Expression of SIRT1 in ocular surface squamous neoplasia.

BACKGROUND: The class III histone deacetylase SIRT1 is overexpressed in many malignancies and has been implicated in inactivating proteins that are involved in tumor suppression and DNA damage repair. In the current study, we examined the expression of SIRT1 in normal epithelium (NE) compared with ocular surface squamous neoplasia (OSSN) to elucidate a possible role for SIRT1 in the development or progression of this malignancy. METHODS: We examined SIRT1 expression by immunohistochemistry in 47 cases of OSSN and 10 specimens of NE. Our sample included 11 benign lesions (papillomas), 25 cases of conjunctival intraepithelial neoplasia, and 11 malignant lesions of squamous cell carcinoma. The extent of staining and intensity was scored and the combined raw data were then converted to the German Immunoreactive Score. RESULTS: Nuclear and cytoplasmic expression of SIRT1 was observed in all cases of OSSN. For the NE specimens, 50% showed negative expression and 30% weak expression, and 20% were considered significantly immunoreactive. The differential expression of SIRT1 between NE and OSSN was statistically significant (P < 0.0001). Additionally, when the staining pattern in cases of conjunctival intraepithelial neoplasia was evaluated, the staining of the more differentiated surface cells was remarkably weaker compared with the cells located closer to the basal membrane. CONCLUSIONS: SIRT1 may play an important role in the development and progression of epithelial tumors of the conjunctiva. Further research into the potential of SIRT1 as a novel therapeutic target is warranted.

Peroxisome proliferator-activated receptor gamma in bladder cancer: a promising therapeutic target.

Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated intracellular transcription factors, members of the nuclear hormone receptor superfamily. The PPAR subfamily consist of three subtypes encoded by distinct genes denoted PPARalpha, PPARbeta/delta, and PPARgamma. The peroxisome proliferator-activated receptor gamma (PPARgamma) is the most extensively studied subtype of the PPARs. Over the last decade, research on PPARgamma unveiled its role in important biological processes, including lipid biosynthesis, glucose metabolism, anti-inflammatory response, and atherosclerosis. Recently, PPARgamma has been shown to be expressed in many cancers including, lung, prostate, bladder, colon, breast, duodenal, thyroid, and has been demonstrated to potentially play an important role in carcinogenesis. In bladder cancer, PPARgamma ligands such as troglitazone and 15d-PGJ2 have shown to inhibit tumor growth. We have recently published the first report to show that a new class of PPARgamma agonists, PPARgamma-active C-DIMs, which are more potent than the previous generation of drugs, exhibit anti-tumorigenic activity against bladder cancer cells in vitro and bladder tumors in vivo. The following review will discuss the molecular structure of PPARgamma, its function and its role in cancer biology and how it is emerging as a promising therapeutic target in bladder cancer.

Inhibition of mammalian target of rapamycin as a therapeutic strategy in the management of bladder cancer.

We examined whether mTOR inhibition by RAD001 (Everolimus) could be therapeutically efficacious in the treatment of bladder cancer. RAD001 markedly inhibited proliferation of nine human urothelial carcinoma cell lines in dose- and sensitivity-dependent manners in vitro. FACS analysis showed that treatment with RAD001 for 48 h induced a cell cycle arrest in the G(0)/G(1) phase in all cell lines, without eliciting apoptosis. Additionally, RAD001 significantly inhibited the phosphorylation of S6 downstream of mTOR and VEGF production in all cell lines. We also found tumor weights from nude mice bearing human KU-7 subcutaneous xenografts treated with RAD001 were significantly reduced as compared to placebo-treated mice. This tumor growth inhibition was associated with significant decrease in cell proliferation rate and angiogenesis without changes in cell death. In conclusion inhibition of mTOR signaling in bladder cancer models demonstrated remarkable antitumor activity both in vitro and in vivo. This is the first study showing that RAD001 could be exploited as a potential therapeutic strategy in bladder cancer.