期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：33
页码：14763-14768
DOI：10.1073/pnas.1009483107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Gallbladder cancer is a highly aggressive disease with poor prognosis that is two to six times more frequent in women than men. The development of gallbladder cancer occurs over a long time (more than 15 y) and evolves from chronic inflammation to dysplasia/metaplasia, carcinoma in situ, and invasive carcinoma. In the present study we found that, in female mice in which the oxysterol receptor liver X receptor-{beta} (LXR{beta}) has been inactivated, preneoplastic lesions of the gallbladder developed and evolved to cancer in old animals. LXR{beta} is a nuclear receptor involved in the control of lipid homeostasis, glucose metabolism, inflammation, proliferation, and CNS development. LXR{beta}-/- female gallbladders were severely inflamed, with regions of dysplasia and high cell density, hyperchromasia, metaplasia, and adenomas. No abnormalities were evident in male mice, nor in LXR{alpha}-/- or LXR{alpha}-/-{beta}-/- animals of either sex. Interestingly, the elimination of estrogens with ovariectomy prevented development of preneoplastic lesions in LXR{beta}-/- mice. The etiopathological mechanism seems to involve TGF-{beta} signaling, as the precancerous lesions were characterized by strong nuclear reactivity of phospho-SMAD-2 and SMAD-4 and loss of E-cadherin expression. Upon ovariectomy, E-cadherin was reexpressed on the cell membranes and immunoreactivity of pSMAD-2 in the nuclei was reduced. These findings suggest that LXR{beta} in a complex interplay with estrogens and TGF-{beta} could play a crucial role in the malignant transformation of the gallbladder epithelium.
