RAS 信号通路的激活与嗜铬细胞瘤中细胞黏附的改变有关。

Activation of RAS Signalling is Associated with Altered Cell Adhesion in Phaeochromocytoma.

机构信息

Department of Biomedical and Clinical Sciences, Linköping University, SE-58183 Linköping, Sweden.

Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Cancer Center Karolinska, SE-17176 Stockholm, Sweden.

出版信息

Int J Mol Sci. 2020 Oct 29;21(21):8072. doi: 10.3390/ijms21218072.

Abstract

Phaeochromocytomas and paragangliomas (PPGLs) are neuroendocrine catecholamine-producing tumours that may progress into inoperable metastatic disease. Treatment options for metastatic disease are limited, indicating a need for functional studies to identify pharmacologically targetable pathophysiological mechanisms, which require biologically relevant experimental models. Recently, a human progenitor phaeochromocytoma cell line named "hPheo1" was established, but its genotype has not been characterised. Performing exome sequencing analysis, we identified a T827I mutation, and the oncogenic Q61K mutation. While mutations are recurring somatic events in PPGLs, mutations have hitherto not been detected in PPGLs. Therefore, we aimed to assess its implications for the hPheo1 cell line, and possible relevance for the pathophysiology of PPGLs. We found that transient downregulation of in hPheo1 led to elevated expression of genes associated with cell adhesion, and enhanced adhesion to hPheo1 cells' extracellular matrix. Analyses of previously published mRNA data from two independent PPGL patient cohorts (212 tissue samples) revealed a subcluster of PPGLs featuring hyperactivated RAS pathway-signalling and under-expression of cell adhesion-related gene expression programs. Thus, we conclude that activity in hPheo1 decreases adhesion to their own extracellular matrix and mirrors a transcriptomic RAS-signalling-related phenomenon in PPGLs.

摘要

嗜铬细胞瘤和副神经节瘤 (PPGL) 是产生儿茶酚胺的神经内分泌肿瘤,可能进展为无法手术的转移性疾病。转移性疾病的治疗选择有限,表明需要进行功能研究以确定可靶向治疗的病理生理机制,这需要具有生物学相关性的实验模型。最近,建立了一种名为“hPheo1”的人原代嗜铬细胞瘤细胞系,但尚未对其基因型进行表征。通过外显子组测序分析,我们发现了 T827I 突变和致癌性 Q61K 突变。虽然 突变是 PPGL 中反复出现的体细胞事件,但迄今为止尚未在 PPGL 中检测到 突变。因此,我们旨在评估其对 hPheo1 细胞系的影响及其对 PPGL 病理生理学的可能相关性。我们发现 hPheo1 中的 瞬时下调导致与细胞黏附相关的基因表达上调,并增强了 hPheo1 细胞与细胞外基质的黏附。对来自两个独立的 PPGL 患者队列(212 个组织样本)的先前发表的 mRNA 数据的分析揭示了一组具有超活化 RAS 信号通路和细胞黏附相关基因表达程序下调的 PPGL。因此,我们得出结论,hPheo1 中的 活性降低了对其自身细胞外基质的黏附,并反映了 PPGL 中与 RAS 信号相关的转录组现象。

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