As a newly discovered long non-coding RNA, small nucleolar RNA host gene 3 (SHNG3) has been reported to be dysregulated in certain cancers. Nevertheless, the details about clinical values and biological effects of SNHG3 on glioma are still covered. In this paper, we determined the expression level of SNHG3 in glioma tissues and cells and evaluated the effect of SNHG3 expression on the prognosis of glioma patients. The functional assays were applied to define the effects of SNHG3 on the biological behaviors in glioma including cell proliferation, cell cycle, and apoptosis. It was revealed that SNHG3 was much more enriched in glioma tissues and cell lines than in normal ones. Furthermore, gain- or loss-of-function experiments indicated that the up-regulation of SNHG3 promoted cell proliferation, accelerate cell cycle progress, and repressed cell apoptosis. The mechanistic assays disclosed that SNHG3 facilitated the malignant progression of glioma through epigenetically repressing KLF2 and p21 via recruiting enhancer of zeste homolog 2 to the promoter of KLF2 and p21. Generally, it was exposed that SNHG3 might function as an oncogene in glioma and could be explored as a potential prognostic biomarker and therapeutic target for glioma.

BackgroundHepatic fibrosis is a prominent pathological feature associated with chronic liver disease including non-alcoholic hepatosteatosis (NASH), and a precursor for liver cancer development. We previously reported that PTEN loss in the liver, which leads to hyperactivated liver insulin signaling results in NASH development. Here we used the same mouse model to study the progression from steatosis to fibrosis.ResultsThe Pten null livers develop progressive liver fibrosis as indicated by Sirius Red staining and increased expression of collagen I, Timp 1, SMAα, and p75NTR. Consistently, hepatic stellate cells (HSCs) isolated from Pten null livers are readily activated when compared with that from mice with intact PTEN. Deletion of AKT2, the downstream target of PTEN signal, blocked NASH development, and alleviated fibrosis. HSCs from the Pten/Akt2 double null mice are quiescent like those isolated from the control livers. Our analysis shows that the activation of HSCs does not depend on the intrinsic signals regulated by PI3K/AKT, the target of PTEN, but does depend on steatosis and injury to the liver. During the progression of liver fibrosis in the Pten null model, Wnt ligands and signaling receptor are induced, concurrent with the reduction of sFRP5, a Wnt antagonist. We showed that treatment of HSCs with Wnt receptor antagonist blocks the observed morphological changes when HSCs undergo activation in culture. This signal appears to be mediated by β-catenin, as manipulating β-catenin signaling alters marker gene expressions of HSC activation.ConclusionsWnt/β-catenin activation serves as an important mediator for fibrosis development resulting from NASH using a mouse model where NASH is mimicked by PTEN loss.

Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)-dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+/-) or microglia-specific Nr4a2 (Nr4a2fl/flCx3cr1cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacological NR4A2 inhibition attenuated the pro-tumorigenic TIME, and targeting the NR4A2 or SQLE enhanced therapeutic efficacy of immune checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2-SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer.

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