Effect of NELL1 on lung cancer stem-like cell differentiation
Effect of NELL1 on lung cancer stem-like cell differentiation
复制标题
NELL1对肺癌干细胞样细胞分化的影响
DOI：
10.3892/or.2019.6954
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发表时间：
2019-03-01
期刊：
影响因子：
4.2
通讯作者：
Liu, Gentao
中科院分区：
文献类型：
--
作者：
Zhai, Yuanfen;Wei, Rongbin;Liu, Gentao
肿瘤干细胞理论近年来在肿瘤生物学中引起了极大的关注。肺癌干细胞样细胞是未分化的肺肿瘤细胞的亚群，对于肺癌肿瘤发生、转移和对治疗的抵抗以及疾病复发至关重要。神经EGFL样1（NELL 1）是一种有效的生长因子，被认为优先靶向骨软骨细胞系的细胞;然而，其在肺癌中的表达和功能在很大程度上是未知的。在本研究中，我们使用特定的培养基聚集肺癌干细胞样细胞的95-D细胞在球体中，并通过流式细胞仪细胞分选的CD 133染色的细胞，这些高表达的CD 133细胞被称为95-D肺癌干细胞样细胞（95-DLCSC）。通过蛋白质印迹分析和定量实时聚合酶链反应（qPCR）分析确定，这些95-D LCSC高表达干性基因CD 133、Oct 4和Sox 2。值得注意的是，我们发现NELL 1的过表达显著降低了软琼脂集落形成和细胞侵袭试验测试的95-D LCSC的集落形成和侵袭。此外，如通过细胞增殖测定所确定的，NELL 1的过表达增加了95-D LCSC对卡铂和顺铂的化疗敏感性。NELL 1还降低磷酸化MET（p-MET）、Notch 3和HES 1的表达，这表明NELL 1可能通过抑制c-MET-Notch信号传导的表达来诱导95-D LCSC分化。我们的研究结果表明，NELL 1诱导肺癌干细胞样分化，这为癌症干细胞提供了一个新的潜在治疗靶点。
The cancer stem cell theory recently has received enormous attention in cancer biology. Lung cancer stem-like cells are a subpopulation of undifferentiated lung tumor cells critical for lung cancer tumorigenesis, metastasis and resistance to therapy and disease relapse. The neural EGFL like 1 (NELL1) is a potent growth factor believed to preferentially target cells committed to the osteochondral lineage; yet, its expression and function in lung cancer are largely unknown. In the present study, we used specific medium to accumulate lung cancer stem-like cells of 95-D cells in spheres and obtained these highly expressed CD133 cells through flow cytometric cell sorting of CD133-stained cells which were termed 95-D lung cancer stem-like cells (95-D LCSCs). These 95-D LCSCs highly expressed stemness genes CD133, Oct4 and Sox2 determined by western blot analysis and quantitative real-time polymerase chain reaction (qPCR) analysis. Notably, we found that overexpression of NELL1 significantly reduced colony formation and invasion of 95-D LCSCs tested by soft agar colony formation and cell invasion assay. In addition, as determined by cell proliferation assay, overexpression of NELL1 increased the chemotherapeutic sensitivity of 95-D LCSCs to carboplatin and cisplatin. NELL1 also reduced the expression of phospho-MET (p-MET), Notch3 and HES1, which suggests that NELL1 may induce 95-D LCSC differentiation by inhibiting the expression of c-MET-Notch signaling. Our results suggest that NELL1 induces lung cancer stem-like cell differentiation, which provides a new potential therapeutic target for cancer stem cells.