SIRT1 Is Downregulated in Gastric Cancer and Leads to G1-phase Arrest via NF-κB/Cyclin D1 Signaling

Abstract

Sirtuin 1 (SIRT1) is a class III histone/protein deacetylase, and its activation status has been well documented to have physiologic benefits in human health. However, the function of SIRT1 in cancer remains controversial. Here, the expression and role of SIRT1 in gastric cancer is delineated. SIRT1 was present in all normal gastric mucosa specimens; however, it was only present in a portion of the matched gastric cancer tumor specimens. In SIRT1-positive tumors, both mRNA and protein levels were downregulated as compared with the corresponding nonneoplastic tissue. Ectopic expression of SIRT1 inhibited cell proliferation, diminished clonogenic potential, and induced a G 1 -phase cell-cycle arrest, the effects of which were not apparent when a catalytic-domain mutant form of SIRT1 was introduced, suggesting that SIRT1 functions in gastric cancer are dependent on its deacetylase activity. Further evidence was obtained from depletion of SIRT1. At the molecular level, SIRT1 inhibited the transcription of Cyclin D1 (CCND1), and inhibition of NF-kB in SIRT1-depleted cells rescued Cyclin D1 expression. Furthermore, inhibition of either NF-kB or Cyclin D1 in SIRT1-depleted cells reversed the inhibitory effects of SIRT1. The inhibitory role of SIRT1 was also verified in vivo using xenografts. This work characterizes SIRT1 status and demonstrates its inhibitory function in gastric cancer development, which involves NF-kB/ Cyclin D1 signaling, offering a therapeutic role for SIRT1 activators.

F-box protein FBXO31 is down-regulated in gastric cancer and negatively regulated by miR-17 and miR-20a

“…So, this inhibitory effect of FBXO31 on colony formation ability was dependent on its F-box domain. The cell cycle arrest is an important anti-proliferation mechanism in cancer [5,18, 19]. Therefore,we used flow cytometry to analyze the cell cycle and determine if the mechanism of the growth suppression of FBXO31 is due to the effect on the cell cycle.…”

“…BGC-823 GC cells transfected with pCMV-myc or pCMV-myc-FBXO31 (5×10 5 viable cells in 0.1 mL PBS) were subcutaneously injected into the two flank region of each mouse. After 1 week, the subcutaneous tumor size was measured every 7 days with a vernier caliper and the tumor volume was calculated by the formula (length)×(width 2 )/2 [5]. The mice were sacrificed after 4 weeks and the dissected tumors were collected and weighed.…”

“…Since it is difficult to be diagnosed in the early stage of this disease, most of the patients have reached the advanced or metastatic stage once be diagnosed. Conventional treatments with surgery, chemotherapies or radiation therapy play a minor role in improving the patients' survival rate [4,5]. Therefore, it is critical to find the new diagnostic or prognostic markers and therapeutic targets to improve the survival rate of GC patients.…”

Prognostic and Clinicopathological Value of SIRT1 Expression in Female Reproductive System Cancer

“…The expression of Sirt1 is increased in hepatocellular carcinoma [10][11], lung cancer [12], pancreatic cancer [13], however it is reduced in gastric cancer [14], breast cancer [15]. For this reason, it remains ambiguous whether the up-regulated expression of sirt1 indicates a good prognosis or not.…”

“…Meanwhile, these studies also revealed that sirt1 expression is linked with many clinicopathological characteristics [10][11][12][13][14][15],some studies revealed that sirt1…”