1. Academic Validation
  2. miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression

miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression

  • Int J Mol Sci. 2022 Feb 4;23(3):1785. doi: 10.3390/ijms23031785.
Bing-Jie Liu 1 Fang-Fang Li 1 Yun-Xia Xie 1 Chong-Yuan Fan 1 Wen-Jing Liu 2 Jian-Ge Qiu 1 Bing-Hua Jiang 2
Affiliations

Affiliations

  • 1 Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China.
  • 2 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Abstract

Tyrosine kinase inhibitor (TKI) therapy has greatly improved lung Cancer survival in patients with epidermal growth factor receptor (EGFR) mutations. However, the development of TKI-acquired resistance is the major problem to be overcome. In this study, we found that miR-196a expression was greatly induced in gefitinib-resistant lung Cancer cells. To understand the role and mechanism of miR-196a in TKI resistance, we found that miR-196a-forced expression alone increased cell resistance to gefitinib treatment in vitro and in vivo by inducing cell proliferation and inhibiting cell Apoptosis. We identified the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) bound to the promoter region of miR-196a and induced miR-196a expression at the transcriptional level. NRF2-forced expression also significantly increased expression levels of miR-196a, and was an upstream inducer of miR-196a to mediate gefitinib resistance. We also found that glycolipid transfer protein (GLTP) was a functional direct target of miR-196a, and downregulation of GLTP by miR-196a was responsible for gefitinib resistance. GLTP overexpression alone was sufficient to increase the sensitivity of lung Cancer cells to gefitinib treatment. Our studies identified a new role and mechanism of NRF2/miR-196a/GLTP pathway in TKI resistance and lung tumor development, which may be used as a new biomarker (s) for TKI resistance or as a new therapeutic target in the future.

Keywords

GLTP; NRF2; gefitinib; miR-196a; non-small cell lung cancer.

Figures
Products
我们的 Cookie 政策

我们使用 Cookies 和类似技术以提高网站的性能和提升您的浏览体验,部分功能也使用 Cookies 帮助我们更好地理解您的需求,为您提供相关的服务。 如果您有任何关于我们如何处理您个人信息的疑问,请阅读我们的《隐私声明》