SIRT6 inhibits growth of gastric cancer by inhibiting JAK2/STAT3 pathway

Abstract

SIRT6, a member of NAD positivity-dependent class III deacetylase sirtuin family, played versatile roles in human cancers. However, the expression and biological function of SIRT6 in gastric cancer (GC) remain to be investigated. In this study, we found that SIRT6 expression level was decreased in gastric cancer tissues and cell lines. Decreased SIRT6 expression was associated with unfavorable clinical parameters including tumor differentiation, tumor size and TNM stage. Importantly, decreased level of SIRT6 was associated with decreased rate of overall survival (OS) and disease‑free survival (DFS). Functionally, overexpression of SIRT6 in both BGC823 and SGC7901 cells inhibited cell viability and proliferation of GC cells. Furthermore, overexpression of SIRT6 in both BGC823 and SGC7901 cells prevented the cell cycle progress and increased cell apoptosis. In vivo experiments demonstrated that forced expression of SIRT6 in SGC-7901 cells inhibited the growth of SGC7901 cells in nude mice. Furthermore, the IHC staining for GC tissues showed that expression level of SIRT6 was decreased in GC tissues while the expression level of p-STAT3 was increased in GC tissues. GC tissues with high SIRT6 level showed significantly decreased level of p-STAT3. Mechanically, we demonstrated that SIRT6 blocked the activation of JAK2/STAT3 and inhibited the expression of cyclin D1 and Bcl2 which were downstream targets of JAK2/STAT3 pathway. Taken together, this study indicates that SIRT6 inhibits the growth of gastric cancer by inhibiting JAK2/STAT3 pathway.

Downregulation of SIRT6 by miR-34c-5p is associated with poor prognosis and promotes colon cancer proliferation through inhibiting apoptosis via the JAK2/STAT3 signaling pathway

“…Previous study has revealed that the JAK2/STAT3 signaling pathway is highly activated in colon cancer, and contributes to proliferation, migration, invasion, cell cycle progression and angiogenesis ( 21 - 24 ). The association between SIRT6 and JAK2/STAT3 has been confirmed in other cancers; however, to the best of our knowledge, it has not been reported in colon cancer ( 20 , 25 ). Therefore, the present study aimed to determine the effects of SIRT6 overexpression on the JAK2/STAT3 signaling pathway.…”

“…SIRT6 acts as a cancer suppressor gene in pancreatic cancer by controlling Lin-28 homolog B ( 30 ), and promotes cytokine production and migration in pancreatic cancer cells by regulating Ca 2+ responses ( 31 ). Decreased expression of SIRT6 promotes tumor cell growth and is closely correlated with the poor prognosis of ovarian cancer, gastric cancer and glioma ( 20 , 25 , 32 ). In non-small cell lung cancer, SIRT6 can suppress cell proliferation via the inhibition of Twist1, and astragaloside IV can sensitize non-small cell lung cancer cells to gefitinib by upregulating SIRT6 ( 33 , 34 ).…”

Long noncoding RNA NEAT1‐modulated miR‐506 regulates gastric cancer development through targeting STAT3

“…40 miR-148a can act as a tumor suppressor by inhibiting CCK-BR and inactivating STAT3 in GC. The miR-93-5p/IFNAR1 axis can promote GC metastasis by stimulating the STAT3 signaling.…”

SIRT6 overexpression induces apoptosis of nasopharyngeal carcinoma by inhibiting NF-κB signaling

“…In accordance with our study, SIRT6 overexpression-induced apoptosis, activated caspase-9 and caspase-3 in human gastric cancer cells, resulting in cell cycle arrest, induced cellular apoptosis through inactivation of JAK2/STAT3 signaling, and by downregulation of cyclin D1 and Bcl2. 28 Apoptosis was also observed in A549 non-small-cell lung cancer cells, 29 mouse embryonic fibroblasts, 30 and hepatocellular carcinoma, 10 with downregulation of cell survival proteins (JAK2/STAT3 and Bcl-2), and upregulation of pro-apoptotic proteins (p53 and E2F-1, Bid and bax). However, several reports implicate a suppressive role of SIRT6 in cellular apoptosis, which is inconsistent with the results of our study.…”