GSBS Student Publications

Title

ASCL1 regulates the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus

Student Author(s)

Ma. Reina D. Improgo

GSBS Program

Neuroscience

UMMS Affiliation

Brudnick Neuropsychiatric Research Institute, Department of Psychiatry

Date

2-1-2010

Document Type

Article

Medical Subject Headings

Basic Helix-Loop-Helix Transcription Factors; Receptors, Nicotinic; Nerve Tissue Proteins; Lung Neoplasms; Small Cell Lung Carcinoma

Disciplines

Cancer Biology | Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology

Abstract

Tobacco contains a variety of carcinogens as well as the addictive compound nicotine. Nicotine addiction begins with the binding of nicotine to its cognate receptor, the nicotinic acetylcholine receptor (nAChR). Genome-wide association studies have implicated the nAChR gene cluster, CHRNA5/A3/B4, in nicotine addiction and lung cancer susceptibility. To further delineate the role of this gene cluster in lung cancer, we examined the expression levels of these three genes as well as other members of the nAChR gene family in lung cancer cell lines and patient samples using quantitative reverse transcription-PCR. Overexpression of the clustered nAChR genes was observed in small-cell lung carcinoma (SCLC), an aggressive form of lung cancer highly associated with cigarette smoking. The overexpression of the genomically clustered genes in SCLC suggests their coordinate regulation. In silico analysis of the promoter regions of these genes revealed putative binding sites in all three promoters for achaete-scute complex homolog 1 (ASCL1), a transcription factor implicated in the pathogenesis of SCLC, raising the possibility that this factor may regulate the expression of the clustered nAChR genes. Consistent with this idea, knockdown of ASCL1 in SCLC, but not in non-SCLC, led to a significant decrease in expression of the alpha 3 and beta 4 genes without having an effect on any other highly expressed nAChR gene. Our data indicate a specific role for ASCL1 in regulating the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. This regulation may contribute to the predicted role that ASCL1 plays in SCLC tumorigenesis.

Rights and Permissions

Citation: Mol Cancer Res. 2010 Feb;8(2):194-203. Epub 2010 Feb 2. Link to article on publisher's website

Related Resources

Link to article in PubMed

Journal Title

Molecular cancer research : MCR

PubMed ID

20124469