Androgen receptor and androgen-dependent gene expression in lung
Introduction
Lung alveoli comprise two epithelial cell types, type I and type II pneumocytes (PTI and PTII, respectively) that enable gaseous exchange. PTI cells form the majority of the epithelium, and while PTII cells account for only about 15% of peripheral lung cells (Stone et al., 1992), they serve as stem cells that produce new PTI and PTII cells and have other specialized functions. For instance, PTII cells secrete surfactant to reduce the surface tension of the alveoli and decrease the work of breathing by preventing the alveoli from collapsing. Glucocorticoid receptor (GR) is essential in promoting differentiation of PTII cells during embryonic life (Ballard, 1989, Gonzales et al., 2001, Gonzales et al., 2002) and, antenatal glucocorticoid administration expedites lung maturation in infants at risk of preterm delivery (Roberts and Dalziel, 2006), largely through increased surfactant protein expression (Ballard, 1989).
Androgen receptor (AR) mediates the effects of male sex steroids in a variety of reproductive and non-reproductive tissues both in males and females under physiological and pathophysiological conditions (Dehm and Tindall, 2006, Heemers and Tindall, 2007, Heinlein and Chang, 2002, Heinlein and Chang, 2004). Lungs of male fetuses develop more slowly than those of females, and males are more prone to neonatal respiratory distress syndrome due to reduced number of PTII cells and lack of surfactant (Perelman et al., 1986). The AR has been studied in the developing human and murine lungs, and it has been shown to influence branching morphogenesis (Kimura et al., 2003) and to attenuate PTII cell maturation (Dammann et al., 2000, Provost et al., 2000). During development, there are several differentially expressed genes in the lungs of female and male mouse fetuses, including apolipoproteins that may be involved in local lipid metabolism and transport related to surfactant lipid synthesis (Simard et al., 2006). However, the effect of androgens on the gene expression profile in adult lung has not been assessed.
Lung cancer is a disease with a clear sex difference. Female patients show better survival rates than males at any stage of the disease (Fu et al., 2005). Histological subtypes of the disease in women include proportionally more adenocarcinoma and less squamous cell carcinoma than men (Chen et al., 2005, Fu et al., 2005). Overall, men appear to have a higher rate of fatal outcome of lung cancer, but tend to be less vulnerable to tobacco carcinogens than women (International Early Lung Cancer Action Program Investigators et al., 2006). It remains to be elucidated whether these differences result from men having lower circulating female sex steroid (estrogen and progesterone) or higher androgen levels than women, or from some as yet unknown confounding associations.
There is a previous report on the presence of AR in adult human lung (Wilson and McPhaul, 1996), but very little is known about functional importance of AR and androgen signaling in lung physiology after embryonal development. To address these issues, we have examined expression of the Ar gene and searched for androgen-dependent target genes in adult murine lung. Androgen-treated A549 cells, representing a transformed human PTII adenocarcinoma cell line, were used to compare androgen-dependent gene expression profiles in human cells with those in murine lung. Since androgens and glucocorticoids are known to regulate expression of the same genes, such as the prostate-specific antigen gene (Cleutjens et al., 1997, Thompson et al., 2006), the A549 cells were also employed to examine similarities and differences between gene expression profiles regulated by androgens and glucocorticoids through the AR and GR, respectively.
Section snippets
Mice and hormone treatments
Wild-type FVB mice were used. One week after castration, one group of male mice received androgen for 5 days [1 mg testosterone (T)/mouse/day in 0.1 ml of mineral oil as sc injections, corresponding to 30 μg T/g of body weight], whereas the control group received only vehicle. The dose of the androgen was based on similar previous experiments with mice (Pajunen et al., 1982). Animals were sacrificed on day 6, and the lungs were collected for RNA and protein isolation as well as for
Lung cell expression of the Ar gene
Ar mRNA was detected in hybridization blots of total murine lung RNA as a distinct ∼10-kb band. The presence of Ar mRNA size heterogeneity has been reported previously (Tilley et al., 1990, Shan et al., 1990), with two mRNA species of ∼10 kb and ∼8 kb in size. This latter Ar mRNA species was barely detectable in murine lung but corresponded to the principal Ar mRNA from in brain (Fig. 1A). The abundance of Ar mRNA in lung was comparable to that in brain, but less than in kidney or prostate. This
Localization of AR expression to specific lung cell types
In addition to fetal lung (Dammann et al., 2000, Kimura et al., 2003, Provost et al., 2004), we have now shown that adult lung is an androgen-responsive tissue in both mice and humans, and the AR is expressed predominantly in the bronchial epithelium and PTII cells. The latter cells are important in the maintenance of alveolar epithelium by (i) providing new epithelial cells and (ii) secreting surfactant. Since T delays maturation of PTII cells during embryonic development (Provost et al., 2004
Acknowledgments
We thank Saija Kotola, Johanna Iso-Oja and Anne Reijula for excellent technical assistance, Massimiliano Gentile for helping with the microarray analysis and Ismo Virtanen for helping with histological techniques. This work was supported by grants from the Academy of Finland, Biocentrum Helsinki, Sigrid Jusélius Foundation, Finnish Foundation for Cancer Research, Paulo Foundation, Oskar Öflund Foundation, Emil Aaltonen Foundation, Finnish Medical Foundation, Helsinki University Central
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