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Can Res文章: 肺腺癌干细胞Catenin/POU5F1/SOX2信号通路预示不良预后

日期:2019/03/29  来源:新葡萄京娱乐场官方网站

  

  肺癌在各类癌症引起的死亡中居首,肺腺癌是肺癌的各种亚类中最常见的类型。肺腺癌的发病年龄较小,女性相对多见,早期一般没有明显的临床症状,确诊时多属于中晚期。肺腺癌发病机制尚不完全明确。有研究报道从肺腺癌、小细胞肺癌细胞株中发现肿瘤干细胞样细胞(Cancer stem-like cells ,CSLCs),在肿瘤发生发展中起着至关重要的作用。来自第三军医大学西南医院的卞修武教授带领的研究人员的研究揭示了一条对于肺腺癌干细胞样细胞自我更新和致瘤潜能维持至关重要的信号机制。相关论文发表在2013年3月的Cancer research杂志上。

  在这篇文章中,研究人员通过对肺腺癌患者的新鲜切片样本进行免疫组化分析,发现肺腺癌细胞中胰岛素样生长因子1受体(IGF-1R)高表达,并且与癌干细胞标记物CD133和ALDH1A1的表达呈正相关。IGF-1R激活通过PI3K/AKT/GSK3β/β-catenin级联反应,促进了人类肺腺癌干细胞样细胞上的POU5F1表达。POU5F1随后与β-catenin和SOX2形成新的复合物,并结合到Nanog启动子上调控转录,这个IGF-1R启动的机制维持了肺腺癌干细胞样细胞自我更新。体外实验证实,通过遗传或药物抑制IGF-1R将破坏肺腺癌干细胞样细胞的体内自我更新和致瘤能力。体内异种移植肿瘤模型证实, 敲减IGF-1R 或敲减POU5F1,都可以抑制人类肺腺癌干细胞样细胞的致瘤潜力。通过分析切取自200名肺腺癌患者的病理学样本,发现高表达的IGF-1R与β- catenin、POU5F1共定位,这预示着不良的预后。

  新研究证实IGF-1R介导POU5F1表达,与β-catenin和SOX2形成一种复合物,对于肺腺癌干细胞样细胞自我更新和致瘤潜能至关重要。临床综合检测IGF-1R、β-catenin和POU5F1的表达,对于预测肺腺癌患者的预后具有重要参考价值。本研究中mRNA表达谱芯片检测工作北京新葡萄京娱乐场官方网站生物技术有限企业完成。


原文摘要: 

        β-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma.

      Cancer stem-like cells (CSLC) are crucial in tumor initiation and progression; however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma showed that high expression of insulin-like growth factor I receptor (IGF-IR) in lung adenocarcinoma cells was positively correlated with the expressions of cancer stem cell markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). IGF-IR activation enhanced POU class 5 homeobox 1 (POU5F1) expression on human lung adenocarcinoma stem-like cells (LACSLC) through PI3K/AKT/GSK3β/β-catenin cascade. POU5F1 could form a novel complex with β-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-IR. Genetic and pharmacologic inhibition of IGF-IR abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-IR or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathologic specimens excised from 200 patients with lung adenocarcinoma, we found that colocalization of highly expressed IGF-IR with β-catenin and POU5F1 predicted poor prognosis. Taken together, we show that IGF-IR-mediated POU5F1 expression to form a complex with β-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-IR, β-catenin, and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma.

原文出处:http://cancerres.aacrjournals.org/content/73/10/3181.long

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