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Oxygen and nutrient deprivation are common features of solid tumors. Although abnormal alternative splicing (AS) has been found to be an important driving force in tumor pathogenesis and progression, the regulatory mechanisms of AS that underly the adaptation of cancer cells to harsh microenvironments remain unclear. Here, we found that hypoxia- and nutrient deprivation-induced asparagine endopeptidase (AEP) specifically cleaved DDX3X in a HIF1A-dependent manner. This cleavage yields truncated carboxyl-terminal DDX3X (tDDX3X-C), which translocates and aggregates in the nucleus. Unlike intact DDX3X, nuclear tDDX3X-C complexes with an array of splicing factors and induces AS events of many premRNAs; for example, enhanced exon skipping (ES) in exon 2 of the classic tumor suppressor PRDM2 leads to a frameshift mutation of PRDM2. Intriguingly, the isoform ARRB1-[DELTA]exon 13 binds to glycolytic enzymes and regulates glycolysis. By utilizing in vitro assays, glioblastoma organoids, and animal models, we revealed that AEP/tDDX3X-C promoted tumor malignancy via these isoforms. More importantly, high AEP/tDDX3X-C/ARRB1- [DELTA]exon 13 in cancerous tissues was tightly associated with poor patient prognosis. Overall, our discovery of the effect of AEP-cleaved DDX3X switching on alternative RNA splicing events identifies a mechanism in which cancer cells adapt to oxygen and nutrient shortages and provides potential diagnostic and/or therapeutic targets., Introduction In the tumor microenvironment, cells often face a certain degree of oxygen and nutrient deprivation. Cancer cells strive to survive and proliferate in this harsh environment in multiple ways, [...]

Background: Isocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood.Methods: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests.Results: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery.Conclusions: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM. [ABSTRACT FROM AUTHOR]

MicroRNA-128 is down-regulated in glioma tissues, which regulates cell proliferation, self-renewal, apoptosis, angiogenesis and differentiation. This study aims at investigating the diagnostic value of serum miR-128 in human glioma. Real-time quantitative reverse transcriptase polymerase chain reaction was used to detect the expression levels of miR-128 in serum samples from 151 glioma patients, 59 postoperative patients, 52 meningioma patients and 53 normal donors. To analyze the association of miR-128 expression with clinicopathological parameters in serum samples and matched tissues, matched 151 glioma tissues were collected in the study. Receiver operating characteristic analysis (ROC) was utilized to evaluate the value of serum miR-128 as a biomarker for the early diagnosis of glioma. Results revealed that miR-128 expression was significantly decreased in glioma preoperative serum compared with normal controls and meningioma serum samples (both P < 0.001). ROC analyses showed that serum miR-128 levels were reliable in distinguishing patients with glioma from normal controls and meningioma, with the area under the curve (AUC) values of 0.9095 and 0.8283, respectively. In addition, the AUC value for discriminating glioma II-IV from I was 0.7362. Importantly, serum miR-128 expression was significantly elevated after surgery (P < 0.001), although it didn't reach to normal levels (P < 0.001). Furthermore, low miR-128 levels in serum and tissue were markedly correlated with high pathological grade and low Karnofsky Performance Status score (KPS). These findings proved that serum miR-128 could be a sensitive and specific biomarker of glioma.