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MINI 35 - Biology (ID 161)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
MINI35.03 - N-Myc Downstream Regulated Gene 1(NDRG1) Promotes the Stem-Like Properties of Lung Cancer Cells Through Stabilized C-Myc (ID 996)
18:30 - 20:00 | Author(s): K. Wang
Tumor-initiating cells (TIC) which were defined their ability to generate tumor play a critical role in tumorigenesis and development of lung cancer. However, the mechanism underlying how TICs keep self-renewal needs to be clarified. We investigated the biological function and clinical significance of N-myc downstream regulated gene 1 (NDRG1) in lung TICs.
Recombinant NDRG1 shRNA lentivirus or NDRG1-overexpressed lentivirus was employed to knock down or reinforce NDRG1 expression respectively. Biological functions of NDRG1 silenced and overexpressed cells were investigated using in vitro and in vivo methods.
NDRG1 was much highly expressed in lung tumor-initiating cells compared with parental lung cancer cells in both human NSCLC cell lines and primary NSCLC cells. Immunohistochemical on the lung cancer tissues showed that NDRG1 was highly expressed. The GSEA analysis showed that patients with increased expression of NDRG1 had a worse survival and prognosis in the analysis of 226 cases of lung cancer specimens. Enhanced expression of NDRG1 promoted stem-like properties of NSCLC cells in A549 and H1975 cells while the knockdown of NDRG1 decreased the expression of iPS factors (OCT4、SOX2、KLF4、C-MYC), the spheres-forming ability in vitro and tumorigenecity and mass of lung cancer H1299 and HCC827 cells in vivo. Furthermore, we revealed that c-Myc was a key molecule of which NDRG1 involved in the self-renewal of TICs. NDRG1 was positively correlated with c-Myc expression. NDRG1 inhibited the ubiquitylation degradation of c-Myc to promote self-renewal of lung TICs through interaction with Skp2. The Interaction between NDRG1 and Skp2 was enforced in lung TICs. Moreover, the distribution of NDRG1 was generally in cellular membrane, cytoplasm and nucleus of lung cancer cells and its nuclear localization was positively regulated by the 79th tyrosine phosphorylation of NDRG1. Phosphorylated NDRG1 at Y79 which was positively regulated by PI3K-AKT pathway increased the expression of c-Myc.
NDRG1 promotes the self-renewal of lung TICs through stabilizing c-Myc by interaction with Skp2. Our study indicates that NDRG1 is one of potential targets for eradication of lung TICs.