1. Institute of Life Sciences, Chongqing Medical University, Chongqing, China
2. Laboratory of Translational Cancer Stem Cell Research, Chongqing Medical University, Chongqing, China
3. College of Biomedical Engineering, State Key Laboratory of Ultrasound Engineering in Medicine, Chongqing Medical University, Chongqing, China
4. Department of Laboratory Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, China
*these authors were contributed to the study equally
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 (Cdh1) 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 Cdh1. Experimentally, we show for the first time that Cdh1 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 Cdh1 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.
Keywords: cancer stem cells, Cdh1, oncogene, self-renewal, oncogenic pathways