacetamide (TAA)-induced model of HE, we found a twofold increase in the levels of ammonia in the brain and in plasma along with a significant change in HE-related behavioral parameters. Mice with HE show an increased brain weight, increased levels of tumor necrosis factor-α (TNF-α), IL-1β (interleukin-1β), interleukin-6 (IL-6), and LPA 18:0 in the cerebral cortex and hippocampus, and increased levels of LPA 18:0 in plasma. Treatment with the autotaxin inhibitor (ATXi) did not affect liver injury, as we observed no change in liver function markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) and no change in ammonia levels in the brain and plasma. However, ATXi treatment significantly ameliorated the neuroinflammation, reduced the levels of LPA 18:0 in the cerebral cortex and hippocampus in the brain and plasma, and reduced brain edema and the levels of IL1β, IL-6, and TNF-α. The neurobehavioral symptoms for HE such as the cognitive and motor function deficit and overall clinical grading score were significantly improved in ATXi-treated mice. Mouse astrocytes and microglia stimulated with NH 4 CL with or without ATXi showed significant attenuation of oxidative stress and the neuroinflammatory effect of NH4CL in ATXi-treated cells.

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