Estrogen-dependent gallbladder carcinogenesis in LXRbeta-/- female mice.
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 (LXRbeta) has been inactivated, preneoplastic lesions of the gallbladder developed and evolved to cancer in old animals. LXRbeta is a nuclear receptor involved in the control of lipid homeostasis, glucose metabolism, inflammation, proliferation, and CNS development. LXRbeta(-/-) 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 LXRalpha(-/-) or LXRalpha(-/-)beta(-/-) animals of either sex. Interestingly, the elimination of estrogens with ovariectomy prevented development of preneoplastic lesions in LXRbeta(-/-) 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 LXRbeta in a complex interplay with estrogens and TGF-beta could play a crucial role in the malignant transformation of the gallbladder epithelium.
Gabbi
Chiara
C
Department of Biosciences and Nutrition, Karolinska Institutet, S-141 86 Novum, Sweden.
Kim
Hyun-Jin
HJ
Barros
Rodrigo
R
Korach-Andrè
Marion
M
Warner
Margaret
M
Gustafsson
Jan-Ake
JA
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005704:Gallbladder / Q000378:metabolism* / Q000473:pathology; D005706:Gallbladder Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D010052:Ovariectomy; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood / Q000378:metabolism
D015820:Cadherins; D004967:Estrogens; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D051899:Smad2 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta