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PTPRM methylation induced by FN1 promotes the development of glioblastoma by activating STAT3 signalling
Pharmaceutical Biology ( IF 3.9 ) Pub Date : 2021-07-05 , DOI: 10.1080/13880209.2021.1944220
Jian Song 1 , Di Zhao 2 , Guozhu Sun 1 , Jiankai Yang 1 , Zhongqiang Lv 1 , Baohua Jiao 1
Affiliation  

Abstract

Context

The phosphorylation of signal transducer and activator of transcription protein 3 (STAT3) is up-regulated in glioblastoma (GBM) cells and is regulated by protein tyrosine phosphatase receptor type M (PTPRM). Fibronectin-1 (FN1) is also reported to be up-regulated in GBM.

Objective

We explored the role of FN1-induced PTPRM methylation in GBM.

Materials and methods

The lentivirus particles of oe-PTPRM, sh-PTPRM, oe-FN1, sh-FN1, or their negative controls (NSCs) were transfected into GBM cells with or without stattic (0.5 μM, 24 h) or 5-aza (1 μM, 0, 2, 4 h) treatments. Methylation-specific PCR was performed to detect PTPRM methylation levels.

Results

PTPRM was down-regulated (0.373 ± 0.124- and 0.455 ± 0.109-fold), FN1 and p-STAT3 were up-regulated (p < 0.001) in A172 and U87 MG cells as compared to NSCs. Overexpressing PTPRM inhibited STAT3 phosphorylation. Interfering with PTPRM increased colony numbers in A172 and U-87 MG cells (2.253 ± 0.111- and 2.043 ± 0.19-fold), and stattic reduced them. Cell viability was reduced after treatment with 5-aza in A172 and U-87 MG cells (p < 0.05). P-STAT3 was down-regulated after 5-aza treatment. Overexpressing FN1 decreased PTPRM levels (p < 0.001), knockdown of FN1 decreased PTPRM methylation and inhibited STAT3 phosphorylation. Overexpressing FN1 increased cell viability (1.497 ± 0.114- and 1.460 ± 0.151-fold), and stattic or 5-aza reversed such effects (p < 0.05).

Discussion and conclusions

The up-regulation of FN1 reduced PTPRM by increasing its methylation, resulting in an increase of STAT3 phosphorylation and promoting GBM cell proliferation. Interfering with FN1 may be a potential therapeutic target for GBM.



中文翻译:

FN1诱导的PTPRM甲基化通过激活STAT3信号促进胶质母细胞瘤的发展

摘要

语境

信号转导和转录激活蛋白 3 (STAT3) 的磷酸化在胶质母细胞瘤 (GBM) 细胞中上调,并受 M 型蛋白酪氨酸磷酸酶受体 (PTPRM) 调节。据报道,纤连蛋白 1 (FN1) 在 GBM 中也被上调。

客观的

我们探讨了 FN1 诱导的 PTPRM 甲基化在 GBM 中的作用。

材料和方法

将 oe-PTPRM、sh-PTPRM、oe-FN1、sh-FN1 或其阴性对照 (NSCs) 的慢病毒颗粒转染到有或没有静态(0.5 μM,24 小时)或 5-aza(1 μM)的 GBM 细胞中, 0, 2, 4 h) 处理。进行甲基化特异性 PCR 以检测 PTPRM 甲基化水平。

结果

与 NSC 相比,PTPRM 在 A172 和 U87 MG 细胞中被下调(0.373 ± 0.124 和 0.455 ± 0.109 倍),FN1 和 p-STAT3 被上调(p  < 0.001)。过表达 PTPRM 会抑制 STAT3 磷酸化。干扰 PTPRM 增加了 A172 和 U-87 MG 细胞的集落数(2.253 ± 0.111 和 2.043 ± 0.19 倍),而静态减少了它们。在 A172 和 U-87 MG 细胞中用 5-aza 处理后细胞活力降低 ( p  < 0.05)。P-STAT3 在 5-aza 处理后下调。过表达 FN1 会降低 PTPRM 水平 ( p  < 0.001),FN1 的敲低会降低 PTPRM 甲基化并抑制 STAT3 磷酸化。过表达 FN1 增加细胞活力(1.497 ± 0.114 倍和 1.460 ± 0.151 倍),stattic 或 5-aza 逆转这种效应(p  < 0.05)。

讨论和结论

FN1 的上调通过增加其甲基化减少 PTPRM,导致 STAT3 磷酸化增加并促进 GBM 细胞增殖。干扰 FN1 可能是 GBM 的潜在治疗靶点。

更新日期:2021-07-06
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