Dataset Information

Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/?-Catenin/IGFR-IR Signaling Axis.

ABSTRACT: Biglycan, a small leucine rich proteoglycan (SLRP), is an important participant in bone homeostasis and development as well as in bone pathology. In the present study biglycan was identified as a positive regulator of MG63 osteosarcoma cell growth (p ? 0.001). IGF-I was shown to increase biglycan expression (p ? 0.01), whereas biglycan-deficiency attenuated significantly both basal and IGF-I induced cell proliferation of MG63 cells (p ? 0.001; p ? 0.01, respectively). These effects were executed through the IGF-IR receptor whose activation was strongly attenuated (p ? 0.01) in biglycan-deficient MG63 cells. Biglycan, previously shown to regulate Wnt/?-catenin pathway, was demonstrated to induce a significant increase in ?-catenin protein expression evident at cytoplasmic (p ? 0.01), membrane (p ? 0.01), and nucleus fractions in MG63 cells (p ? 0.05). As demonstrated by immunofluorescence, increase in ?-catenin expression is attributed to co-localization of biglycan with the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) resulting in attenuated ?-catenin degradation. Furthermore, applying anti-?-catenin and anti-pIGF-IR antibodies to MG-63 cells demonstrated a cytoplasmic and to the membrane interaction between these molecules that increased upon exogenous biglycan treatment. In parallel, the downregulation of biglycan significantly inhibited both basal and IGF-I-dependent ERK1/2 activation, (p ? 0.001). In summary, we report a novel mechanism where biglycan through a LRP6/?-catenin/IGF-IR signaling axis enhances osteosarcoma cell growth.

SUBMITTER: Aggelidakis J

PROVIDER: S-EPMC6206209 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/β-Catenin/IGFR-IR Signaling Axis.

Aggelidakis John J Berdiaki Aikaterini A Nikitovic Dragana D Papoutsidakis Antonis A Papachristou Dionysios J DJ Tsatsakis Aristidis M AM Tzanakakis George N GN

Frontiers in oncology 20181023

Biglycan, a small leucine rich proteoglycan (SLRP), is an important participant in bone homeostasis and development as well as in bone pathology. In the present study biglycan was identified as a positive regulator of MG63 osteosarcoma cell growth (p ≤ 0.001). IGF-I was shown to increase biglycan expression (p ≤ 0.01), whereas biglycan-deficiency attenuated significantly both basal and IGF-I induced cell proliferation of MG63 cells (p ≤ 0.001; p ≤ 0.01, respectively). ...[more]

PMID: 30406034

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Project description:BackgroundAlthough 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.MethodsTumor 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.ResultsmiR-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.ConclusionOverall, 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.

Dataset Information

Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/?-Catenin/IGFR-IR Signaling Axis.

Publications

Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/β-Catenin/IGFR-IR Signaling Axis.

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