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Int J Biol Sci 2021; 17(5):1191-1202. doi:10.7150/ijbs.57871 This issue Cite

Research Paper

Characteristics of the PI3K/AKT and MAPK/ERK pathways involved in the maintenance of self-renewal in lung cancer stem-like cells

Jingyuan Li^1*, Jianyu Wang^2*, Dan Xie¹, Qin Pei¹, Xue Wan¹, H.Rosie Xing^3✉, Ting Ye^1✉

1. Department of Laboratory Medicine, the Affiliated Hospital of Southwest Medical University, Sichuan, China.
2. Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
3. College of Biomedical Engineering, State Key Laboratory of Ultrasound Engineering in Medicine, Chongqing Medical University, Chongqing, China.
* These authors contributed equally.

✉ Corresponding authors: H.Rosie Xing, College of Biomedical Engineering, State Key Laboratory of Ultrasound Engineering in Medicine, Chongqing Medical University, Chongqing, China. Email: xinglab310com; Ting Ye, Department of Laboratory Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, China. Email: yeting1103com. Address: No. 25, Taiping Street, Jiangyang District, Luzhou, Sichuan 646000, China. More

Abstract

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.

Keywords: lung cancer stem-like cells, PI3K/AKT pathway, MAPK/ERK pathway, characteristics, self-renewal.

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