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This is a personal, informal and non-sponsored commentary on papers recently published by the Italian biomedical research community.
The purpose is to draw attention not only to good Italian research,
but also to good scientific reporting and publishing from Italy.
The selection of articles is purely subjective, but your suggestions are welcome. Write to me, Valerie Matarese, at vmatarese@ uptoit.org; copies of non-OA papers are welcome.
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Up To it! Home > Italian biomedical research highlights
The neuronal acetylcholine receptor is an ion channel involved in synaptic signal transmission. This multisubunit receptor is also bound and modulated by nicotine. Several studies over the past few years have implicated the receptor's alpha-5 subunit (CHRNA5) in the risk of developing nicotine dependence, chronic obstructive pulmonary disease and lung cancer. In particular, a single nucleotide polymorphism in the coding sequence (leading to an amino acid change, Asp/Asn) and a series of polymorphisms in the 5' non-coding region (modulating the level of mRNA) have been linked to nicotine dependence and lung cancer.
Researchers from Milan continued these investigations, focusing on the changes in mRNA levels. First, they sequenced the promoter and 5' untranslated region of CHRNA5 from 20 samples of normal lung tissue with either high or low levels of alpha-5 mRNA. This permitted the identification of four polymorphisms (one insertion-deletion mutation and three single nucleotide polymorphisms) which, in these samples, defined three haplotypes. Then, they genotyped non-tumoral lung tissue from 68 patients with lung adenocarcinoma. This analysis associated the insTGG haplotype with the Asn398 variant and with relatively low alpha-5 mRNA levels, a combination that previous studies have shown to predict high risk for nicotine dependence, chronic obstructive pulmonary disease and lung cancer. The other two haplotypes were associated with the Asp398 variant and with intermediate (insATC) or high (delTTC) mRNA levels, phenotypes associated with low disease risk. When recombinant vectors bearing the polymorphisms were used to drive the expression of a luciferase reporter gene in lung cancer cell lines, mixed results were obtained: only in one of four lines did the researchers observe the expected pattern of relatively lower expression with insTGG, whereas in the other cell lines the delTTC haplotype gave the lowest levels. While these in vitro studies confirmed the importance of these haplotypes in regulating CHRNA5 mRNA, it remains to be determined which pathological changes in the three cell lines inverted the expected expression pattern.
These experiments advance our understanding of the genetic determinants of CHRNA5 expression in normal lung tissue and lead the way for further investigation into the transcription factors that bind the gene at these polymorphic sites. Such future research may help unravel the complex question of how variations in the neuronal acetylcholine receptor and, in particular, in its alpha-5 subunit can lead to apparently diverse pathologies such as nicotine dependence and lung cancer. The study was published as a brief communication in the September 2010 issue of the Journal of the National Cancer Institute (PMID: 20733116). Posted 25 January 2011.
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