N-myc downstream regulated gene 1(NDRG1) promotes the stem-like properties of lung cancer cells through stabilized c-Myc

• Published in: Cancer letters 2017-08, Vol.401, p.53-62
• Main Authors: Wang, Yongfang, Zhou, You, Tao, Feng, Chai, Shoujie, Xu, Xia, Yang, Ying, Yang, Yiming, Xu, Haiyan, Wang, Kai
• Format: Article
• Language: English
• Subjects: A549 Cells; Adult; Aged; Breast cancer; c-Myc; c-Myc protein; Cancer initiating cells; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cyclin-dependent kinase 2; Cyclin-Dependent Kinase 2 - metabolism; Degradation; Enrichment; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genomics; Hematology, Oncology and Palliative Medicine; Humans; Inactivation; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kidney cancer; Kinases; KLF4 protein; Laboratory animals; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Metastasis; Middle Aged; Mortality; Myc protein; NDRG1; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Non-small cell lung carcinoma; Oct-4 protein; Phenotype; Phosphorylation; Pluripotency; Polymerase chain reaction; Prognosis; Protein Stability; Proteins; Proteolysis; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA Interference; S-Phase Kinase-Associated Proteins - metabolism; Signal Transduction; Skp2; Skp2 protein; Spheroids, Cellular; Stem cells; Survival; Survival Analysis; Transfection; Tumor Cells, Cultured; Tumorigenesis; Tumorigenicity; Tumors; Ubiquitination
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.04.031

Abstract Tumor-initiating cells (TICs) play an important role in tumorigenesis and development for many various tissue origin cancers including non-small cell lung cancer (NSCLC). However, the mechani s m to maintain TICs in NSCLC is still largely unknown. Here, we evaluated differences of mRNA expression between parental and oncosphere cells that enriched TICs. We found that N-myc downstream regulated gene 1(NDRG1) was upregulated in oncosphere cells derived from human NSCLC cell lines and primary NSCLC cells. NDRG1 promoted stem-like properties of LTICs in NSCLC including iPSC (induced pluripotent stem cell) factors ( OCT4, SOX2, KLF4, and C-MYC ), the spheres-forming ability and the tumorigenicity of NSCLC. NDRG1 prevented the degradation of c-Myc through Skp2-mediated ubiquitination. NDRG1 directly interacted with Skp2, and decreased phosphorylation of Skp2 through inactivation of CDK2. Finally, we confirmed that NDRG1 was negatively correlated with survival and prognosis. Thus, our findings indicate that NDRG1 is a potential target for eradicating TICs in NSCLC.