Axin downregulates TCF-4 transcription via beta-catenin, but not p53, and inhibits the proliferation and invasion of lung cancer cells

作者：Yang, Lian-He; Xu, Hong-Tao; Han, Yang; Li, Qing-Chang; Liu, Yang; Zhao, Yue; Yang, Zhi-Qiang; Dong, Qian-Ze; Miao, Yuan; Dai, Shun-Dong; Wang, En-Hua^*

来源：Molecular Cancer, 2010, 9: 25.

DOI：10.1186/1476-4598-9-25

• WNT SIGNALING PATHWAY
• ADENOMATOUS POLYPOSIS-COLI
• SYNTHASE KINASE 3-BETA
• TUMOR PROGRESSION
• COMPLEX-FORMATION
• UP-REGULATION
• EXPRESSION
• CARCINOMA
• DOMAINS
• DIFFERENTIATION

Background: We previously reported that overexpression of Axin downregulates T cell factor-4 (TCF-4) transcription. However, the mechanism(s) by which Axin downregulates the transcription and expression of TCF-4 is not clear. It has been reported that beta-catenin promotes and p53 inhibits TCF-4 transcription, respectively. The aim of this study was to investigate whether beta-catenin and/or p53 is required for Axin-mediated downregulation of TCF-4.
Results: Axin mutants that lack p53/HIPK2 and/or beta-catenin binding domains were expressed in lung cancer cells, BE1 (mutant p53) and A549 (wild type p53). Expression of Axin or Axin Delta p53 downregulates beta-catenin and TCF-4, and knock-down of beta-catenin upregulates TCF-4 in BE1 cells. However, expression of Axin Delta beta-ca into BE1 cells did not downregulate TCF-4 expression. These results indicate that Axin downregulates TCF-4 transcription via beta-catenin. Although overexpression of wild-type p53 also downregulates TCF-4 in BE1 cells, cotransfection of p53 and Axin Delta beta-ca did not downregulate TCF-4 further. These results suggest that Axin does not promote p53-mediated downregulation of TCF-4. Axin, Axin Delta p53, and Axin Delta beta-ca all downregulated beta-catenin and TCF-4 in A549 cells. Knock-down of p53 upregulated beta-catenin and TCF-4, but cotransfection of Axin Delta beta-ca and p53 siRNA resulted in downregulation of beta-catenin and TCF-4. These results indicate that p53 is not required for Axin-mediated downregulation of TCF-4. Knock-down or inhibition of GSK-3 beta prevented Axin-mediated downregulation of TCF-4. Furthermore, expression of Axin and Axin Delta p53, prevented the proliferative and invasive ability of BE1 and A549, expression of Axin Delta beta-ca could only prevented the proliferative and invasive ability effectively.
Conclusions: Axin downregulates TCF-4 transcription via beta-catenin and independently of p53. Axin may also inhibits the proliferation and invasion of lung cancer cells via beta-catenin and p53.

• 出版日期2010-2-2
• 单位中国医科大学