27,

28 In addition, when mice expressing a constitutively

27,

28 In addition, when mice expressing a constitutively active form of PPARγ in mammary glands were bred to transgenic mice prone to mammary gland cancer, the resulting offspring develop tumors with greatly accelerated kinetics,8 suggesting a pro-oncogenic role of PPARγ. Moreover, in human pancreatic and ovarian cancers expression profiles indicate a strong overexpression of PPARγ that positively correlate with higher pT stages and higher tumor grade.29, 30 Interestingly, our experiments showed that in Tg(HBV)CreKOγ mice TZD administration inhibits tumor formation with a potency significantly higher than in parental and control mice. Moreover, PPARγ ectopic expression in PPARγ-deficient hepatocytes reduced the antiproliferative IWR 1 effect of TZD (Supporting Information Fig. 6). How PPARγ expression limits TZD anticancer

activities remains speculative. We hypothesize that the net effect of TZD in cancer cells is the result of the balance of PPARγ-mediated (pro-oncogenic) and PPARγ-independent (anti-oncogenic) mechanisms that depends on different factors including receptor expression levels, phosphorylation status, expression of the heterodimeric partners, and the presence Angiogenesis inhibitor of endogenous ligands.31 This might explain the limited therapeutic efficacy of TZD treatment in oncological trials except for tumor types with reduced levels and possible loss of function of PPARγ such as prostate and thyroid cancers.32, 33 In vitro studies have suggested that TZD mediate antiproliferative effects through a complexity of PPARγ-independent mechanisms. Experimental evidence indicates that troglitazone and ciglitazone block

BH3 domain-mediated interactions between Bcl-2 family members and facilitate the degradation of cyclin D1 through proteasome-mediated proteolysis.34, 35 In our study, we identified a novel molecular target by which TZD inhibit hepatocyte proliferation in vivo. Proteomic analysis showed that TZD reduce the expression of NPM, a nucleolar protein characterized as a central regulator of ribosomal RNA processing that has been found to be more abundant in tumor and growing cells than in corresponding normal cells.17 In HCC, NPM 上海皓元 overexpression is correlated with clinical parameters, such as serum α-fetoprotein level and tumor pathological grading, suggesting that NPM might serve as a potential marker for HCC.36 In agreement, in our mouse model we found a progressive age-related increase of NPM that parallels the increase of PCNA-LI in hepatocytes (Supporting Information Fig. 7). TZD inhibited the expression of NPM at protein and mRNA levels in both isolated hepatocytes and hepatoma cell lines, and significantly repressed NPM promoter activity independently of the ectopic expression of wild-type PPARγ or DN-PPARγ. These data are in agreement with the absence of PPRE in the NPM promoter (A. Galli, E. Ceni, L. Cioni, unpublished observation, 2009).

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