The Notch Pathway Promotes Osteosarcoma Progression through Activation of Ephrin Reverse Signaling

Yu, Ling; Xia, Kezhou; Gao, Tian; Chen, Jingteng; Zhang, Zhengpei; Sun, Xiangran; Simões, Bruno M; Eyre, Rachel; Fan, Zhengfu; Guo, Weichun; Clarke, Robert B.

doi:10.1158/1541-7786.mcr-19-0493

Cited by 28 publications

(25 citation statements)

References 36 publications

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“…As a result, we highlighted JMJD2C and HIF1α as downstream signaling molecules of miR-216b, wherein miR-216b reduced JMJD2C expression, likely interfering with mRNA stability and JMJD2C action in the demethylation of HES1 gene at the promoter region. More importantly, high expression levels of HES1 have been previously correlated with enhanced OS cell proliferation, migration and invasion as well as boosted chemoresistance [44]. What's more, our findings revealed that miR-216b diminished the expression of HES1 via the removal of H3K9 methylation at the gene promoter site of HES1 in OS cells, which has been previously emphasized as a critical factor for HES1 activation [27].…”

Section: Discussionsupporting

confidence: 67%

microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis

Yang

Fan

et al. 2020

J Exp Clin Cancer Res

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Background Although cisplatin-based chemotherapy represents the standard regimen for osteosarcoma (OS), OS patients often exhibit treatment failure and poor prognosis due to chemoresistance to cisplatin. Emerging research has highlighted the tumor suppressive properties of microRNAs (miRNAs or miRs) in various human cancers via the inhibition of the histone demethylase jumonji domain containing protein 2C (JMJD2C). As a coactivator for hypoxia-inducible factor 1α (HIF1α), JMJD2C targets hairy and enhancer of split-1 (HES1) gene. Hence, the current study aimed to elucidate the role of miR-216b in OS cell cisplatin resistance to identify the underlying mechanism of miR-216b regulating the JMJD2C//HIF1α/HES1 signaling. Methods Tumor and paracancerous tissues were collected from OS patients to determine the expression patterns of miR-216b and JMJD2C. After ectopic expression and knockdown experiments in the OS cells, CCK-8 assay and flow cytometry were employed to determine cell viability and apoptosis. The interaction of miR-216b, JMJD2C, HIF1α and HES1 was subsequently determined by dual luciferase reporter, co-immunoprecipitation (IP) and ChIP-qPCR assays. In vivo experiments were conducted to further verify the role of the miR-216b in the resistance of OS cells to cisplatin. Results miR-216b expression was reduced in the OS tissues, as well as the MG63 and SaOS-2 cells. Heightened miR-216b expression was found to be positively correlated with patient survival, and miR-216b further enhanced cisplatin-induced apoptosis of MG63 and SaOS-2 cells. Mechanistically, miR-216b inhibited JMJD2C expression by binding to its 3’UTR. Through interaction with HIF1α, JMJD2C removed the H3K9 methylation modification at the HES1 promoter region, leading to upregulation of HES1 in vitro. Furthermore, miR-216b was observed to increase the tumor growth in nude mice in the presence of cisplatin treatment. HES1 overexpression weakened the effects of miR-216b in MG63 and SaOS-2 cells and in nude mouse xenografts. Conclusion Overall, miR-216b enhanced the sensitivity of OS cells to cisplatin via downregulation of the JMJD2C/HIF1α/HES1 signaling axis, highlighting the capacity of miR-216b as an adjunct to cisplatin chemotherapy in the treatment of OS.

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Section: Discussionsupporting

confidence: 67%

microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis

Yang

Fan

et al. 2020

J Exp Clin Cancer Res

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“…Through the synergistic effect among different drugs, the multi-drug treatment can improve the therapeutic effect, reduce adverse reactions, and inhibits the occurrence of drug resistance, which may be an effective strategy to overcome the insufficient treatment of cisplatin [48,49]. Recent studies showed that Notch may be involved in the mechanism of cisplatin resistance [50,51], and γ-secretase is a key enzyme in the activation of the Notch pathway, and its specific inhibitor DAPT can block the activation of Notch signaling [52]. However, the role of Notch signaling pathway in the mechanism of cisplatin resistance remains to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Microscopic Raman illustrating antitumor enhancement effects by the combination drugs of γ‐secretase inhibitor and cisplatin on osteosarcoma cells

Wang

et al. 2022

Journal of Biophotonics

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By using Raman microspectroscopy, it aims to elucidate the cellular variations caused by the combination drug of γ‐secretase inhibitor (DAPT) and cisplatin in osteosarcoma (OS) cells. Illustrated by the obtained results of spectral analysis, the intracellular composition significantly changed after combined drug actions compared to the solo DAPT treatment, indicating the synergistic effect of DAPT combined with cisplatin on OS cells. Meanwhile, multivariate curve resolution‐alternating least squares (MCR‐ALS) algorithm was utilized to address the biochemical constitution changes in all investigated groups including the untreated (UT), DAPT (40D) and combined drug (40D + 20C) treated cells. K‐means cluster and univariate imaging were both utilized to visualize the changes in subcellular morphology and biochemical distribution. The presented study provides a unique understanding on the cellular responses to DAPT combined with cisplatin from the natural biochemical perspectives, and laids an experimental foundation for exploring the therapeutic strategies of other combined anticancer drugs in cancer cell model.

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“…Notch signaling is important in the maintenance of stem cells in intestinal crypts, by regulating the expression of EphrinB1, where the reciprocal gradients of EphB2 and EphrinB1 define the balance of intestinal stem cell self-renewal and differentiation ( 90 ). In cancer context also Notch1 is reported to regulate EphrinB1 signaling, as shown in osteosarcoma ( 91 ). Notably, another tubulin isotype, βIVb is shown to directly regulate EphrinB1 surface localization in oral cancer stem cells and their niche ( 5 ).…”

Section: Tubulins Implicated In the Regulation Of Cscs And Their Nichementioning

confidence: 98%

Tubulin Isotypes: Emerging Roles in Defining Cancer Stem Cell Niche

2022

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Although the role of microtubule dynamics in cancer progression is well-established, the roles of tubulin isotypes, their cargos and their specific function in the induction and sustenance of cancer stem cells (CSCs) were poorly explored. But emerging reports urge to focus on the transport function of tubulin isotypes in defining orchestrated expression of functionally critical molecules in establishing a stem cell niche, which is the key for CSC regulation. In this review, we summarize the role of specific tubulin isotypes in the transport of functional molecules that regulate metabolic reprogramming, which leads to the induction of CSCs and immune evasion. Recently, the surface expression of GLUT1 and GRP78 as well as voltage-dependent anion channel (VDAC) permeability, regulated by specific isotypes of β-tubulins have been shown to impart CSC properties to cancer cells, by implementing a metabolic reprogramming. Moreover, βIVb tubulin is shown to be critical in modulating EphrinB1signaling to sustain CSCs in oral carcinoma. These tubulin-interacting molecules, Ephrins, GLUT1 and GRP78, are also important regulators of immune evasion, by evoking PD-L1 mediated T-cell suppression. Thus, the recent advances in the field implicate that tubulins play a role in the controlled transport of molecules involved in CSC niche. The indication of tubulin isotypes in the regulation of CSCs offers a strategy to specifically target those tubulin isotypes to eliminate CSCs, rather than the general inhibition of microtubules, which usually leads to therapy resistance.

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The Notch Pathway Promotes Osteosarcoma Progression through Activation of Ephrin Reverse Signaling

Cited by 28 publications

References 36 publications

microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis

microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis

Microscopic Raman illustrating antitumor enhancement effects by the combination drugs of γ‐secretase inhibitor and cisplatin on osteosarcoma cells

Tubulin Isotypes: Emerging Roles in Defining Cancer Stem Cell Niche

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