Achaete-scute complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer.
Achaete-scute complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer.
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DOI：
10.1158/0008-5472.can-08-2762
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Ball DW
中科院分区：
文献类型：
--
作者：
Jiang T;Collins BJ;Jin N;Watkins DN;Brock MV;Matsui W;Nelkin BD;Ball DW
碱性螺旋-环-螺旋转录因子ASCL1(Achaete-Scute Complex Homolog-1)是正常肺神经内分泌(NE)细胞以及其他内分泌和神经组织发育所必需的。具有NE特征的小细胞肺癌和非小细胞肺癌表达ASCL1，该因子可能在这些肿瘤的毒力和原始NE表型中发挥作用。在本研究中，RNA干扰敲除培养的SCLC中的ASCL1导致软琼脂克隆形成能力的抑制和诱导细胞凋亡。在表达研究、流式细胞术和染色质免疫沉淀的支持下，cDNA微阵列分析发现了两个候选干细胞标记基因CD133和ALDH1A1(乙醛脱氢酶1A1)，它们在小细胞肺癌中受到ASCL1的直接调控。在小细胞肺癌直接移植瘤中，我们检测到相对丰富的CD133高ASCL1高Aldh1亚群，与CD133表达弱的细胞相比，其致瘤性显著增强。CD133高表达亚群的致瘤性依赖于ASCL1的持续表达。CD133高表达细胞很容易重建原始移植瘤中CD133的表达范围，而CD133低表达细胞则不能。我们的发现表明，大范围的SCLC细胞具有致瘤能力，而不是一个小的离散群体。固有的肿瘤细胞异质性，包括ASCL1等关键调控因子的变异，可以调节小细胞肺癌的致瘤性。
The basic helix-loop-helix transcription factor ASCL1 (Achaete-scute complex homolog-1) is essential for the development of normal lung neuroendocrine (NE) cells as well as other endocrine and neural tissues. SCLC and NSCLC with NE features express ASCL1, where the factor may play a role in the virulence and primitive NE phenotype of these tumors. In this study, RNA interference knockdown of ASCL1 in cultured SCLC resulted in inhibition of soft agar clonogenic capacity and induction of apoptosis. cDNA microarray analyses bolstered by expression studies, flow cytometry, and chromatin immunoprecipitation identified two candidate stem cell marker genes, CD133 and ALDH1A1 (aldehyde dehydrogenase 1A1), to be directly regulated by ASCL1 in SCLC. In SCLC direct xenograft tumors, we detected a relatively abundant CD133high-ASCL1high-Aldh1high sub-population with markedly enhanced tumorigenicity compared to cells with weak CD133 expression. Tumorigenicity in the CD133high sub-population depended on continued ASCL1 expression. Whereas CD133high cells readily reconstituted the range of CD133 expression seen in the original xenograft tumor, CD133low cells could not. Our findings suggest that a broad range of SCLC cells have tumorigenic capacity, rather than a small discrete population. Intrinsic tumor cell heterogeneity, including variation in key regulatory factors such as ASCL1, can modulate tumorigenicity in SCLC.