摘要
背景:上皮间质转化(EMT)是肿瘤转移的主要决定因素,与TGF-β1密切相关。细胞内蛋白质,包括E.钙粘蛋白,N.钙粘蛋白和波形蛋白与EMT直接相关,影响细胞迁移和粘附;另一方面,非肌肉肌球蛋白(NM)在胞质分裂,迁移和粘附中具有核心作用。目的:通过调控非肌肉肌球蛋白II-A(NMII-A)及其与己糖胺生物合成途径(HBP)的相互作用,探讨EMT与转移与TGF-β1的关系。 方法:蛋白质表达的变化通过免疫印迹和免疫荧光染色进行评估,而通过qRT-PCR评估转录水平的变化。 EMT通过表型分析,伤口愈合,增殖和transwell迁移实验体外评估,而在BALB / c裸鼠体内研究肺原位和尾静脉转移模型。 结果:我们证明TGF-β1对JNK / P38 / PI3K的调节导致了NMII-A的下调,促进了EMT和肺癌的转移。 NMII-A的这种下调表达反过来上调核心2 N-乙酰葡糖胺基转移酶粘蛋白型(C2GnT-M)的表达,并进一步促进了N-乙酰葡糖胺转移酶(GnT)-V和-III的上调和下调;此外,NMII-A K.D细胞在体内显示出向脑部迁移3倍的倾向。 结论:本研究报道了NMII-A通过上调C2GnT-M,GnT-V和GnT-III的下调表达负调节EMT和转移的新途径。这些肺癌的发现可能还需要研究其他癌症类型。
关键词: NMII-A,EMT,C2GnT-M,GnT-III,GnT-V,GlcNAc,HBP,肺癌转移。
图形摘要
Current Cancer Drug Targets
Title:TGF-β1 Causes EMT by Regulating N-Acetyl Glucosaminyl Transferases via Downregulation of Non Muscle Myosin II-A through JNK/P38/PI3K Pathway in Lung Cancer
Volume: 18 Issue: 2
关键词: NMII-A,EMT,C2GnT-M,GnT-III,GnT-V,GlcNAc,HBP,肺癌转移。
摘要: Background: Epithelial to mesenchymal transition (EMT) is a major determinant of cancer metastasis and is closely linked with TGF-β1. Intracellular proteins, including E. Cadherin, N. Cadherin and Vimentin are directly related to EMT that affect cell migration and adhesion; on the other hand, non muscle myosin (NM) has a central role in cytokinesis, migration and adhesion.
Objective: We aimed to explore the association of EMT and metastasis with TGF-β1 through regulation of non-muscle myosin II-A (NMII-A) and its interaction with Hexosamine Biosynthesis Pathway (HBP).
Method: Protein expression changes were assessed by western blotting and immunofluorescent staining while transcription level changes were assessed by qRT-PCR. EMT was assessed by phenotypic analysis, wound healing, proliferation and transwell migration assay in vitro while in vivo studies were conducted in BALB/c nude mice for lung orthotopic and tail vein metastasis models.
Results: We demonstrated that regulation of JNK/ P38/PI3K by TGF-β1 led to down expression of NMII-A which promoted EMT and lung cancer metastasis. This down expression of NMII-A conversely upregulated the expression of Core 2 N-acetyl Glucosaminyl Transferase mucin type (C2GnT-M) and further facilitated up-regulation and down-regulation of N-acetylglucosaminyltransferase (GnT) -V and -III respectively; moreover, NMII-A K.D cells showed 3 times more tendency to migrate towards brain in vivo.
Conclusion: The study reports a novel pathway through which NMII-A negatively regulates EMT and metastasis via up regulation of C2GnT-M, GnT-V and down expression of GnT-III. These findings of lung cancer may further be required to study other cancer types.
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TGF-β1 Causes EMT by Regulating N-Acetyl Glucosaminyl Transferases via Downregulation of Non Muscle Myosin II-A through JNK/P38/PI3K Pathway in Lung Cancer, Current Cancer Drug Targets 2018; 18 (2) . https://dx.doi.org/10.2174/1568009617666170807120304
DOI https://dx.doi.org/10.2174/1568009617666170807120304 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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