NDLI: Achaete-Scute Complex Homolog 1 Regulates Tumor-Initiating Capacity in Human Small Cell Lung Cancer

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Achaete-Scute Complex Homolog 1 Regulates Tumor-Initiating Capacity in Human Small Cell Lung Cancer

Content Provider	PubMed Central
Author	Jiang, Tianyun Collins, Brendan J. Jin, Ning Watkins, David N. Brock, Malcolm V. Matsui, William Nelkin, Barry D. Ball, Douglas W.
Abstract	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.
Related Links	http://dx.doi.org/10.1158/0008-5472.CAN-08-2762
Ending Page	854
Page Count	10
Starting Page	845
File Format	PDF
ISSN	15387445
e-ISSN	15387445
Journal	Cancer research
Issue Number	3
Volume Number	69
Language	English
Publisher Date	2009-02-01
Access Restriction	Open
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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