Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies.

Oct-4 and nanog promote the epithelial-mesenchymal transition of breast cancer stem cells and are associated with poor prognosis in breast cancer patients Oct-4 and Nanog promote the epithelial-mesenchymal transition of breast cancer stem cells and are associated with poor prognosis in breast cancer patients

Introduction: We investigated Nestin expression in triple-negative breast cancer and examined how the modulation of Nestin expression affects cell cycle progression, survival, invasion and regulatory signaling in breast cancer stem cells (CSC) in vitro. Methods: Nestin expression in 150 triple-negative breast cancer specimens were examined by immunohistochemistry. The role of Nestin expression in tumorigenesis was examined by assaying naturally occurring Nestin^high/Nestin^low CSC from 12 breast cancer tissues, as well as CSC from 26 clinical specimens, where Nestin overexpression and silencing was achieved by genetic manipulation, for their ability to form mammospheres and induce solid tumors. Cell cycle progression, spontaneous apoptosis and invasiveness of Nestin-silenced breast CSC were investigated by flow cytometry and transwell assays. The relative levels of expression of epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathway-related molecules were determined by western blotting. Results: Nestin expression was significantly associated with poor survival in patients with triple-negative breast cancer (P = 0.01). Nestin^high breast CSC rapidly formed typical mammospheres in vitro. Nestin^high, but not Nestin^low CSC, efficiently formed solid tumors in vivo. Nestin silencing induced cell cycle arrest at G2/M (52.03% versus 19.99% in controls) and promoted apoptosis (36.45% versus 8.29% in controls). Nestin silencing also inhibited breast CSC invasiveness, and was associated with significantly upregulated E-cadherin, while N-cadherin, vimentin, a-smooth muscle actin (a-SMA), matrix metalloproteinase-2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF) expression was downregulated (P <0.05 for all). Nestin silencing also upregulated Axin, glycogen synthase kinase-3 beta (GSK-3β), adenomatous polyposis coli (APC), and peroxisome proliferator-activated receptor alpha (PPARa), and downregulated β-catenin, c-Myc, cyclin D and MMP-7 expression in CSC. Inhibition of the Wnt/β-catenin pathway mitigated mammosphere formation in Nestin^high CSC, while inhibition of GSK-3β promoted the mammosphere formation in Nestin^low CSC (P <0.05 for all). Conclusions: Our data indicates that Nestin positively regulates the proliferation, survival and invasiveness of breast CSC by enhancing Wnt/β-catenin activation.

The purpose of this study was to evaluate the outcome of the ratio between metastatic and examined lymph nodes (N ratio) in gastric cancer patients with 25%. All the enrolled categories were evaluated by the best cutoff approach. The univariate analysis showed that age, tumor site, tumor size, surgery, T categories, number of metastatic nodes, and N ratio significantly affected prognosis in groups 1 and 2. By multivariate analysis, the N ratio (but not the TNM N category) classification was retained as an independent prognostic factor in groups 1 and 2 compared with the N category system. However, patients with N1 disease in group 1 obtained a better postoperative prognosis than those with N1 disease in group 2 according to the N stage classification (P=0.003). When the N ratio classification was applied, no significant differences were found for N ratios 0, 1, 2, or 3 between the 2 groups (P>0.05). The metastatic lymph node ratio is an independent prognostic factor regardless of the examined number of lymph nodes. In predicting the prognosis of gastric cancer, the staging system based on the metastatic lymph node ratio is more reliable than the system based on the number of metastatic lymph nodes regardless of the examined number of lymph nodes. This can help improve the TNM staging classification of gastric cancer and reduce the International Union Against Cancer N categories of stage migration.

We investigated the expression status of periostin in breast cancer stem cells and its clinical implications in order to lay a foundation for managing breast cancer. CD44+/CD24−/line- tumor cells (CSC) from clinical specimens were sorted using flow cytometry. Periostin expression status was detected in CSC cells and 1,086 breast cancer specimens by Western blot and immunohistochemistry staining, with the CSC ratio determined by immunofluorescence double staining. The relationship between the periostin protein and clinico-pathological parameters and prognosis was subsequently determined. As a result, CSC cells are more likely to generate new tumors in mice and cell microspheres that are deficient in NOD/SCID compared to the control group. Periostin protein was expressed higher in CSC cells compared to the control cells and was found to be related to CSC chemotherapy resistance. Moreover, periostin expression was found to be related to the CSC ratio in 1,086 breast cancer specimens (P = 0.001). In total, 334 (30.76%) of the 1,086 breast cases showed high periostin expression. After universal and Spearman regression correlation analysis, periostin was observed to be related to histological grade, CSC ratio, lymph node metastasis, tumor size, and triple-negative breast cancer (all P<0.05). Furthermore, periostin was shown to attain a significantly more distant bone metastasis and worse disease-specific survival than those with none or low-expressed periostin protein (P = 0.001). In the Cox regression test, periostin protein was detected as an independent prognostic factor (P = 0.001). In conclusion, periostin was found to be related to the CSC and an independent prognostic factor for breast cancer. It is also perhaps a potential target to breast cancer.