Recently, long noncoding RNAs (lncRNAs) have been shown to have important regulatory roles in human cancer biology. The aim of this study was to evaluate the expression and biological role of lncRNA CASC2 in non-small cell lung cancer (NSCLC). By bioinformatics analysis, we found that CASC2 was significantly decreased in NSCLC. qRT-PCR was performed to investigate the expression of CASC2 in tumor tissues and corresponding non-tumor NSCLC tissues from 76 patients. The lower expression of CASC2 was remarkably correlated with advanced TNM stage and tumor size. Multivariate analyses found that CASC2 expression served as an independent predictor for overall survival of NSCLC. Moreover, overexpression of CASC2 significantly inhibited NSCLC cell proliferation both in vitro and in vivo. In conclusion, our study demonstrated that CASC2 is involved in the development and progression of NSCLC and shows that CASC2 may be a potential diagnostic and target for new therapies in patients with NSCLC.
Background: Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that mediate neuronal excitability and synaptic plasticity in the central nervous system, and emerging evidence suggests a role of mGluRs in the biology of cancer. Previous studies showed that mGluR1 was a potential therapeutic target for the treatment of breast cancer and melanoma, but its role in human glioma has not been determined. Methods: In the present study, we investigated the effects of mGluR1 inhibition in human glioma U87 cells using specific targeted small interfering RNA (siRNA) or selective antagonists Riluzole and BAY36-7620. The anti-cancer effects of mGluR1 inhibition were measured by cell viability, lactate dehydrogenase (LDH) release, TUNEL staining, cell cycle assay, cell invasion and migration assays in vitro, and also examined in a U87 xenograft model in vivo. Results: Inhibition of mGluR1 significantly decreased the cell viability but increased the LDH release in a dose-dependent fashion in U87 cells. These effects were accompanied with the induction of caspase-dependent apoptosis and G0/G1 cell cycle arrest. In addition, the results of Matrigel invasion and cell tracking assays showed that inhibition of mGluR1 apparently attenuated cell invasion and migration in U87 cells. All these anti-cancer effects were ablated by the mGluR1 agonist L-quisqualic acid. The results of western blot analysis showed that mGluR1 inhibition overtly decreased the phosphorylation of PI3K, Akt, mTOR and P70S6K, indicating the mitigated activation of PI3K/Akt/mTOR pathway. Moreover, the anti-tumor activity of mGluR1 inhibition in vivo was also demonstrated in a U87 xenograft glioma model in athymic nude mice. Conclusion: The remarkable efficiency of mGluR1 inhibition to induce cell death in U87 cells may find therapeutic application for the treatment of glioma patients.
Circular RNAs (circRNAs) are reported to play vital roles in tumour process and might be potential prognostic biomarkers and therapeutic targets for tumours. But the expression and function of circRNAs in glioma remain unclear. Here, we performed circRNA microarray analysis of glioma tissues and matched normal brain tissue samples to explore the circRNA profile in glioma. GO analysis, KEGG and Reactom pathway analysis of linear mRNA transcripts corresponding to circRNAs were performed to study the involved biological process and pathways. The clinical significance of the selected circRNA was investigated by Kaplan‐Meier survival analysis. Relevant biological function, such as cell proliferation and metastasis, was detected in vitro and in vivo. And possible mechanism of the regulatory function of the selected circRNA in glioma was explored. We found that circCPA4 (hsa_circ_0082374) up‐regulated the most in glioma tissues and high levels of circCPA4 were positively related to poor outcome of glioma. And knockdown of circCPA4 suppresses cell proliferation and metastasis in glioma. Moreover, circCPA4 interacts with let‐7 and serves as a sponge for let‐7. Through the competitive endogenous RNA (ceRNA) mechanism, circCPA4 sponges let‐7 to regulate the expression of CPA4 and glioma progression. The circCPA4/let‐7/CPA4 axis regulates glioma progression by ceRNA mechanism, and circCPA4 could be a novel prognostic biomarker and target for glioma treatment.
Background: Valproic acid (VPA), an established antiepileptic drug, was assessed for antitumor activity, including its effects on glioblastoma, but its role has not been determined. Methods: In the present study, we investigated VPA-induced apoptosis effects on human U87 cells by cell viability, lactate dehydrogenase (LDH) release, TUNEL/Hoechst staining and flow cytometric in vitro, then we further explored the underlying molecular mechanisms using the selective antagonists PD98059, LY294002 and SB216763. Results: The data showed that VPA dose-dependent induction of glioma U87 cells to undergo apoptosis through the mitochondria-dependent pathway in vitro. VPA activated the ERK/Akt pathways by increasing their protein phosphorylation and in turn inhibited GKS3β activation by the induction of GKS3β phosphorylation. However, the MAPK inhibitor PD98059 and/or PI3K inhibitor LY294002 were able to antagonize the effects of VPA by abolishing ERK/Akt activations and cancelling GSK3β suppression, thus it impaired VPA apoptosis-inducing effects on glioma cells. Furthermore, the GSK3β inhibitor SB216763 caused a strong suppression of GSK3β activity, which showed similar effects of VPA on regulation of protein expression and apoptosis. Conclusion: These findings suggest that GSK3β may be the central hub for VPA-induced apoptosis and VPA can be further evaluated as a novel agent for glioma therapy.
Purpose: AHNAK is originally identified as a giant protein based on the estimated size of approximately 700 kDa. The aim of this study is to identify the role of AHNAK in the pathogenesis of glioma.Methods: We tested AHNAK mRNA level in a panel of six human glioma cell lines, and in 30 cases of normal brain tissues and 73 cases of glioma tissue samples using a qRT-PCR method. Further, we analyzed the relationship of AHNAK expression with clinicopathological characteristics in glioma patients. Meanwhile, we analyzed the relationship of expression of AHNAK and survival of glioma patients in survival analyses. Then, in vitro, we analyzed the biological effects of AHNAK in glioma cell lines (U87 and U251) including proliferation assay, cell transwell assay, and apoptosis. And in vivo, we examined the effects of AHNAK on tumor growth using xenograft model of human glioma cells in nude mice. Then we examined the expression of Ki-67-positive cells in these tumors.Results: We found that the mRNA levels of AHNAK were down-regulated in 4 of 6 human glioma cell lines, especially in U87 and U251 cell lines. Meanwhile, in glioma patients, a negative correlation was found between the expression of AHNAK and the glioma histopathology. And a low expression of AHNAK was a significant and independent prognostic factor for poor survival of glioma patients. Through over expression of AHNAK in both of U87 and U251, we demonstrated that overexpression of AHNAK could inhibit glioma cell proliferation and invasion, induce apoptosis, and inhibit in vivo glioma tumor growth and ki-67 expression.Conclusions: The AHNAK acts as a potential tumor suppressor. Our study provides a preclinical basis for developing AHNAK as a reliable clinical prognostic indicator for glioma patients, and a new biomarker for treatment response, and a potentially therapeutic target in glioma management options.
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