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FGF18, a prominent player in FGF signaling, promotes gastric tumorigenesis through autocrine manner and is negatively regulated by miR-590-5p.
Oncogene ( IF 6.9 ) Pub Date : 2019-Jan-01 , DOI: 10.1038/s41388-018-0430-x
Jinglin Zhang , Yuhang Zhou , Tingting Huang , Feng Wu , Yi Pan , Yujuan Dong , Yan Wang , Aden K. Y. Chan , Liping Liu , Johnny S. H. Kwan , Alvin H. K. Cheung , Chi Chun Wong , Angela K. F. Lo , Alfred S. L. Cheng , Jun Yu , Kwok Wai Lo , Wei Kang , Ka Fai To

Fibroblast growth factors (FGFs) and their receptors are significant components during fundamental cellular processes. FGF18 plays a distinctive role in modulating the activity of both tumor cells and tumor microenvironment. This study aims to comprehensively investigate the expression and functional role of FGF18 in gastric cancer (GC) and elucidate its regulatory mechanisms. The upregulation of FGF18 was detected in seven out of eleven (63.6%) GC cell lines. In primary GC samples, FGF18 was overexpressed in genomically stable and chromosomal instability subtypes of GC and its overexpression was associated with poor survival. Knocking down FGF18 inhibited tumor formation abilities, induced G1 phase cell cycle arrest and enhanced anti-cancer drug sensitivity. Expression microarray profiling revealed that silencing of FGF18 activated ATM pathway but quenched TGF-β pathway. The key factors that altered in the related signaling were validated by western blot and immunofluorescence. Meanwhile, treating GC cells with human recombinant FGF18 or FGF18-conditioned medium accelerated tumor growth through activation of ERK-MAPK signaling. FGF18 was further confirmed to be a direct target of tumor suppressor, miR-590-5p. Their expressions showed a negative correlation in primary GC samples and more importantly, re-overexpression of FGF18 partly abolished the tumor-suppressive effect of miR-590-5p. Our study not only identified that FGF18 serves as a novel prognostic marker and a therapeutic target in GC but also enriched the knowledge of FGF-FGFR signaling during gastric tumorigenesis.

中文翻译:

FGF18是FGF信号的重要参与者,它通过自分泌方式促进胃癌发生,并受miR-590-5p负调控。

成纤维细胞生长因子(FGFs)及其受体是基本细胞过程中的重要组成部分。FGF18在调节肿瘤细胞和肿瘤微环境的活性中起着独特的作用。本研究旨在全面研究FGF18在胃癌(GC)中的表达及其功能,并阐明其调控机制。在11个(63.6%)GC细胞系中,有7个检测到FGF18的上调。在主要的GC样品中,FGF18在GC的基因组稳定和染色体不稳定亚型中过表达,并且其过表达与不良的存活率相关。敲低FGF18抑制肿瘤形成能力,诱导G1期细胞周期停滞并增强抗癌药敏感性。表达芯片分析表明,FGF18沉默激活了ATM途径,但淬灭了TGF-β途径。通过Western印迹和免疫荧光验证了相关信号中改变的关键因素。同时,用人重组FGF18或FGF18条件培养基处理GC细胞可通过激活ERK-MAPK信号传导来加速肿瘤生长。进一步证实FGF18是肿瘤抑制物miR-590-5p的直接靶标。它们的表达在主要的GC样品中显示出负相关,更重要的是,FGF18的重新过表达部分消除了miR-590-5p的肿瘤抑制作用。我们的研究不仅确定了FGF18在GC中是一种新的预后标志物和治疗靶标,还丰富了胃癌发生过程中FGF-FGFR信号转导的知识。通过Western印迹和免疫荧光验证了相关信号中改变的关键因素。同时,用人重组FGF18或FGF18条件培养基处理GC细胞可通过激活ERK-MAPK信号传导来加速肿瘤生长。进一步证实FGF18是肿瘤抑制物miR-590-5p的直接靶标。它们的表达在主要的GC样品中显示出负相关,更重要的是,FGF18的重新过表达部分消除了miR-590-5p的肿瘤抑制作用。我们的研究不仅确定了FGF18在GC中是一种新的预后标志物和治疗靶标,还丰富了胃癌发生过程中FGF-FGFR信号转导的知识。通过Western印迹和免疫荧光验证了相关信号中改变的关键因素。同时,用人重组FGF18或FGF18条件培养基处理GC细胞可通过激活ERK-MAPK信号传导来加速肿瘤生长。进一步证实FGF18是肿瘤抑制物miR-590-5p的直接靶标。它们的表达在主要的GC样品中显示出负相关,更重要的是,FGF18的重新过表达部分消除了miR-590-5p的肿瘤抑制作用。我们的研究不仅确定了FGF18在GC中是一种新的预后标志物和治疗靶标,还丰富了胃癌发生过程中FGF-FGFR信号转导的知识。用人重组FGF18或FGF18条件培养基处理GC细胞通过激活ERK-MAPK信号传导加速了肿瘤的生长。进一步证实FGF18是肿瘤抑制物miR-590-5p的直接靶标。它们的表达在主要的GC样品中显示出负相关,更重要的是,FGF18的重新过表达部分消除了miR-590-5p的肿瘤抑制作用。我们的研究不仅确定了FGF18在GC中是一种新的预后标志物和治疗靶标,还丰富了胃癌发生过程中FGF-FGFR信号转导的知识。用人重组FGF18或FGF18条件培养基处理GC细胞通过激活ERK-MAPK信号传导加速了肿瘤的生长。进一步证实FGF18是肿瘤抑制物miR-590-5p的直接靶标。它们的表达在主要的GC样品中显示出负相关,更重要的是,FGF18的重新过表达部分消除了miR-590-5p的肿瘤抑制作用。我们的研究不仅确定了FGF18在GC中是一种新的预后标志物和治疗靶标,还丰富了胃癌发生过程中FGF-FGFR信号转导的知识。它们的表达在主要的GC样品中显示出负相关,更重要的是,FGF18的重新过表达部分消除了miR-590-5p的肿瘤抑制作用。我们的研究不仅确定了FGF18在GC中是一种新的预后标志物和治疗靶标,还丰富了胃癌发生过程中FGF-FGFR信号转导的知识。它们的表达在主要的GC样品中显示出负相关,更重要的是,FGF18的重新过表达部分消除了miR-590-5p的肿瘤抑制作用。我们的研究不仅确定了FGF18在GC中是一种新的预后标志物和治疗靶标,还丰富了胃癌发生过程中FGF-FGFR信号转导的知识。
更新日期:2018-08-06
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