Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
Laboratory of Translational Cancer Stem Cell Research, Chongqing Medical University, Chongqing, China.
Int J Biol Sci. 2020 Jan 1;16(3):447-459. doi: 10.7150/ijbs.38672. eCollection 2020.
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.
尽管有新的治疗方法发展，肺癌的死亡率仍然是所有癌症中最高的。虽然癌症干细胞（CSCs）可能在癌症中发挥关键作用，但由于缺乏可靠和稳定的 CSC 细胞模型，CSCs 自我更新的机制及其与癌症进展的相关性尚未得到明确阐明。在本研究中，我们通过对包括肺腺癌（LUAD）在内的广泛人类癌症的生物信息学分析，揭示了钙黏蛋白 1（）的新致癌基因功能，为广泛报道的功能增加了新的维度。在实验上，我们首次表明促进肺 CSCs 的自我更新，这与其在胚胎和正常干细胞中的肿瘤抑制功能一致。使用 LLC-对称分裂（LLC-SD）模型，我们揭示了致癌途径和干细胞途径之间错综复杂的相互作用，其中通过激活磷脂酰肌醇 3-激酶（PI3K）和抑制丝裂原活化蛋白激酶（MAPK）途径分别促进肺 CSC 更新，从而发挥致癌基因的作用。总之，这项研究提供了证据，证明 CSCs 有效地利用正常干细胞更新机制来促进致癌和进展。
