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The dismal prognosis for glioblastoma multiform (GBM) patients is primarily attributed to the highly invasive tumor residual that remained after surgical intervention. The development of precise intraoperative imaging and postoperative residual removal techniques will facilitate the gross total elimination of GBM. Here, a self-disassembling porphyrin lipoprotein-coated calcium peroxide nanoparticles (PLCNP) is developed to target GBM via macropinocytosis, allowing for fluorescence-guided surgery of GBM and improving photodynamic treatment (PDT) of GBM residual by alleviating hypoxia. By reducing self-quenching and enhancing lysosome escape efficiency, the incorporation of calcium peroxide (CaO 2 ) cores in PLCNP amplifies the fluorescence intensity of porphyrin-lipid. Furthermore, the CaO 2 core has diminished tumor hypoxia and improves the PDT efficacy of PLCNP, enabling low-dose PDT and reversing tumor progression induced by hypoxia aggravation following PDT. Taken together, this self-disassembling and oxygen-generating porphyrin-lipoprotein nanoparticle may serve as a promising all-in-one nanotheranostic platform for guiding precise GBM excision and empowering post-operative PDT, providing a clinically applicable strategy to combat GBM in a safe and effective manner., (© 2024 Wiley‐VCH GmbH.)

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 pre-mRNAs; 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-Δexon 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-Δexon 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.

Glioblastoma multiforme (GBM) is well known as a highly aggressive brain tumor subtype. Here, we show that overexpression (OE) of dematin actin-binding protein (DMTN) inhibits GBM proliferation and invasion by affecting cell cycle regulation and actin remodeling, respectively. RT-qPCR, western blotting, and immunohistochemical (IHC) staining demonstrated a significant reduction in DMTN expression in gliomas, especially in high-grade gliomas (HGG) compared with normal brains, which correlates with worse survival in HGG patients. Functional studies revealed inhibitory effects of DMTN on tumor proliferation and migratory capacities. The attenuation in tumor proliferative ability upon DMTN OE was accompanied by RhoA suppression and CDK1, CDK2, CDK4, and cyclin D1 downregulation, while RhoA rescue restored the proliferative phenotype. Meanwhile, overexpression of DMTN produced profoundly disorganized stress fibers, which led to impaired tumor invasion. Furthermore, DMTN overexpression produced substantial suppression of tumor growth upon subcutaneous and intracranial implantation in mice, and this was accompanied by significantly reduced vinculin expression and Ki67 positivity. Taken together, these findings demonstrate the role of DMTN in regulating GBM cell proliferation, actin cytoskeleton, and cell morphology and identify DMTN as a vital tumor suppressor in GBM progression., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) is one of the most devastating cancers and is characterized by rapid cell proliferation and aggressive invasiveness. Legumain (LGMN), a substrate-specific protease, is associated with poor progression of GBM. Circular RNAs (circRNAs) are aberrantly expressed in various cancers and play crucial roles in tumor progression; however, the functional roles of circRNAs originating from LGMN remain largely unknown in GBM. Herein, we found that hsa_circ_0033009 (circLGMN) was the most abundantly expressed circRNA derived from LGMN. CircLGMN was upregulated in high-grade glioma (HGG), and high expression of circLGMN was associated with poor prognosis in patients with glioma. CircLGMN overexpression promoted GBM cell proliferation and enhanced cell invasion. Mechanistically, circLGMN acts as a sponge for miR-127-3p, and prevents miR-127-3p-mediated degradation of LGMN mRNA, ultimately leading to increased LGMN protein expression. Treatment with miR-127-3p mimic suppressed proliferation and reduced invasion of GBM cells overexpressing circLGMN. Moreover, circLGMN overexpression promoted GBM malignancy in vivo, while miR-127-3p overexpression alleviated this effect. Taken together, circLGMN is a novel tumor-promoting circRNA that acts by sponging miR-127-3p, which ultimately leads to LGMN upregulation. Thus, targeting the circLGMN/miR-127-3p/LGMN axis might be a promising strategy for GBM treatment. More importantly, the discovery of the self-regulatory mechanism of LGMN expression by circLGMN, will facilitate further research on LGMN., (Copyright © 2021. Published by Elsevier B.V.)

Pseudogenes, which are long noncoding RNAs that originate from protein-coding genes, have been suggested to play important roles in disease. Although studies have revealed high expression of legumain (LGMN) in many types of tumors, the regulation of LGMN remains largely unknown. Here, we found that a novel LGMN pseudogene (LGMNP1) was upregulated in glioblastoma (GBM) tissues and high LGMNP1 expression in GBM cells enhanced proliferation and invasion. Biochemical analysis showed that cytoplasmic LGMNP1 functionally targeted miR-495-3p in a manner involving an RNA-induced silencing complex. Dual-luciferase reporter assays demonstrated that LGMN was a target of miR-495-3p, and LGMN was upregulated and positively correlated with LGMNP1 in GBM. Moreover, miR-495-3p was downregulated and negatively correlated with LGMNP1 in GBM tissues. Notably, the tumor-promoting effects of LGMNP1 upregulation could be alleviated by miR-495-3p mimics. Furthermore, GBM cells overexpressing LGMNP1 exhibited more aggressive tumor progression and elevated LGMN expression in vivo. Thus, our data illustrate that LGMNP1 exerts its oncogenic activity, at least in part, as a competitive endogenous RNA (ceRNA) that elevates LGMN expression by sponging miR-495-3p. CeRNA-mediated miRNA sequestration might be a novel therapeutic strategy in GBM., (Copyright © 2020. Published by Elsevier B.V.)

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., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Circular RNAs (circRNAs), a newly discovered type of endogenous noncoding RNA, have been proposed to mediate the progression of diverse types of tumors. Systematic studies of circRNAs have just begun, and the physiological roles of circRNAs remain largely unknown. Here, we focused on elucidating the potential role and molecular mechanism of circular forkhead box O3 (circFOXO3) in glioblastoma (GBM) progression., Methods: First, we analyzed circFOXO3 alterations in GBM and noncancerous tissues through real-time quantitative reverse transcription PCR (qRT-PCR). Next, we used loss- and gain-of-function approaches to evaluate the effect of circFOXO3 on GBM cell proliferation and invasion. Mechanistically, fluorescent in situ hybridization, RNA pull-down, dual luciferase reporter, and RNA immunoprecipitation assays were performed to confirm the interaction between circFOXO3 and miR-138-5p/miR-432-5p in GBM. An animal model was used to verify the in vitro experimental findings., Results: CircFOXO3 expression was significantly higher in GBM tissues than in noncancerous tissues. GBM cell proliferation and invasion were reduced by circFOXO3 knockdown and enhanced by circFOXO3 overexpression. Further biochemical analysis showed that circFOXO3 exerted its pro-tumorigenic activity by acting as a competing endogenous RNA (ceRNA) to increase expression of nuclear factor of activated T cells 5 (NFAT5) via sponging both miR-138-5p and miR-432-5p. Notably, tumor inhibition by circFOXO3 downregulation could be reversed by miR-138-5p/miR-432-5p inhibitors in GBM cells. Moreover, GBM cells with lower circFOXO3 expression developed less aggressive tumors in vivo., Conclusions: Our data demonstrate that circFOXO3 can exert regulatory functions in GBM and that ceRNA-mediated microRNA sequestration might be a potential strategy for GBM therapy., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glioblastoma is a lethal brain tumor type, which is frequently resistant to radiotherapy. The aim of the present study was to explore the function of legumain pseudogene 1 (LGMNP1) on radioresistance in glioblastoma. Reverse transcription‑quantitative PCR was used to detect the relative expression of LGMNP1 in glioma cell lines after radiotherapy. Ectopic expression of LGMNP1 was achieved by transfection of a lentiviral vector. A clonogenic assay was used to determine the colony formation ability following radiotherapy. A comet assay, flow cytometry and western blot analysis were applied to detect DNA damage, the apoptotic rate, and levels of apoptotic proteins, respectively. The results revealed that LGMNP1 was significantly upregulated in glioma cells after radiation. Glioma cells stably overexpressing LGMNP1 were successfully established. Overexpression of LGMNP1 in glioma cells reduced DNA damage processes and the percentage of apoptotic cells after radiotherapy. In addition, overexpression of LGMNP1 in glioblastoma multiforme cells decreased apoptotic protein expression after radiotherapy. The present results indicated that upregulation of LGMNP1 conferred radiotherapy resistance by increasing the ability of DNA damage protection and reducing the apoptotic population in glioma cells.

Long non-coding RNAs (lncRNAs) play vital roles in the pathobiology of glioblastoma multiforme (GBM). Though radiotherapy remains the most effective component of multiple therapies for patients with GBM, lncRNAs conferring GBM radioresistance are less unknown. Here, the present study identified that the antisense transcript of hypoxia-inducible factor-1α (AHIF) was upregulated in GBM cells after radiotherapy. The deregulation of AHIF affected GBM cell clonogenic formation, DNA repair and apoptosis. Notably, knockdown of AHIF inhibited tumorigenesis after radiotherapy in vivo. Further biochemical analysis identified that AHIF regulated proteins associated with apoptosis after radiotherapy. Thus, the present data illustrate that suppression of AHIF increases radiosensitivity in GBM cells, which may be a potential diagnostic and therapeutic target for GBM patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) has the highest mortality rate among patients with brain tumors, and radiotherapy forms an important part of its treatment. Thus, there is an urgent requirement to elucidate the mechanisms conferring GBM progression and radioresistance. In the present study, it was identified that antisense transcript of hypoxia‑inducible factor‑1α (AHIF) was significantly upregulated in GBM cancerous tissues, as well as in radioresistant GBM cells. The expression of AHIF was also upregulated in response to radiation. Knockdown of AHIF in GBM cells decreased viability and invasive capacities, and increased the proportion of apoptotic cells. By contrast, overexpression of AHIF in GBM cells increased viability and invasive capacities, and decreased the proportion of apoptotic cells. Furthermore, exosomes derived from AHIF‑knockdown GBM cells inhibited viability, invasion and radioresistance, whereas exosomes derived from AHIF‑overexpressing GBM cells promoted viability, invasion and radioresistance. Further biochemical analysis identified that AHIF regulates factors associated with migration and angiogenesis in exosomes. To the best of our knowledge, the present study is the first to establish that AHIF promotes glioblastoma progression and radioresistance via exosomes, which suggests that AHIF is a potential therapeutic target for GBM.

Glioblastoma multiforme (GBM) is the most deadly brain tumor, and it is characterized by extremely poor therapeutic response and overall survival. Adjuvant radiotherapy remains the standard of care following surgical resection. Thus, elucidating the mechanisms conferring radioresistance in GBM is extremely urgent. In the present study, miR-96 was demonstrated to be significantly upregulated in radioresistant GBM cells. Knockdown of miR-96 in the radioresistant GBM cells T98G elevated the % of apoptotic cells and reduced their clonogenic formation ability following radiotherapy. By contrast, overexpression of miR-96 in the radiosensitive GBM cells U87-MG reduced the % of apoptotic cells and increased their clonogenic formation ability following radiotherapy. Results from phosphorylated-H2A histone family member X (γH2AX) foci staining and comet assays revealed that miR-96 enhanced the DNA repair processes. Furthermore, miR-96 overexpression conferred radioresistance by downregulating programmed cell death protein 4 (PDCD4). Luciferase assay results revealed that miR-96 bound to the 3'UTR of PDCD4 mRNA. Finally, U87-MG cells regained radiosensitivity following PDCD4 overexpression. Taken together, the present is the first study to establish that upregulation of miR-96 in GBM cells confers radioresistance via targeting PDCD4, which might be a potential therapeutic target for GBM.

Temozolomide (TMZ), as a kind of alkylating agent, is widely utilized for the treatment of glioblastoma (GBM). However, temozolomide resistance (TR) often develops quickly and results in tumor recurrence and poor outcome. Recent advances have demonstrated that miRNAs exert critical roles in chemoresistance. Downregulation of miR‑146b‑5p promotes glioma cell proliferation, reduces apoptosis, and correlates with poor survival of patients. Nonetheless, the function of miR‑146b‑5p in temozolomide resistance remains unclear. In the present study, we successfully generated U87 and U251‑TR cells, and found that miR‑146b‑5p was downregulated in TR cells. Overexpression of miR‑146b‑5p restored sensitivity of U87/U251‑TR cells to TMZ by targeting tumor necrosis factor receptor-associated factor 6 (TRAF6). The levels of TRAF6 were inversely related to miR‑146b‑5p levels, and overexpression of TRAF6 in miR‑146b‑5p‑OE cells enhanced the resistance against TMZ. Moreover, temozolomide-resistant GBM cells had a higher level of phosphorylated protein kinase B (AKT) and P65. Overexpression of miR‑146b‑5p or TRAF6 knockdown significantly decreased the level of p‑AKT and p‑p65. Collectively, our data demonstrated that miR‑146b‑5p, as a tumor suppressor, mediated temozolomide resistance in GBM cells through negatively regulating TRAF6 expression, indicating that miR‑146b‑5p and its targeted genes would be potential therapeutic targets for glioma therapy.

Forkhead transcription factor FoxO3a has been reported to have ambiguous functions and distinct mechanisms in various solid tumors, including glioblastoma (GBM). Although a preliminary analysis of a small sample of patients indicated that FoxO3a aberrations in glioma might be related to aggressive clinical behavior, the clinical significance of FoxO3a in glioblastoma remains unclear. We investigated the expression of FoxO3a in a cohort of 91 glioblastoma specimens and analyzed the correlations of protein expression with patient prognosis. Furthermore, the functional impact of FoxO3a on GBM progression and the underlying mechanisms of FoxO3a regulation were explored in a series of in vitro and in vivo assays. FoxO3a expression was elevated in glioblastoma tissues, and high nuclear FoxO3a expression in human GBM tissues was associated with poor prognosis. Moreover, knockdown of FoxO3a significantly reduced the colony formation and invasion ability of GBM cells, whereas overexpression of FoxO3a promoted the colony formation and invasion ability. The results of in vivo GBM models further confirmed that FoxO3a knockdown inhibited GBM progression. More, the pro-oncogenic effects of FoxO3a in GBM were mediated by the activation of c-Myc, microtubule-associated protein 1 light chain 3 beta (LC3B) and Beclin1 in a mixed-lineage leukemia 2 (MLL2)-dependent manner. These findings suggest that high FoxO3a expression is associated with glioblastoma progression and that FoxO3a independently indicates poor prognosis in patients. FoxO3a might be a novel prognostic biomarker or a potential therapeutic target in glioblastoma., (© 2017 UICC.)

Aberrant PDGF-PDGFR signaling and its effects on downstream effectors have been implicated in glioma development. A crucial AKT regulator, ACK1 (TNK2) has been shown to be a downstream mediator of PDGF signaling; however, the exact underlying mechanisms in gliomas remain elusive. Here, we report that in glioma cells, PDGFR-β activation enhanced the interaction between ACK1 and AKT, resulting in AKT activation. PDGF treatment consistently promoted the formation of complexes containing PDGFR-β and ACK1. Mutational analysis suggested that Y635 of ACK1 is a PDGFR-β phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT. Moreover, PDK1 interacted with ACK1 during PDGF stimulation, which is required for the binding of ACK1 to PDGFR-β. Further mutational analysis showed that T325 of ACK1 was crucial for the ACK1 and PDK1 interaction. ACK1 Y635F or T325A mutants abolished PDGFR-β-induced AKT activation, the subsequent nuclear translocation of β-catenin and the expression of cyclin D1. Glioma cell cycle progression, proliferation and tumorigenesis were accordingly blocked by ACK1 Y635F or T325A. In glioblastoma multiforme samples from 51 patients, increased ACK1 tyrosine phosphorylation correlated with upregulated PDGFR-β activity and AKT activation. Taken together, our data demonstrate that ACK1 plays a pivotal role in PDGF-PDGFR-induced AKT signaling in glioma tumorigenesis. This knowledge contributes to our understanding of glioma progression and may facilitate the identification of novel therapeutic targets for future glioma treatment., (© 2014 UICC.)

Background: Glioblastoma multiforme (GBM) is the most aggressive and invasive brain tumor, for which novel prognostic markers and predictors of therapeutic response are urgently needed. We reported previously that levels of peptide-O-linked mannose β-1,2-N-acetylglucosaminyltransferase 1 (PomGnT1) in glioma specimens correlated with tumor grade. However, the prognostic significance of PomGnT1 in glioma patients and its function in GBM progression remain unknown., Methods: Clinical relevance of PomGnT1 in GBM patients' prognosis was analyzed both in a clinically annotated expression dataset of 446 GBM tumor specimens and in 82 GBM tumor samples collected at our institution. The function of PomGnT1 in glioma growth and invasion, and the underlying mechanisms of PomGnT1 regulation were explored in vitro and in vivo., Results: PomGnT1 expression in GBM tissues was closely associated with poor prognosis in GBM patients. Forced overexpression of PomGnT1 in glioblastoma cells impaired cell adhesion and increased their proliferation and invasion in vitro. Subsequent in vivo experiments showed that overexpression of PomGnT1 promoted tumor growth and shortened the survival time of tumor-bearing mice in an orthotopic model. Conversely, stable short hairpin RNA-mediated knockdown of PomGnT1 expression produced opposite effects both in vitro and in vivo. Mechanistic studies revealed that activation of epidermal growth factor receptor (EGFR) resulted in EGFR/extracellular signal-regulated kinase-dependent upregulation of PomGnT1, downregulation of receptor-type protein tyrosine phosphatase β, and activation of β-catenin pathway signaling., Conclusion: These findings suggest that PomGnT1 promotes GBM progression via activation of β-catenin and may serve as a prognostic factor for glioma patient survival as well as a novel molecular target for anticancer therapy in malignant glioma., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glioblastoma multiforme (GBM) is characterized by poor therapeutic response and poor overall survival. It is crucial that more effective therapies be developed for the treatment of GBM. Inhibitor of DNA binding protein-1 (ID1) has been shown to maintain the self-renewal capacity of neural stem cells and might be involved in the therapeutic resistance of GBM. In the present study, we explored survival data from the The Cancer Genome Atalas database that were based on ID1 expression for patients diagnosed with primary GBMs. Interestingly, patients with high ID1 expression had better survival than patients with low ID1 expression, and a strong correlation was found between radiotherapy efficacy, ID1 expression, and overall survival. We further investigated the relationship between ID1 expression and the radiosensitivity of glioblastoma using glioblastoma cell lines. The clonogenic formation assay showed that U87 ID1-shRNA cells were much less sensitive to radiation. Moreover, both the results of the γH2AX foci staining assay and the comet assay further revealed that ID1 negatively regulates DNA repair processes by downregulating the expression of genes such as DNA ligase IV (LIG4) and ataxia-telangiectasia-mutated. Additionally, ID1 induces G2/M arrest in U87 cells. Taken together, these results suggest that ID1 may be a new prognostic marker for GBM and have important implications for the therapeutic strategies used to treat GBM patients.

Background: Protein p62 (sequestosome 1) encoded by gene SQSTM1 plays a vital role in mediating protectively selective autophagy in tumor cells under stressed conditions. CircSQSTM1 (hsa_circ_0075323) is a circular transcript generated from gene SQSTM1 (chr5:179260586–179260782) by back-splicing. However, the potential role of hsa_hsa_circ_0075323 in glioblastoma (GBM) remains unclear. Here, we aimed to explore the biological function of hsa_circ_0075323 in GBM and its relationship with autophagy regulation. Results: Hsa_circ_0075323 is highly expressed in GBM cells and mainly locates in the cytoplasm. Inhibition of hsa_circ_0075323 in U87-MG and T98G cells attenuated proliferation and invasion ability significantly, while upregulation of has_ circ_0075323 enhanced proliferation and migration of U251-MG and A172 cells. Mechanistically, depletion of hsa_circ_0075323 in GBM cells resulted in impaired autophagy, as indicated by increased expression of p62 and decreased expression of LC3B. Conclusions: Hsa_circ_0075323 regulates p62-mediated autophagy pathway to promote GBM progression and may serve as a prognostic biomarker potentially. [ABSTRACT FROM AUTHOR]

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]

Asparagine endopeptidase (AEP), also called legumain, is currently the only known cysteine protease that specifically cleaves peptide bonds in asparaginyl residue in the mammalian genome. Since 2003, AEP has been reported to be widely expressed in a variety of carcinomas and is considered a potential therapeutic target. In the following years, researchers intensively investigated the substrates of AEP and the mechanism of AEP in partial tumors. With the identification of substrate proteins such as P53, integrin αvβ3, MMP-2, and MMP-9, the biochemical mechanism of AEP in carcinomas is also more precise. This review will clarify the probable mechanisms of AEP in the progression of breast carcinoma, glioblastoma, gastric carcinoma, and epithelial ovarian carcinoma. This review will also discuss the feasibility of targeted therapy with AEP inhibitor (AEPI) in these carcinomas. [ABSTRACT FROM AUTHOR]