High Expression Of SIRT1 Research Articles

Prognostic role of SIRT6 in gastrointestinal cancers: a meta-analysis.

Sirtuin 6 (SIRT6) plays a critical role in the progression and development of gastrointestinal cancers. However, the association between SIRT6 expression and clinicopathological parameters and prognosis in gastrointestinal cancer patients remains inconclusive. Consequently, we conducted this meta-analysis to evaluate the importance of SIRT6 expression in various types of gastrointestinal cancers. PubMed, EMBASE, and Web of Science databases were systematically searched to screen the relevant literature. The reported or estimated hazard ratio (HR) and odds ratio (OR) and their corresponding 95% confidence interval (CI) were pooled to assess the strength of the association. Nine studies involving 867 patients were included in the meta-analysis. Overall analysis showed that high SIRT6 expression was related to better overall survival in gastrointestinal cancers (HR = 0.62, 95% CI = 0.47–0.82). High SIRT6 expression was also related to a favorable tumor node metastasis (TNM) stage (OR = 0.44, 95% CI = 0.28–0.70) among gastrointestinal cancer patients. Our meta-analysis revealed that high SIRT6 expression might be a potential biomarker predicting better prognosis in gastrointestinal cancers, which may offer options for gastrointestinal cancer treatment.

High Expression of SIRT1 Associates with the Doxorubicin Resistance of Breast Cancer through the Activation of Akt.

Although limited by side effects and development of resistance, doxorubicin still represents the most common chemotherapy for breast cancer. Thus, the identification of critical molecules to alleviate doxorubicin resistance is crucial. Here, we provide a molecular rationale for the breast cancer patients potentially benefitting from doxorubicin based on the expression levels of SIRT1, an identified member of longevity genes. SIRT1-overexpressed and SIRT1-knockdown breast cancer cells were established to investigate the functions of SIRT1 in regulating doxorubicin resistance both in vitro and in vivo. Cell proliferation was analyzed via CCK8 assay, cell apoptosis was studied by TUNEL analysis. Molecule interaction was analyzed through co-immunoprecipitation and immunofluorescence techniques. Sensibility to doxorubicin was assessed in vivo through the nude mice tumorigenicity experiment. First, SIRT1 was found higher-expressed in breast cancer doxorubicin-resistant cells MCF-7/ADR than that in the doxorubicin- sensitive cells MCF-7. Moreover, SIRT1-knockdown MCF-7/ADR cells showed higher susceptible to doxorubicin both in vitro and in vivo models, whereas overexpressing of SIRT1 inhibited this phenotype. Accordingly, SIRT1 was found interacted with Akt, consequently promoted the activity of Akt in MCF-7/ADR cells in vitro and positively correlated with the expression of P-Akt in vivo. Reversing the activity of Akt partially downturned the doxorubicin-resistant effects mediated by SIRT1. This investigation suggested the value of SIRT1 as a biomarker of response to doxorubicin, leading to the development of new tools for the management of breast cancer patients.

Associations of sirtuins with clinicopathological variables and prognosis in human ovarian cancer.

Ovarian cancer (OC) is the fifth most frequent cause of cancer-associated mortality worldwide, and is accompanied by asymptomatic progression. Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide-dependent protein deacetylases, comprising seven members (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7). Accumulating evidence has demonstrated that SIRTs act as prognostic estimators in certain types of cancer such as lung cancer, prostate cancer, gastric cancer, breast cancer and colorectal cancer. However, it remains unknown whether individual SIRTs can serve as independent prognostic factors in OC. In the present study, the Kaplan-Meier plotter online database was utilized to examine the prognostic values of SIRT mRNA expression in patients with OC. The results demonstrated that the overexpression of SIRT3, SIRT5, SIRT6 and SIRT7 mRNAs was associated with a good prognosis in patients, whereas elevated mRNA levels of SIRT1 and SIRT4 indicated poor survival in patients with OC. In addition, among the favorable predictors, SIRT3, SIRT5, SIRT6 and SIRT7 overexpression were associated with overall survival (OS), according to clinical characteristics, such as histological classification, clinical stage, pathology grade, drug therapy and tumor protein p53 mutation status in patients with OC. Similarly, SIRT4 mRNA overexpression was associated with poor OS in pathological grade III cancer. High SIRT1 and SIRT4 expression were associated with unfavorable OS at all clinical stages. Furthermore, SIRT1 and SIRT4 were negatively associated with OS in drug-treated patients. In summary, the present study demonstrated that the SIRT family is associated with the prognosis of human OC, suggesting that individual SIRTs may also act as prognostic predictors in patients.

SIRT6-Autophagy-Warburg Effect Axis in Papillary Thyroid Cancer

Background: Our previous study has demonstrated SIRT6 promotes aggression and epithelial-mesenchymal transition (EMT) in papillary thyroid cancer (PTC). In this study, we focused on the regulatory axis between SIRT6-Autophagy-Warburg effect. Methods: Autophagy activation was confirmed by Western Blotting, quantitative PCR, immunofluorescence and transmission electron microscopy. Warburg effect was examined by Seahorse XF96 analysis and PET imaging. Regulation of SIRT6 in negatively regulates reactive oxygen species (NRROS) was confirmed by chromatin immunoprecipitation. Findings: We innovatively confirmed overexpression of SIRT6 depleted histone H3 lysine 56 acetylation (H3K56ac) of NRROS in vitro, thus increased reactive oxygen species (ROS). Then, accumulated ROS activated endoplasmic reticulum stress (ER stress), and subsequently induced autophagy. Furthermore, the overexpression of SIRT6 inhibited Glucose Transporter 1 (Glut1) via autophagic degradation, thus ulteriorly suppressed Warburg effect. Treatment of ROS scavenger N-acetyl-L-cysteine (NAC, 5mM) or autophagy inhibitor chloroquine (CQ) both rescued the inhibition of Warburg effect. In addition, higher concentration of NAC (15mM) deepened the inhibited Warburg effect. This concentration-dependent bilateral effects of NAC in this process had been confirmed owe to regulation of AMPK signaling pathway. Finally, we further determined above mechanism in vivo via subcutaneous xenografts in nude mice applied with 18F-FDG PET/CT. Interpretation: We identified a SIRT6-ROS-ERstress-Autophagy-Glut1-Warburg effect axis in PTC, which may provide new target for therapy. In addition, NAC (low concentration) and CQ which previously been considered as tumor inhibitors, have been shown to promote tumorigenesis in PTC with high SIRT6 expression via activation of Warburg effect. Funding Statement: This study was funded by Specialty Feature Construction Project of Pudong Health and Family Planning Commission of Shanghai (Min Ye, Grant No.PWZzb2017-21). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All participating patients gave their written informed consent. This study was approved by the Ethical Committee of Shanghai Pudong Hospital.

Targeting Sirt6 with OSS_128167 Displays Anti-Tumor Activities in Diffuse Large B-Cell Lymphoma through Down-Regulation of PI3K Signaling

Introduction Sirt6, a member of the mammalian sirtuins family, functions as a highly conserved ADP-ribosylase and NAD+ dependent deacylase. Evidence from recent years indicates that Sirt6 is closely related to the occurrence and development of various solid tumors and multiple myeloma (MM). OSS_128167 is a novel small molecular inhibitor specifically targeting Sirt6, and induced chemosensitization in MM cells. Nevertheless, the role of Sirt6 in lymphoid malignancies is still unclear. Herein, we investigated the function of Sirt6 and identified the anti-tumor effects of OSS_128167 in diffuse large B-cell lymphoma (DLBCL). Methods Immunohistochemistry (IHC) was conducted to assess the expression of Sirt6 on paraffin-embedded tissues from 70 de novo DLBCL patients and 35 reactive hyperplasia patients with informed contents. Microarray dataset GSE32918 was obtained from Gene Expression Omnibus and survival analysis was performed. Lentivirus vectors either encoding shSirt6, lvSirt6 or empty lentiviral vector were stably transfected into DLBCL cells. shSirt6 transfected or shControl transfected LY1 cell samples were performed RNA sequencing (RNA-seq) analysis, functional enrichment analyses of gene ontology (GO) and gene set enrichment analysis (GSEA). DLBCL cells were subcutaneously injected to SCID-Beige mice to establish xenograft models. All animal experiments were performed in accordance with the principles of the Institutional Animal Care. A p value of less than 0.05 was interpreted as having statistical significance. Results Aberrantly overexpression of Sirt6 was confirmed in DLBCL tissues compared with reactive hyperplasia by IHC staining (Fig 1a). The expression level of Sirt6 was revealed in significant positive correlation with advanced age (p=0.009), Ann Arbor stage (p=0.036) and IPI score (p=0.045, Fig. 1b). Sirt6 high expression was turned up to be correlated with reduced overall survival of enrolled patients according to GSE32918 (n=249, Fig. 1c). Stable shSirt6 transfected DLBCL cells exhibited growth suppression compared to those transfected with empty vector in vitro (Fig. 2a) and in vivo (Fig. 2b-c). Lower expression level of Ki-67 was confirmed in the xenograft tumor tissues derived from shSirt6 cells by IHC staining (Fig. 2d). Sirt6 knockdown caused enforced apoptosis rates, induced G2/M phase arrest (Fig. 2e-f) and enhanced sensitivity to Doxorubicin (ADR) and bendamustine (Fig. 2g-h). These results were further confirmed in GO analysis according to RNA-seq (Fig. 2i) and WB (Fig. 2j). The exciting finding was, OSS_128167 obviously decreased cell proliferation (Fig. 3a), induced cell apoptosis (Fig. 3b) and blocked cell cycle (Fig. 3c) in DLBCL cell lines. Addition to ADR or bendamustine with 100µM OSS_128167 exhibited enhanced cytotoxicity in DLBCL cells (p< 0.05; Fig. 3d-e). Xenograft DLBCL mice model were treated with intraperitoneal injection of either OSS_128167 or a control vehicle every two days for 2 weeks. Consistent with our in vitro results, obviously decreased tumor growth were observed in the OSS_128167 group (Fig. 3f). Also, lowly expression level of c-Myc was found in OSS_128167 treated mice (Fig. 3g). We then investigated the underlying mechanism driving the tumor genesis potential of Sirt6. In accordance with the GSEA analysis, we observed that the phosphorylation of PI3K p110α and its downstream targets, including Akt (Ser473) and mTOR protein, were dramatically decreased in Sirt6 knockdown cells than in the control cells (Fig. 4a-b). In vivo western blotting analysis further confirmed it (Fig. 4c). The Sirt6 deletion-induced reductive of cell viability was only fewer restored by IGF-1 (Fig. 4d). Conclusion At present, the function of Sirt6 in tumorigenesis is still controversial. Our findings demonstrated for the first time the oncogenic role of Sirt6 in the pathogenesis of DLBCL. High expression of Sirt6 may serve as a prognostic marker for inferior outcome in DLBCL patients. OSS_128167, a novel targeted inhibitor of Sirt6, exerted excellent anti-lymphoma effects via activating PI3K/Akt/mTOR signaling. In addition, blockade of Sirt6 expression enhanced the sensitivity of DLBCL cells to chemotherapeutic agents. These findings provide mechanistic insights into the oncogenic activity of Sirt6 and highlighted the potency of OSS_128167 for novel therapeutic strategies in DLBCL. Disclosures No relevant conflicts of interest to declare.

Proteasome inhibitor induced SIRT1 deacetylates GLI2 to enhance hedgehog signaling activity and drug resistance in multiple myeloma.

Multiple myeloma (MM) is still incurable despite the successful application of proteasome inhibitors in clinic. Bortezomib represents the most common chemotherapy for MM, whereas acquired drug resistance and eventually developed relapse remain the major obstruction. In the current study, we established bortezomib-resistant myeloma cell lines and screened gene expression profiles using single cell RNA-sequencing. Resistant MM cells exhibited increased clonogenic potential, specific metabolic, and epigenetic signatures, along with the self-renewal signaling characteristic of MM stem-like cells. Aberrant activation of hedgehog (Hh) signaling was correlated with drug resistance and stem cell-like transcriptional program. The key transcriptional factor GLI2 of the Hh pathway was restricted in the high acetylation and low ubiquitination states in bortezomib-resistant myeloma cells. Further investigation revealed that SIRT1 deacetylates and stabilizes GLI2 protein at lysine 757 and consequentially activates the Hh signaling, and itself serves as a direct target of Hh signaling to format a positive regulating loop. Using combination screening with an epigenetic compound library, we identified the SIRT1 specific inhibitor S1541 and S2804 had very obvious synergetic antimyeloma effect. Sirt1 inhibition could partially impeded the Hh pathway and conferred bortezomib sensitivity in vitro and in vivo. Notably, elevated SIRT1 level was also a prominent hallmark for the resistant myeloma cells, and this expression pattern was confirmed in myeloma patients, but independent of RAS/RAF mutations. Clinically, SIRT1 expression in patients with complete response was suppressed but elevated in relapsed patients, and retrospective analysis showed patients with higher SIRT1 expression had poorer outcomes. In conclusion, the cooperation of SIRT1 and Hh is an important mechanism of drug resistance in myeloma, and therapeutics combining SIRT1 inhibitors will sensitize myeloma cells to proteasome inhibitors.

SIRT1 downregulated FGB expression to inhibit RCC tumorigenesis by destabilizing STAT3

Renal cell carcinoma (RCC) is one of the common lethal urologic tumors. Recent studies revealed that SIRT1 might function as a tumor suppressor during the progression of RCC. In addition, studies showed that FGB expression was abnormally upregulated in RCC and related to the progress of RCC. This study aimed to define the function of SIRT1 and underlying mechanism in the RCC progression. The expression of SIRT1 and FGB in RCC specimens and cells were detected by immunoblotting and immunostaining. Luciferase reporter assay was performed to confirm FGB as the target gene of STAT3. Other methods including stable transfection, co-immunoprecipitation, Western blot, and in vitro and in vivo proliferation assays were also performed. Our results showed that SIRT1 expression was downregulated in RCC tissues compared to adjacent normal tissues and relatively high expression of SIRT1 conferred a better prognosis for patients. Next, we showed that SIRT1 overexpression inhibited RCC tumorigenesis both in vitro and in vivo. In addition, FGB expression was upregulated in RCC tissues and overexpressing SIRT1 reduced FGB expression levels. Furthermore, inhibition of RCC proliferation by SIRT1 overexpression was rescued by FGB overexpression, indicating that SIRT1 inhibited RCC proliferation by repressing FGB expression. Mechanistically, we confirmed that FGB was the target gene of STAT3, and SIRT1 repressed the expression of FGB by deacetylation of STAT3, leading to STAT3 destabilization and degradation. SIRT1 inhibited RCC tumorigenesis by downregulating FGB expression, and this novel SIRT1-STAT3-FGB axis provided a potential target for RCC therapy.

Interval running training improves age-related skeletal muscle wasting and bone loss: Experiments with ovariectomized rats.

What is the central question of this study? What is the effect and mechanism of interval running training on age-related muscle wasting and bone loss in an ovariectomized rat model? What is the main finding and its importance? Interval running training improved muscle growth and osteogenic differentiation by enhancing the expression of bone morphogenic proteins and sirtuins in ageing-induced ovariectomized rats. Therefore, the repetition of low and high intensities within a single exercise bout, such as interval running training, may be recommended as a practical intervention to prevent skeletal muscle wasting and bone loss in the elderly. Effective prophylactic strategies are needed for the suppression of age-related muscle wasting and bone loss after menopause. Exercise training is attractive due to its potential for improving energy metabolism, as well as age-related muscle wasting and bone loss. In particular, interval running (IR) training involves a repetition of low and high intensities within a single exercise bout. Therefore, this study elucidated the effect of interval training on muscle and bone health, as well as anti-ageing, in ovariectomized (OVX) rats. The anti-ageing effect of IR on muscle and bone was tested using western blotting and micro-computed tomography analysis, tartrate-resistant acid phosphatase and immunohistochemical staining. IR significantly inhibited the expression of inflammatory molecules, and improved antioxidant activity via down-regulation of mitogen-activated protein kinases (MAPKs) in the ageing-induced OVX rats skeletal muscle. IR compared with continuous running (CR) improved muscle mass and growth in OVX rats by the promotion of muscle growth-related factors including MyoD, myogenin, phospho-mechanistic target of rapamycin (p-mTOR), sirtuins (SIRTs), and bone morphogenic proteins (BMPs). IR also effectively recovered OVX-induced bone loss via the down-regulation of bone resorption and osteoclast formation in receptor activator of nuclear factor κB ligand (RANKL)-treated bone marrowmacrophages (BMMs). In particular, IR led to high expression of SIRT1 and 6, which promoted osteogenic differentiation and bone formation via modulating the BMP signalling pathway compared with CR training. The in vivo effect of IR was confirmed by immunohistochemical staining with the improvement of bone formation molecules such as BMPs and SIRTs. These results suggested that IR training affected myogenic and osteogenic formation. So, IR training may be considered for prevention of muscle wasting and bone loss for the elderly.

Butyrate inhibits HBV replication and HBV-induced hepatoma cell proliferation via modulating SIRT-1/Ac-p53 regulatory axis.

Butyrate, a histone deacetylase inhibitor, has several therapeutic applications, including cancer. However, the effect of butyrate in HBV replication is not known so far. It was hypothesized that butyrate might inhibit HBV replication and host cell proliferation via SIRT-1. It was found that the increased expression of SIRT-1 in Hep G2.2.15 cells (HBV expressing cells) than Hep G2 cells. Next the expression of SIRT-1 and Acetylated p53 (Ac-p53) were measured in the liver biopsy samples of chronic hepatitis B (CHB) patients with high viral load and compared to CHB patients with low viral load and found that there was a high SIRT-1 expression and a low Ac-p53 levels in CHB patients with high viral load compared to CHB patients with low viral load. Incubation of butyrate inhibited SIRT-1 expression and cell proliferation. Inhibition of SIRT-1 by butyrate or SIRT-1 siRNA increased the levels of Ac-p53. The elevated Ac-p53 decreased p-akt, cyclin D1, and thereby inhibited cell proliferation. Incubation of butyrate with Hep G2.2.15 cells also inhibited HBx protein expression, HBV-DNA and hepatitis B surface antigen (HBsAg). Taken together, the data showed that butyrate inhibited HBV replication and cell proliferation by inhibiting SIRT-1 expression in hepatoma cells.

MicroRNA‑486‑5p functions as a tumor suppressor of proliferation and cancer stem‑like cell properties by targeting Sirt1 in liver cancer.

Cancer stem‑like cells (CSCs) are critical for the initiation, progression, chemoresistance and postsurgical recurrence of liver cancer. They are thought to be novel targets for the treatment of liver cancer, however, efficient agents that target liver cancer stem cells (CSCs) have not been identified. MicroRNAs (miRNAs) are small non‑coding RNAs that target the 3'untranslated region (3'UTR) of mRNAs. Their dysregulation has been implicated in several types of cancer including liver cancer, but it still remains unknown if they play a role in targeting liver CSCs. We compared the miRNA profiles between liver cancer samples and adjacent non‑tumor tissues using The Cancer Genome Atlas (TCGA) datasets. Several miRNAs including miR‑486‑5p (miR‑486) were found to be significantly downregulated in liver cancer tissues. These differentially expressed miRNAs were screened between CSC‑enriched tumor spheres and adherent cells. miR‑486 was significantly downregulated in tumor spheres and liver cancer samples. Ectopic expression of miR‑486 significantly repressed the self‑renewal and invasion of CSCs in vitro and tumorigenesis in vivo. Notably, we found that sirtuin 1 (Sirt1) served as a direct target of miR‑486. The high expression of Sirt1 was involved in maintaining the self‑renewal and tumorigenic potential of liver CSCs. The results of the present study indicated that the miR‑486‑Sirt1 axis was involved in suppressing CSC traits and tumor progression.

SIRT6 As a Potential Therapeutic Target in Diffuse Large B-Cell Lymphoma

IntroductionSirt6 is a member of the mammalian sirtuins (SIRTs) family, involved in diverse biological processes. It is dysregulated in various solid tumors and multiple myeloma. Sirt6 can be considered a double-edged sword in cancer, as its dual role of both an oncogene and a tumor suppressor. However, no literature has been reported regarding the functional significance of Sirt6 in diffuse large B-cell lymphoma (DLBCL) to date. Thus we evaluated the expression and function of Sirt6 in both DLBCL tissues and cell lines in this present study, as well as assessed the proliferation of DLBCL cells when treated with a pan-sirtuin inhibitor Nicotinamide (NAM) and a selected Sirt6 inhibitor, OSS_128167.MethodsMicroarray datasets GSE83632 and GSE32918 were obtained from Gene Expression Omnibus. Differential expression analysis in gene expression profiles GSE83632 were performed through classical Bayesian method provided by the Limma package and then extracted the SIRT6 gene expression value. GSE32918 was annotated with the R-package illumineHumanWGDASLv3.db data probe, converted into gene symbol, and extracted expression data of Sirt6 for survival analysis. Immunohistochemistry (IHC) was conducted to assess the expression of Sirt6 on araffin-embedded tissues from 60 de novo DLBCL patients (study group) and 30 reactive hyperplasia patients (control group) with informed contents. Then further analysis was performed to find the correlations between Sirt6 expression and the clinical characteristics of DLBCL patients. Peripheral blood mononuclear cells (PBMCs) were obtained from healthy volunteers with informed consents. Expression levels of Sirt6 mRNA and protein in DLBCL cell lines (LY1, LY8, LY3 and Val) and PBMCs (control) were detected by quantitative RT-PCR and western blotting. Lentivirus vectors transfected DLBCL cells to stably knockdown or overexpress Sirt6. Apoptosis was assessed by PE/7AAD. DLBCL cell lines were treated with NAM and OSS_128167, cell proliferation was analyzed by cell counting kit (CCK-8).ResultsBioinformatics analysis showed that SIRT6 was significantly up-regulated in DLBCL than in normal samples. High Sirt6 expression in DLBCL was turned up to be correlate with shorter overall survival according to GSE32918 (Figure 1A-B). These data indicated a relevant role for Sirt6 in the biology of DLBCL. We observed markedly increased level of Sirt6 in DLBCL lymph nodes by IHC. Expression of Sirt6 was positively correlated with Ann Arbor stage and international prognostic index (IPI) score of DLBCL patients. Aberrantly overexpression of Sirt6 was also confirmed in DLBCL cell lines at mRNA and protein level (Figure 2A-C). Our findings on Sirt6 were consistent with those from publicly available data sets.Sirt6 knockdown caused increased apoptosis rate, and on the contrary, Sirt6 over-expression had brought about decreased apoptosis (Figure 3A-C). We then investigated the function of Sirt inhibitors on the proliferation of DLBCL cells. LY1 and Val cells were treated with different doses of NAM at 24-72 hours. Cell proliferation was inhibited in a dose-dependent manner. LY1 and LY8 cells were treated with different doses of OSS_128167 at 24-72 hours and triggered similar effect, cell proliferation was inhibited by 60% at the concentration of 100µM for 48 hours (Figure 4A-B).ConclusionOur investigations identified for the first time that expression levels of Sirt6 were up-regulated in DLBCL and associated with adverse outcome by bioinformatics analysis and in vitro experiments. Knockdown of Sirt6 lead to increased apoptosis and over-expression of Sirt6 had the opposite effect. DLBCL cells treated with pan-Sirt inhibitor and selective Sirt6 inhibitor, revealed reduced proliferation in a dose-dependent manner. This study suggests that Sirt6 could be a potential molecular target for the treatment of DLBCL. Further research on it is under way. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dental pulp-derived stem cells can counterbalance peripheral nerve injury-induced oxidative stress and supraspinal neuro-inflammation in rat brain

Previously, we reported the successful regeneration of injured peripheral nerves using human dental pulp stem cells (DPSCs) or differentiated neuronal cells from DPSCs (DF-DPSCs) in a rat model. Here, we attempted to evaluate oxidative stress and supraspinal neuro-inflammation in rat brain after sciatic nerve injury (SNI). We divided our experimental animals into three SNI groups based on time. The expression of a microglial (Iba1) marker and reactive oxygen species (ROS) was lower in DPSCs and higher in DF-DPSCs. In contrast, the expression of an astroglial (GFAP) marker was higher in DPSCs and lower in DF-DPSCs at 2 weeks. However, the expression of ROS, Iba1 and GFAP gradually decreased at 8 and 12 weeks in the SNI DPSCs and DF-DPSCs groups compared to the SNI control. Furthermore, anti-inflammatory cytokine (IL-4 and TGF-β) expression was lower at 2 weeks, while it gradually increased at 8 and 12 weeks after surgery in the SNI DPSCs and DF-DPSCs groups. Similarly, SNI DPSCs had a high expression of pAMPK, SIRT1 and NFkB at the onset of SNI. However, 12 weeks after surgery, pAMPK and SIRT1 expression levels were higher and NFkB was down-regulated in both DPSCs and DF-DPSCs compared to the control group. Finally, we concluded that DPSCs responded early and more efficiently than DF-DPSCs to counterbalance peripheral nerve injury (PNI)-induced oxidative stress and supraspinal neuro-inflammation in rat brain.

Associations of sirtuins with clinicopathological parameters and prognosis in non-small cell lung cancer.

BackgroundLung cancer is the leading cause of cancer-related death worldwide and it is critical to discover specific biomarkers to provide better individualized treatment and subsequently better prognosis. The sirtuins (SIRT1–7) have been reported to be involved in cancers including non-small cell lung cancer (NCSLC), however, the results are not consistent and not all the seven sirtuins are explored and compared.MethodsTCGA data was downloaded and used to investigate and compare the associations of sirtuins mRNA levels with clinicopathological parameters and prognosis in NSCLC.ResultsOur results suggested SIRT1, SIRT3, SIRT4, and SIRT7 were highly expressed in adeno-carcinoma (ADC) patients and female patients while SIRT5 were highly expressed in squamous cell carcinoma (SCC) patients and male patients. Associations of high SIRT7 with younger onset age, high SIRT1 with distant metastasis and low T stage, and high SIRT4 with high T stage and TNM stage were also found. Kaplan-Meier plot curves and univariate Cox proportional regression analyses indicated that high SIRT2, SIRT4, and SIRT6 expressions were associated with longer overall survival (OS) time. Multivariate analyses indicated that SIRT2 and SIRT6 were still associated with OS. For recurrence-free survival (RFS), high SIRT1 expression was significantly associated with shorter RFS time while high SIRT2-3 and SIRT5-7 expressions were associated with longer RFS time in univariate analyses. After adjusting the confounding factors, significant associations were still found in SIRT1-2 and SIRT5-7 but not in SIRT3. We also stratified the patients by combining SIRT1 and SIRT2 and revealed that the combination of SIRT1 and SIRT2 was a better prediction model for RFS in NSCLC. To preliminarily understand the potential mechanisms of sirtuins in NSCLC carcinogenesis, the genes co-expressed with sirtuins were analyzed and annotated.Conclusionsirtuins might be the potential therapy targets and prognostic biomarkers in NSCLC.

The clinicopathological significance of SIRT1 expression in colon cancer: An immunohistochemical study and meta-analysis

ObjectiveThe aim of this study was to determine the clinicopathological significance and potential prognostic role of SIRT1 expression in colorectal cancer (CRC) using immunohistochemistry and meta-analysis. MethodsImmunohistochemistry was performed on 265 archival paraffin-embedded human CRC specimens to investigate the correlation between SIRT1 expression and clinicopathological characteristics, including patient survival. To elucidate the potential prognostic value of SIRT1 expression, a meta-analysis was performed using data on 2132 patients from eight eligible studies. ResultsSIRT1 was highly expressed in 24.5% of the 265 CRC specimens analyzed. High SIRT1 expression correlated with vascular invasion (P = 0.041). High SIRT1 expression also significantly correlated with expression of SNAI (P = 0.001), but not E-cadherin (P = 0.958). However, there was no significant correlation between SIRT1 expression and other clinicopathological parameters. High SIRT1 expression in the CRC specimens significantly correlated with a worse overall survival rate, independent of SNAI expression. However, based on the meta-analysis, high SIRT1 expression was not significantly correlated with overall survival rates [hazard ratio (HR) 1.111, 95% confidential interval (CI) 0.799–1.544]. ConclusionIn our retrospective study, high SIRT1 expression significantly correlated with vascular invasion and a worse prognosis. However, because the results from the meta-analysis differed the retrospective arm of our study, additional cumulative studies are needed to determine the prognostic value of SIRT1 in CRC.

SIRT1, miR-132 and miR-212 link human longevity to Alzheimer\u2019s Disease

Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly. Centenarians – reaching the age of >100 years while maintaining good cognitive skills – seemingly have unique biological features allowing healthy aging and protection from dementia. Here, we studied the expression of SIRT1 along with miR-132 and miR-212, two microRNAs known to regulate SIRT1, in lymphoblastoid cell lines (LCLs) from 45 healthy donors aged 21 to 105 years and 24 AD patients, and in postmortem olfactory bulb and hippocampus tissues from 14 AD patients and 20 age-matched non-demented individuals. We observed 4.0-fold (P = 0.001) lower expression of SIRT1, and correspondingly higher expression of miR-132 (1.7-fold; P = 0.014) and miR-212 (2.1-fold; P = 0.036), in LCLs from AD patients compared with age-matched healthy controls. Additionally, SIRT1 expression was 2.2-fold (P = 0.001) higher in centenarian LCLs compared with LCLs from individuals aged 56–82 years; while centenarian LCLs miR-132 and miR-212 indicated 7.6-fold and 4.1-fold lower expression, respectively. Correlations of SIRT1, miR-132 and miR-212 expression with cognitive scores were observed for AD patient-derived LCLs and postmortem AD olfactory bulb and hippocampus tissues, suggesting that higher SIRT1 expression, possibly mediated by lower miR-132 and miR-212, may protect aged individuals from dementia and is reflected in their peripheral tissues.

Resveratrol pretreatment enhanced homing of SDF-1α-preconditioned bone marrow-derived mesenchymal stem cells in a rat model of liver cirrhosis.

Stromal cell-derived factor-1α (SDF-1α) has been known to implicate in homing of MSCs, and resveratrol has been reported to have a positive influence on SDF-1 level in the site of injury. In this study, a combined strategy was applied to evaluate bone marrow-derived MSCs (BMSCs) homing to the rat model of liver cirrhosis induced by common bile duct ligation (CBDL): (1) pretreatment delivery of resveratrol into the cirrhotic liver, and (2) transplantation of ex vivo BMSC preconditioning with SDF-1α. BMSCs were preconditioned with 10 ng/µL SDF-1α for 1 h and then labeled with the CM-Dil. Cirrhosis was induced by CBDL. Animals received intraperitoneal injection of resveratrol for 7 days, started on day 28 of CBDL post-operative. On day 36 post-operative, 1 × 106 of SDF-1α-preconditioned BMSCs was injected via caudal vein. Animals were sacrificed at 72 h post-cell transplantation. Immunofluorescence and flow cytometry assessments showed that the BMSC+SDF+RV group had an increased rate of homing into the liver, but it had a decreased rate of homing into the lung and spleen, as compared with the other groups (P < 0.05). The BMSC+SDF+RV group showed high protein expression of SIRT1, but low protein expression of p53 in the liver (P < 0.05 vs other groups). CXCR4 and matrix metalloproteinase (MMP)-9 highly expressed in SDF-1α-preconditioned BMSCs in vitro, and that AKTs and CXCL12 expressed in injured liver undergoing resveratrol injection. Our findings suggest that reseveratrol pretreatment prior to SDF-1α preconditioning could be a promising strategy for designing cell-based therapies for liver cirrhosis.

Prognostic and clinicopathological significance of SIRT1 expression in NSCLC: a meta-analysis.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. The prognosis of NSCLC is extremely poor and it is urgently to find a new marker. Numerous studies have confirmed that silent mating type information regulation 2 homolog-1 (sirtuin1; SIRT1) is abnormally expressed in NSCLC. This meta-analysis was performed to investigate the prognostic and clinicopathological significance of SIRT1 in NSCLC. A total of seven eligible studies, including 6 on clinicopathological features, 7 on prognosis were identified from the databases. Pooled hazard ratios (HRs) or odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated using random- or fixed-effects models. Results revealed that high expression of SIRT1 was associated with poor overall survival in NSCLC patients (HR=1.99, 95% CI: 1.33-2.98, P=0.0009). Moreover, SIRT1 were related to histological grade (OR= 2.00, 95% CI= 1.05–3.78, P= 0.02) of NSCLC patients. In conclusion, our present meta-analysis indicated that SIRT1 may serve as a promising marker for prognosis of patients with NSCLC.

Impact of expression of SIRT1 and SIRT2 on outcome in the very elderly patients with colorectal cancer.

e15107 Background: Surtuins(SIRTs), NAD+-dependent deacetylases, participate in cell metabolism and ageing associated diseases including cancer. The elderly has higher cancer incidence and mortality compared to the young. Many of patients with colorectal cancer are over the age of 80. The role of SIRT 1 and 2 in tumorigenesis remains debated and it has not been reported for the very elderly patients with cancer. We investigated the relationship of clinicopathologic parameters and expression of SIRT1 and 2 in colorectal cancer patients 80 years of age or older and the impact of ageing comparing with the younger patients. Methods: The expression of SIRT1 and 2 were evaluated in colorectal cancer tissues of 101 patients aged ≥80 years and 29 patients aged ≤40 years by immunohistochemistry. And correlations between expression of these proteins and clinicopathological features were analyzed. Results: High expression of SIRT1 was observed in 65/101 (64.4%) elderly patients and 11/29 (37.9%) young patients(p = 0.011). Similarly, high expression of SIRT2 was more commonly observed in 58/99 (58.6%) elderly patients than 8/29 (27.6%) young patients(p = 0.003). In all patients high SIRT2 expression was associated with comorbid DM, and stage of CRC were not associated with SIRT1 or SIRT2 expression status. Comparison of Kaplan-Meier survival curve using log rank test revealed that high expressions of SIRT1 and SIRT2 were significantly associated with worse prognosis (median OS 24.9ms vs 38.6ms, p = 0.027) and better prognosis (median OS 37.9ms vs 17.3ms, p = 0.006) respectively in elderly patients. No prognostic significances were observed in younger patients. In multivariate analysis, only high SIRT1 expression retained statistical significance as a poor prognostic factor in elderly patients with CRC. Conclusions: :High SIRT1 expression might become a significant poor prognostic factor for elderly CRC patients although further study is needed for younger patients to clarify the difference of expression according to the age between elderly and young patients with CRC. High SIRT2 expression showed association with comorbid DM, further studies are warranted to establish prognostic significance in CRC patients.

RASSF1A and SIRT6 in non-small cell lung cancer: Relationship with clinical outcome.

This study investigated the expression of RASSF1A and SIRT6 in non-small cell lung cancer (NSCLC) and its relationship with clinical prognosis. The expression in 122 cases of NSCLC tissues (NSCLC group) and 122 cases of normal lung tissues (NOR group) during the same period were detected by immunohistochemical Super Pic Ture™ Polymer two-step method, and the relationship between its expression and the clinicopathological features and prognosis of patients was analyzed. The positive expression rates of RASSF1A and SIRT6 in NSCLC group were lower than those in the normal group (55.74 vs. 84.43% and 52.46 vs. 82.49%, P<0.01). The differences in expression intensity of RASSF1A in NSCLC tissues between different tumor pathological types, tumor differentiation degrees and lymph node metastases were statistically significant, and the differences in expression intensity of SIRT6 between different TNM stages, tumor differentiation degrees and lymph node metastases were statistically significant. There was a positive correlation between the expression of RASSF1A and SIRT6 in NSCLC group (r=0.532, P<0.01). The 3-year survival rate of patients with high-expression of RASSF1A was higher than in those with low-expression of RASSF1A (81.33 vs. 39.45%, log-rank χ2=19,102, P<0.01); the 3-year survival rate of patients with high-expression of SIRT6 was higher than in those with low-expression of SIRT6 (83.51 vs. 42.43%, log-rank χ2=17,180, P<0.01). The low expression of RASSF1A and SIRT6 and lymph node metastasis were the risk factors affecting the prognosis of NSCLC patients. There is a better correlation between the expression of RASSF1A and SIRT6 in NSCLC tissues, and the detection of their expression is of great significance in the judgement of clinicopathological features and prognosis of NSCLC patients.

Co-ordinated overexpression of SIRT1 and STAT3 is associated with poor survival outcome in gastric cancer patients.

In many gastric cancer patients, the disease is diagnosed in an advanced stage and therefore the mortality levels are high. Because there is a need to identify novel early diagnostic and prognostic biomarkers, we tested whether SIRT1 and STAT3 are good candidates. Towards this, we used patient tissues representing different stages of gastric cancer including gastric pre-cancerous lesions, early gastric cancer, and advanced gastric cancer, and probed SIRT1, STAT3 and phosphorylated STAT3 (pSTAT3) levels using immunohistochemistry. Our results revealed upregulated expression of SIRT1 in all stages of gastric cancer compared with noncancerous gastric mucosa, suggesting that high SIRT1 levels are likely involved in establishing gastric neoplasticity. However, STAT3 and pSTAT3 levels remained low until the gastric mucosa reached the tumor stage. Moreover, co-ordinated high expression of SIRT1 and STAT3 predicted poor overall survival for advanced gastric cancer patients. In addition, through analysis of gastric cancer patients from the TCGA dataset, we identified SIRT2 as an independent prognostic factor in gastric cancer patients. We postulate that SIRT1 and STAT3 are potential early diagnostic and prognostic markers of gastric cancer. Our study also shows that SIRT1 acts a gatekeeper during gastric tumorigenesis.