Krüppel-like factor 2 suppresses human gastric tumorigenesis through inhibiting PTEN/AKT signaling
نویسندگان
چکیده
Krüppel-like factors (KLFs) are a large family of DNA-binding transcriptional regulators that affect basic cellular processes such as growth, survival, migration and differentiation and serve a complicated function in cancers. KLF2, one member of the KLF family, is dysregulated in many tumors. However, the specific role of KLF2 in human gastric tumorigenesis is unknown. Here we show that the expression of KLF2 protein was lower in gastric tumors when compared with adjacent normal tissue. Moreover, downregulated KLF2 expression in primary gastric tumor was closely correlated with patients' survival. Various cell experiments showed that ectopic KLF2 expression suppressed the proliferation, migration and invasion of gastric cancer cells. Moreover, KLF2 overexpression remarkably enhanced cell apoptosis and induced cell cycle arrest. Impaired expression of KLF2 markedly promoted cell growth in vitro and significantly expanded tumor size in vivo. Mechanically, the mRNA and protein level of PTEN was reduced in KLF2 deficient cells and xenograft tumors, suggesting that PTEN/AKT signaling was involved in the gastric tumor inhibitory effect of KLF2. Administration of AKT inhibitor AZD5363 or Insulin-like growth factor-1 (IGF-1) in KLF2 knockdown or ectopic expression cell lines, respectively, substantially reversed the proliferation phenotype. Collectively, our findings provide clinical evidence and a potential mechanism supporting that KLF2 suppresses human gastric tumorigenesis through inhibiting the PTEN/AKT axis.
منابع مشابه
Akt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency
Although PTEN/Akt signaling is frequently deregulated in human gastric cancers, the in vivo causal link between its dysregulation and gastric tumorigenesis has not been established. Here we show that inactivation of PTEN in mouse gastric epithelium initiates spontaneous carcinogenesis with complete penetrance by 2 months of age. Mechanistically, activation of Akt suppresses the abundance of p53...
متن کاملMig-6 suppresses endometrial cancer associated with Pten deficiency and ERK activation.
PTEN mutations are the most common genetic alterations in endometrial cancer. Loss of PTEN and subsequent AKT activation stimulate estrogen receptor α-dependent pathways that play an important role in endometrial tumorigenesis. The major pathologic phenomenon of endometrial cancer is the loss of ovarian steroid hormone control over uterine epithelial cell proliferation and apoptosis. However, t...
متن کاملMolecular and Cellular Pathobiology Mig-6 Suppresses Endometrial Cancer Associated with Pten Deficiency and ERK Activation
PTEN mutations are the most common genetic alterations in endometrial cancer. Loss of PTEN and subsequent AKT activation stimulate estrogen receptor a–dependent pathways that play an important role in endometrial tumorigenesis. The major pathologic phenomenon of endometrial cancer is the loss of ovarian steroid hormone control over uterine epithelial cell proliferation and apoptosis. However, t...
متن کاملPLZF Mediates the PTEN/AKT/FOXO3a Signaling in Suppression of Prostate Tumorigenesis
Promyelocytic leukemia zinc finger (PLZF) protein expression is closely related to the progression of human cancers, including prostate cancer (PCa). However, the according context of a signaling pathway for PLZF to suppress prostate tumorigenesis remains greatly unknown. Here we report that PLZF is a downstream mediator of the PTEN signaling pathway in PCa. We found that PLZF expression is clo...
متن کاملIn Vivo Role of INPP4B in Tumor and Metastasis Suppression through Regulation of PI3K-AKT Signaling at Endosomes.
UNLABELLED The phosphatases PTEN and INPP4B have been proposed to act as tumor suppressors by antagonizing PI3K-AKT signaling and are frequently dysregulated in human cancer. Although PTEN has been extensively studied, little is known about the underlying mechanisms by which INPP4B exerts its tumor-suppressive function and its role in tumorigenesis in vivo. Here, we show that a partial or compl...
متن کامل