Characteristics of the PI3K/AKT and MAPK/ERK pathways involved in the maintenance of self-renewal in lung cancer stem-like cells.
Characteristics of the PI3K/AKT and MAPK/ERK pathways involved in the maintenance of self-renewal in lung cancer stem-like cells.
复制标题
参与肺癌干细胞自我更新维持的PI3K/AKT和MAPK/ERK信号通路的特征。
DOI：
10.7150/ijbs.57871
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发表时间：
2021
影响因子：
9.2
通讯作者：
Ye T
中科院分区：
文献类型：
--
作者：
Li J;Wang J;Xie D;Pei Q;Wan X;Xing HR;Ye T
肺癌由于其早期无症状和晚期转移而成为世界范围内癌症相关死亡的主要原因。虽然癌症干细胞（CSC）可能在肺癌的发生和发展中起着至关重要的作用，但CSC自我更新的机制仍不清楚。本研究构建了一个临床相关的CSCs富集识别模型，并通过生物信息学分析，评价了磷脂酰肌醇3-激酶（PI 3 K）/AKT通路（PI 3 K/AKT）和丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）通路在肺癌中的潜在功能，为深入探讨其发生机制提供基础。实验证实PI 3 K/AKT通路主要通过抗凋亡促进肺腺癌细胞增殖，而MAPK/ERK通路在调节肺CSC增殖方面具有压倒性优势。此外，利用干细胞评分模型、LLC-对称分裂（LLC-SD）细胞和小鼠原位肺移植模型，我们阐明了致癌途径和干细胞重编程途径之间的复杂串扰，其影响体外和体内肺CSC的干细胞特性以及癌症生物学特征。总之，我们的研究结果揭示了一个新的见解，即PI 3 K/AKT和MAPK/ERK通路作为致癌信号通路和/或干细胞信号通路，在调节肺CSCs自我更新方面具有独特和协同作用。
Lung cancer is the leading cause of cancer-related mortality worldwide due to its early asymptomatic and late metastasis. While cancer stem cells (CSCs) may play a vital role in oncogenesis and development of lung cancer, mechanisms underlying CSCs self‐renewal remain less clear. In the present study, we constructed a clinically relevant CSCs enrichment recognition model and evaluated the potential functions of phosphatidylinositol 3-kinase (PI3K)/AKT pathway (PI3K/AKT) and mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathways in lung cancer via bioinformatic analysis, providing the basis for in depth mechanistic inquisition. Experimentally, we confirmed that PI3K/AKT pathway predominantly promotes proliferation through anti-apoptosis in lung adenocarcinoma cells, while MAPK/ERK pathway has an overwhelming superiority in regulating the proliferation in lung CSCs. Further, utilizing stemness score model, LLC-Symmetric Division (LLC-SD) cells and mouse orthotopic lung transplantation model, we elucidated an intricate cross-talk between the oncogenic pathway and the stem cell reprograming pathway that impact stem cell characteristics as well as cancer biology features of lung CSCs both in vitro and in vivo. In summary, our findings uncovered a new insight that PI3K/AKT and MAPK/ERK pathways as oncogenic signaling pathway and/or stem cell signaling pathway act distinctively and synergistically to regulate lung CSCs self-renewal.
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