Previous studies reported that miR-433 exerts function widely in human tumorigenesis and development. Here, we further investigate the potential role of miR-433 in glioma. Quantitative real-time PCR demonstrated that miR-433-3p and miR-433-5p were low expressed in glioma tissues and cell lines. Functional studies suggested that the overexpression of miR-433-3p suppressed proliferation, induced apoptosis and inhibited invasion and migration of human glioma cells. But the growth and metastasis of glioma cells were not significantly influenced by overexpression of miR-433-5p. In a xenograft model, we also showed that miR-433-3p had an inhibitory effect on the growth of glioma. Bioinformatics coupled with luciferase and western blot assays revealed that CREB is a direct target of miR-433-3p, and the overexpression of CREB can rescue the phenotype changes induced by miR-433-3p overexpression. Besides, miR-433-3p could increase chemosensitivity of glioma to temozolomide by targeting CREB in vitro and in vivo. Taken together, these results suggest that miR-433-3p may function as a potential marker in diagnostic and therapeutic target for glioma.

Abstract. the HiWi gene is one of the members of the PiWi gene family that is important for stem cell self-renewal and expressed highly in certain human tumors. Some studies have demonstrated that HiWi plays a key role in the development of tumors in cervical, colon and liver cancer. Previous studies have demonstrated that HiWi is associated with prognosis of patients with glioma. However, there is no report on the analysis of HiWi in the biological characteristics of glioma cells. the aim of the study was to investigate whether HiWi plays an important role in the progress of glioma. Silencing HiWi inhibited cell proliferation by promoting apoptosis and increased cell cycle arrest. the expression of proteins related to apoptosis and the cell cycle, including p21, cyclin D1, Bcl-2, and Bax was significantly altered. Moreover, knockdown of HiWi inhibited the migration and invasion of glioma cells by reducing the expression of MMP-2 and MMP-9. furthermore, we found that reduction of HiWi inhibited tumor growth in vivo. These findings suggest that HIWI is an oncogene involved in the progression of glioma.

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Background: T cell exhaustion (TEX) heterogeneity leads to unfavorable immunotherapeutic responses in patients with cancer. Classification of TEX molecular phenotypes is pivotal to overcoming TEX and improving immunotherapies in the clinical setting. Cuproptosis is a novel form of programmed cell death associated with tumor progression. However, the relation between cuproptosis-related genes (CuRGs) and the different TEX phenotypes has not been investigated in lung adenocarcinoma (LUAD).Methods: Unsupervised hierarchical clustering and principal component analysis (PCA) algorithm were performed to determine CuRGs-related molecular subtypes and scores for patients with LUAD. The tumor immune microenvironment (TIME) landscape in these molecular subtypes and scores was estimated using ESTIMATE and ssGSEA algorithms. Furthermore, TEX characteristics and phenotypes were evaluated in distinct molecular subtypes and scores through GSVA and Spearman correlation analysis. Finally, TIDE scores, immunophenoscore, pRRophetic, GSE78220, and IMvigor210 datasets were employed to appraise the distinguishing capacity of CuRGscore in immunotherapy and pharmacotherapy effectiveness.Results: We identified three CuRGclusters, three geneClusters, and CuRGscore based on 1012 LUAD transcriptional profiles from five datasets. Compared with other molecular subtypes, CuRGcluster B, geneCluster C, and low-CuRGscore group with good prognosis presented fewer TEX characteristics, including immunosuppressive cells infiltration and TEX-associated gene signatures, signal pathways, checkpoint genes, transcription and inflammatory factors. These molecular subtypes were also responsive in distinguishing TEX phenotype in the terminal, GZMK+, and OXPHOS- TEX subtypes, but not the TCF7+ TEX subtype. Notably, copper importer and exporter, SLC31A1 and ATP7B, were remarkably associated with four TEX phenotypes and nine checkpoint genes such as PDCD1, CTLA4, HAVCR2, TIGIT, LAG3, IDO1, SIGLEC7, CD274, PDCD1LG2, indicating that cuproptosis was involved in the development of TEX and immunosuppressive environment in patients with LUAD. Moreover, CuRGscore was significantly related to the TIDE score, immunophenoscore, and terminal TEX score (Spearman R = 0.62, p < 0.001) to effectively predict immunotherapy and drug sensitivity in both training and external validation cohorts.Conclusion: Our study demonstrated the extensive effect of cuproptosis on TEX. CuRGs-related molecular subtypes and scores could illuminate the heterogeneity of TEX phenotype as reliable tools in predicting prognosis and directing more effective immunotherapeutic and chemotherapeutic strategies for patients with LUAD.