Role of MEK partner-1 in cancer stemness through MEK/ERK pathway in cancerous neural stem cells, expressing EGFRviii

Kwon, Sophia; Kwon, Ok‐Seon; Kim, Keun-Tae; Go, Young-Hyun; Yu, Si-in; Lee, Byeong-ha; Miyoshi, Hiroyuki; Oh, Eunsel; Cho, Seung-Ju; Cha, Hyuk‐Jin

doi:10.1186/s12943-017-0703-y

Cited by 23 publications

(22 citation statements)

References 59 publications

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“…2 D). This all making sense as reported previously, that MAPKinase signaling and β-catenin proto-oncogene in case of Glioma promote proliferation and cancer stemness 47 , 48 .…”

Section: Resultssupporting

confidence: 77%

Antagonistic role of GSK3 isoforms in glioma survival

2018

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GSK3 (Glycogen Synthase Kinase-3) function in brain is contributed by two distinct gene GSK3 alpha and GSK3 beta. Present findings indicate that imbalance in between GSK3 alpha and beta isoform contributes oncogenesis. In gliomas, GSK3 isoform specific functions are different then as reported for melanoma, prostate cancer, lung cancer etc. Both the isoforms of GSK3 are inversely regulating hnRNPA1 (RNA binding protein) expression, subsequently affecting RNA alternative splicing (BIN1, RON, Mcl1, PKM) in gliomas. Elevated expression of c-Myc, hnRNPA1, Phospo-ERK1/2 and Cyclin D1 in GSK3 alpha knock down cells, resembles GSK3 beta isoform overexpressing glioma cells, promotes cell survival. HnRNPA1 dependent survival signaling pathway were elaborated using si RNA approach or by over expressing cloned hnRNPA1 gene in U87 glioma cells. Therefore, performed study empirically support GSK3β inhibition along with restoration of GSK3α would be a good strategy to target gliomas.

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“…2 D). This all making sense as reported previously, that MAPKinase signaling and β-catenin proto-oncogene in case of Glioma promote proliferation and cancer stemness 47 , 48 .…”

Section: Resultssupporting

confidence: 77%

Antagonistic role of GSK3 isoforms in glioma survival

2018

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“…S4C-S4F). These results are consistent with previous reports that both NFAT1 and NDEL1 are associated with the activation of Erk (29,30), which plays an important role in the stemness maintenance of GSCs (31,32). In addition, blocking Erk activation using the inhibitor SCH772984 reduced the viability, invasion, self-renewal, and levels of stemness markers in NFAT1-OE G03-GSCs (Supplementary Fig.…”

Section: Nfat1-ndel1 Signaling Affects Erk Activation and Stemness Masupporting

confidence: 93%

NFAT1-Mediated Regulation of NDEL1 Promotes Growth and Invasion of Glioma Stem-like Cells

et al. 2019

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Glioma stem-like cells (GSC) promote tumor generation and progression. However, the mechanism of GSC induction or maintenance is largely unknown. We previously demonstrated that the calcium-responsive transcription factor nuclear factor of activated T cells-1 (NFAT1) is activated in glioblastomas and regulates the invasion of tumor cells. In this study, we further explored the role of NFAT1 in GSC. We found that NFAT1 expression was associated with an aggressive phenotype and predicted poor survival in gliomas. Compared with normal glioma cells, NFAT1 was upregulated in GSC. NFAT1 knockdown reduced GSC viability, invasion, and self-renewal in vitro and inhibited tumorigenesis in vivo, whereas NFAT1 overexpression enhanced the growth and invasion of GSCs. RNA sequencing showed that NFAT1 depletion was associated with reduced neurodevelopment protein 1-like 1 (NDEL1, a potential downstream target of NFAT1) expression, whereas NFAT1 overexpression induced NDEL1 expression. In addition, NFAT1 regulated the promoter activities of NDEL1, whereas rescue of NDEL1 in NFAT1-silenced GSC partially restored tumor growth and invasion. Upregulation of NFAT1-NDEL1 signaling elevated Erk activation, increased protein levels of stemness markers in GSC, and resulted in dedifferentiation of normal neuronal cells and astrocytes. Our results indicate that NFAT1 controls the growth and invasion of GSC partially through regulation of NDEL1. Targeting the NFAT1-NDEL1 axis therefore might be of potential benefit in the treatment of patients with glioma.Significance: NFAT1 controls the growth and invasion of GSCs, partially by regulating NDEL1. Targeting the NFAT1-NDEL1 axis might provide opportunities in treating patients with glioma. Immunofluorescence staining of NFAT1 in LN229, G10, and T98G GSCs. DAPI was used for nuclear staining. Scale bar, 25 mm. Results are presented as the mean AE SEM of triplicate samples from three independent experiments. Ã , P < 0.05; ÃÃ , P < 0.01.

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“…Interestingly, low-dose garcinol (≤ 5 μM) deregulated STAT3/5A signaling with repressed AKT and (Yuan et al, 2015), as well as evidence implicating high ERK1/2 activity in the acquisition and maintenance of SOX2-expressing Glioma stem cells (Kwon et al, 2017).…”

Section: Discussionmentioning

confidence: 95%

Aberrant Activation of hsa-miR-181d/STAT3 and hsa-miR-181d/5A Ratios Mediate the Anticancer Effect of Garcinol in STAT3/5A-Addicted GBM

Liu¹,

Lee²,

Bamodu³

et al. 2019

Preprint

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Background: Glioblastoma (GBM), a malignant grade IV tumor, is the most malignant brain tumor due to its hyper-proliferative and apoptosis-evading characteristics. The signal transducer and activators of transcription (STAT) family genes, including STAT3 and STAT5A, have been indicated to play important roles in GBM progression. Increasing number of reports suggest that Garcinol, a polyisoprenylated benzophenone and major bioactive component of Garcinia indica contains potent anti-cancer activities. Material & Methods: The present study investigated the anti-GBM effects of garcinol, focusing on the STAT3/STAT5A activation, using a combination of bioinformatics, in vitro, and ex vivo assays. Results: Our bioinformatics analysis of TCGA - GBM cohort (n=173) showed that STAT3 and STAT5A are preferentially elevated in primary and recurrent GBM, compared to non-tumor brain tissues, and is significantly correlated with reduced overall survival. In support, our immunohistochemical staining of a GBM cohort (n=30) showed an estimated 5.3-fold (p<0.001) elevation in STAT3 and STAT5A protein expression in primary and recurrent GBM versus the non-tumor group. In vitro, garcinol treatment significantly suppressed the proliferative, invasive, and migratory potential of U87MG or GBM8401 cells, dose-dependently. In addition, garcinol anticancer effect significantly attenuated the GBM stem cell-like phenotypes, as reflected by diminished ability of U87MG or GBM8401 to form colonies and tumorspheres and suppressed expression of OCT4 and SOX2. Furthermore, analysis on GBM transcriptome revealed an inverse correlation between the level of STAT3/5A and hsa-miR-181d. Garcinol-mediated anti-GBM effects were associated with an increased hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratio. Conclusion: We present evidence of anti-GBM efficacy of garcinol mediated by enhancing the hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratios in GBM cells. Our findings suggest a potential new therapeutic agent for combating aggressive GBM.

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Role of MEK partner-1 in cancer stemness through MEK/ERK pathway in cancerous neural stem cells, expressing EGFRviii

Cited by 23 publications

References 59 publications

Antagonistic role of GSK3 isoforms in glioma survival

Antagonistic role of GSK3 isoforms in glioma survival

NFAT1-Mediated Regulation of NDEL1 Promotes Growth and Invasion of Glioma Stem-like Cells

Aberrant Activation of hsa-miR-181d/STAT3 and hsa-miR-181d/5A Ratios Mediate the Anticancer Effect of Garcinol in STAT3/5A-Addicted GBM

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