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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1459978

The NEDD4/FLRT2 axis regulates NSCLC cell stemness

Provisionally accepted
Yuping Yang Yuping Yang 1FEI YAN FEI YAN 2Ziwei Gao Ziwei Gao 1Houke Li Houke Li 1Shengke Wen Shengke Wen 1Qi Li Qi Li 1Jiayuan Li Jiayuan Li 1Na Huang Na Huang 1Wei Zhao Wei Zhao 1*
  • 1 Chengdu Medical College, Chengdu, China
  • 2 Jiangsu Cancer Hospital, Nanjing, China

The final, formatted version of the article will be published soon.

    Lung cancer is the leading cause of cancer-related death worldwide. The treatment for lung cancer, particularly for non-small cell lung cancer (NSCLC), remains a clinical challenge. Cancer stem cells are vital for lung cancer development. This study aimed to determine the influence of the neuronally expressed developmentally downregulated 4-fibronectin leucine-rich transmembrane 2 (NEDD4-FLRT2) axis on cancer cell stemness in NSCLC. Here, we reported that FLRT2 expression was reduced in NSCLC tissues, cells, and NSCLC stem cells. FLRT2 upregulation inhibited NSCLC stem cell proliferation, sphere formation, and drug resistance and promoted drug-resistant cell apoptosis. Furthermore, FLRT2 overexpression demonstrated antitumor effects in a xenograft tumor mouse model. Mechanically, FLRT2 was ubiquitinated and degraded by E3 ligase NEDD4. NEDD4 overexpression significantly abolished the inhibitory effects of FLRT2 on NSCLC stemness, as evidenced by in vitro and in vivo experiments. This study revealed that FLRT2 acted as a tumor suppressor by inhibiting cancer cell stemness in NSCLC. NEDD4 promoted ubiquitination degradation of FLRT2 protein. NEDD4 counteracted the inhibitory effects of FLRT2 on NSCLC stem cell tumorigenesis.

    Keywords: FLRT2, Nedd4, Non-small cell lung cancer, Stemness, degradation

    Received: 05 Jul 2024; Accepted: 23 Sep 2024.

    Copyright: © 2024 Yang, YAN, Gao, Li, Wen, Li, Li, Huang and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Wei Zhao, Chengdu Medical College, Chengdu, China

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