miR181 家族对神经母细胞瘤肿瘤抑制因子 CDON 依赖性受体的调控作用。
Regulation by miR181 family of the dependence receptor CDON tumor suppressive activity in neuroblastoma.
机构信息
Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue,' LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon, France (BG, CDB, OM, SLG, JF, BD, FL, MC, AMN, PM); CNRS UMR 8126, University Paris-Sud 11, Institut Gustave Roussy, Villejuif, France (C-HG, JB); Stem Cell and Brain Research Institute, INSERM U846, Bron, France (FB); INSERM, U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France (IJL, OD); Department Epigenetics and Cancer FRE 3377, Centre National de la Recherche Scientifique, Commissariat à l'Energie Atomique Saclay, Gif-sur-Yvette, France (AHB); Université Paris-Sud, Gif-sur-Yvette, France (AH-B); Present address: INSERM UMR 1078, Etablissement Français du Sang, Centre Hospitalier Régional Universitaire de Brest, SFR ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, Brest, France (C-HG).
出版信息
J Natl Cancer Inst. 2014 Oct 13;106(11). doi: 10.1093/jnci/dju318. Print 2014 Nov.
BACKGROUND
The Sonic Hedgehog (SHH) signaling pathway plays an important role in neural crest cell fate during embryonic development and has been implicated in the progression of multiple cancers that include neuroblastoma, a neural crest cell-derived disease. While most of the SHH signaling is mediated by the well-described canonical pathway leading to the activation of Smoothened and Gli, it has recently been shown that cell-adhesion molecule-related/downregulated by oncogenes (CDON) serves as a receptor for SHH and contributes to SHH-induced signaling. CDON has also been recently described as a dependence receptor, triggering apoptosis in the absence of SHH. This CDON proapoptotic activity has been suggested to constrain tumor progression.
METHODS
CDON expression was analyzed by quantitative-reverse transcription-polymerase chain reaction in a panel of 226 neuroblastoma patients and associated with stages, overall survival, and expression of miR181 family members using Kaplan Meier and Pearson correlation methods. Cell death assays were performed in neuroblastoma cell lines and tumor growth was investigated in the chick chorioallantoic model. All statistical tests were two-sided.
RESULTS
CDON expression was inversely associated with neuroblastoma aggressiveness (P < .001). Moreover, re-expression of CDON in neuroblastoma cell lines was associated with apoptosis in vitro and tumor growth inhibition in vivo. We show that CDON expression is regulated by the miR181 miRNA family, whose expression is directly associated with neuroblastoma aggressiveness (survival: high miR181-b 73.2% vs low miR181-b 54.6%; P = .03).
CONCLUSIONS
Together, these data support the view that CDON acts as a tumor suppressor in neuroblastomas, and that CDON is tightly regulated by miRNAs.
背景
Sonic Hedgehog（SHH）信号通路在胚胎发育过程中对神经嵴细胞命运起着重要作用，并且与包括神经母细胞瘤在内的多种癌症的进展有关，神经母细胞瘤是一种源自神经嵴细胞的疾病。虽然大部分 SHH 信号是通过描述良好的经典途径介导的，导致 Smoothened 和 Gli 的激活，但最近表明细胞黏附分子相关/癌基因下调（CDON）作为 SHH 的受体，并有助于 SHH 诱导的信号转导。CDON 最近也被描述为依赖性受体，在没有 SHH 的情况下触发细胞凋亡。这种 CDON 促凋亡活性被认为限制了肿瘤的进展。
方法
通过定量逆转录聚合酶链反应（qRT-PCR）分析了 226 名神经母细胞瘤患者的 CDON 表达，并使用 Kaplan-Meier 和 Pearson 相关方法将其与分期、总生存率和 miR181 家族成员的表达相关联。在神经母细胞瘤细胞系中进行细胞死亡测定，并在鸡胚绒毛尿囊膜模型中研究肿瘤生长。所有统计检验均为双侧检验。
结果
CDON 表达与神经母细胞瘤侵袭性呈负相关（P<0.001）。此外，在神经母细胞瘤细胞系中重新表达 CDON 与体外细胞凋亡和体内肿瘤生长抑制相关。我们表明 CDON 表达受 miR181 miRNA 家族的调控，其表达与神经母细胞瘤侵袭性直接相关（生存：高 miR181-b 73.2% vs 低 miR181-b 54.6%；P=0.03）。
结论
综上所述，这些数据支持 CDON 作为神经母细胞瘤中的肿瘤抑制因子的观点，并且 CDON 受到 miRNA 的严格调控。
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