MUC4 modulates human glioblastoma cell proliferation and invasion by upregulating EGFR expression

Li, Weihua; Wu, Chun‐Ming; Yao, Yu; Dong, Bin; Wei, Zhenqing; Lv, Xiupeng; Zhang, Jian; Xu, Yunhua

doi:10.1016/j.neulet.2014.02.033

Cited by 22 publications

(25 citation statements)

References 37 publications

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“…In addition to identifying common molecular signatures between grades, we wanted to characterise signatures specific to grade II and III as these tumours are more therapeutically challenging. Among the 191 proteins defining a grade II signature we found mucin-4 (MUC4), its overexpression enhanced proliferation and invasive potential of GBM cells by upregulating EGFR expression [60]; indeed, silencing EGFR in pancreatic cancer cells decreased MUC4 expression by reducing the phosphorylation of STAT1 [61]. Within the grade III-specific proteins we identified the glycolytic enzyme HK2, known for its key role in aerobic glycolysis and thus, the “Warburg effect” in rapidly growing cancer cells [33].…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis discovers the differential expression of novel proteins and phosphoproteins in meningioma including NEK9, HK2 and SET and deregulation of RNA metabolism

et al. 2019

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BackgroundMeningioma is the most frequent primary intracranial tumour. Surgical resection remains the main therapeutic option as pharmacological intervention is hampered by poor knowledge of their proteomic signature. There is an urgent need to identify new therapeutic targets and biomarkers of meningioma.MethodsWe performed proteomic profiling of grade I, II and III frozen meningioma specimens and three normal healthy human meninges using LC-MS/MS to analyse global proteins, enriched phosphoproteins and phosphopeptides. Differential expression and functional annotation of proteins was completed using Perseus, IPA® and DAVID. We validated differential expression of proteins and phosphoproteins by Western blot on a meningioma validation set and by immunohistochemistry.FindingsWe quantified 3888 proteins and 3074 phosphoproteins across all meningioma grades and normal meninges. Bioinformatics analysis revealed commonly upregulated proteins and phosphoproteins to be enriched in Gene Ontology terms associated with RNA metabolism. Validation studies confirmed significant overexpression of proteins such as EGFR and CKAP4 across all grades, as well as the aberrant activation of the downstream PI3K/AKT pathway, which seems differential between grades. Further, we validated upregulation of the total and activated phosphorylated form of the NIMA-related kinase, NEK9, involved in mitotic progression. Novel proteins identified and validated in meningioma included the nuclear proto-oncogene SET, the splicing factor SF2/ASF and the higher-grade specific protein, HK2, involved in cellular metabolism.InterpretationOverall, we generated a proteomic thesaurus of meningiomas for the identification of potential biomarkers and therapeutic targets.FundThis study was supported by Brain Tumour Research.

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Section: Discussionmentioning

confidence: 99%

Proteomic analysis discovers the differential expression of novel proteins and phosphoproteins in meningioma including NEK9, HK2 and SET and deregulation of RNA metabolism

et al. 2019

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“…Aberrant glycosylation was closely related to the development and progression of several cancers, including that of the brain (26,27). Some highly glycosylated proteins, such as MUC4 and ST3GAL1, have been found to be overexpressed in glioblastoma and to play roles in tumorigenesis and invasion (28,29). We thus propose that UAP1L1 may promote glioma cell proliferation through regulating the glycosylation status of some key proteins.…”

Section: Discussionmentioning

confidence: 87%

UAP1L1 plays an oncogene-like role in glioma through promoting proliferation and inhibiting apoptosis

Yang¹,

Yang²,

et al. 2021

Ann Transl Med

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Background: Uridine diphosphate-N-acetylglucosamine pyrophosphorylase-1-like-1 (UAP1L1) is involved in protein glycosylation and promotes proliferation in some tumors. By analyzing the publicly available Gene Expression Omnibus (GEO) database, we found that UAP1L1 displayed a significant change between paired glioma and normal brain tissues. The purpose of this study was to investigate the expression and functional role of UAP1L1 in glioma. Methods:To determine the expression level of UAP1L1 in glioma, immunohistochemistry (IHC) staining was performed in tissue microarrays of 160 gliomas and 24 normal brain tissues. The correlation between UAP1L1 expression and the outcomes of glioma patients was analyzed. Human glioblastoma cell lines, U251 and U87, were employed in this study. Endogenous UAP1L1 expression in U251 and U87 cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). A lentiviral short hairpin RNA (shRNA) vector (shUAP1L1) was constructed and used to infect U251 and U87 cells to knock down the expression of UAP1L1. We performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, flow cytometry, human apoptosis antibody array, and in vivo subcutaneous xenograft model to investigate the biological functions of UAP1L1.Results: We revealed that UAP1L1 expression was obviously upregulated in the glioma tissues. The increased UAP1L1 expression level was clinically associated with higher tumor grades and poorer patient prognoses. Moreover, we demonstrated that UAP1L1 knockdown suppressed proliferation and increased apoptosis of glioma cells in vitro. In the xenograft mouse model, we further verified that UAP1L1 knockdown could attenuate the growth of glioma cells in vivo.Conclusions: These results indicated that UAP1L1 may play an oncogene-like role in glioma, especially in high grade glioma, and thus may be of clinical importance as a future therapeutic target.

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“…1B), the observed reprogramming in the O-glycosylation machinery could indicate, according to known biosynthetic pathways, that the glioblastoma's glyco-code may be characterized by a high Tn antigen score. In addition, mucins known to carry the Tn antigen, such as MUC1 or MUC4, have been previously reported to be expressed in glioblastoma (39)(40)(41). Thus, we hypothesized that aberrant glycosyltransferase expression in patients with glioblastomas points to a glyco-code characterized by the prevalence of immature O-glycans such as the Tn antigen.…”

Section: Resultsmentioning

confidence: 99%

Glioblastomas exploit truncated O - linked glycans for local and distant immune modulation via the macrophage galactose-type lectin

Dusoswa

Verhoeff

Abels

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Glioblastoma is the most aggressive brain malignancy, for which immunotherapy has failed to prolong survival. Glioblastoma-associated immune infiltrates are dominated by tumor-associated macrophages and microglia (TAMs), which are key mediators of immune suppression and resistance to immunotherapy. We and others demonstrated aberrant expression of glycans in different cancer types. These tumor-associated glycans trigger inhibitory signaling in TAMs through glycan-binding receptors. We investigated the glioblastoma glycocalyx as a tumor-intrinsic immune suppressor. We detected increased expression of both tumor-associated truncated O-linked glycans and their receptor, macrophage galactose-type lectin (MGL), on CD163+ TAMs in glioblastoma patient-derived tumor tissues. In an immunocompetent orthotopic glioma mouse model overexpressing truncated O-linked glycans (MGL ligands), high-dimensional mass cytometry revealed a wide heterogeneity of infiltrating myeloid cells with increased infiltration of PD-L1+ TAMs as well as distant alterations in the bone marrow (BM). Our results demonstrate that glioblastomas exploit cell surface O-linked glycans for local and distant immune modulation.

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MUC4 modulates human glioblastoma cell proliferation and invasion by upregulating EGFR expression

Cited by 22 publications

References 37 publications

Proteomic analysis discovers the differential expression of novel proteins and phosphoproteins in meningioma including NEK9, HK2 and SET and deregulation of RNA metabolism

Proteomic analysis discovers the differential expression of novel proteins and phosphoproteins in meningioma including NEK9, HK2 and SET and deregulation of RNA metabolism

UAP1L1 plays an oncogene-like role in glioma through promoting proliferation and inhibiting apoptosis

Glioblastomas exploit truncated O - linked glycans for local and distant immune modulation via the macrophage galactose-type lectin

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