Cdh1 functions as an oncogene by inducing self-renewal of lung cancer stem-like cells via oncogenic pathways

• Published in: International journal of biological sciences 2020, Vol.16 (3), p.447-459
• Main Authors: Ye, Ting, Li, Jingyuan, Sun, Zhiwei, Liu, Doudou, Zeng, Bin, Zhao, Qiting, Wang, Jianyu, Xing, H Rosie
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - metabolism; Animals; Antibodies; Bioinformatics; Blotting, Western; Cadherins; Cadherins - genetics; Cadherins - metabolism; Cell culture; Cell Line, Tumor; Cell self-renewal; Computational Biology - methods; Crosstalk; Datasets; DNA methylation; E-cadherin; Embryo cells; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Gene Expression Regulation, Neoplastic - physiology; Gene Ontology; Humans; Kinases; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; MAP kinase; Medical prognosis; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Oncogenes; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Protein Binding; Protein kinase; Proteins; Research Paper; Software; Stem cells; Tumor suppressor genes; Tumorigenesis; Tumors
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.38672

The mortality rate of lung cancer remains the highest amongst all cancers despite of new therapeutic developments. While cancer stem cells (CSCs) may play a pivotal role in cancer, mechanisms underlying CSCs self-renewal and their relevance to cancer progression have not been clearly elucidated due to the lack of reliable and stable CSC cellular models. In the present study, we unveiled the novel oncogene function of cadherin 1 ( ) via bioinformatic analysis in a broad spectrum of human cancers including lung adenocarcinoma (LUAD), adding a new dimension to the widely reported tumor suppressor function of . Experimentally, we show for the first time that promotes the self-renewal of lung CSCs, consistent with its function in embryonic and normal stem cells. Using the LLC-Symmetric Division (LLC-SD) model, we have revealed an intricate cross-talk between the oncogenic pathway and stem cell pathway in which functions as an oncogene by promoting lung CSC renewal via the activation of the Phosphoinositide 3-kinase (PI3K) and inhibition of Mitogen-activated protein kinase (MAPK) pathways, respectively. In summary, this study has provided evidence demonstrating effective utilization of the normal stem cell renewal mechanisms by CSCs to promote oncogenesis and progression.