FGD5-AS1/miR-5590-3p/PINK1 induces Lenvatinib resistance in hepatocellular carcinoma

  • Cell Signal. 2023 Jul 28;110828. doi: 10.1016/j.cellsig.2023.110828.
Meifang Song  1 ,  Luyuan Ma  1 ,  Chuan Shen  1 ,  Wenpeng Liu  2 ,  Pengfei Zhang  2 ,  Ranran Bi  1 ,  Caiyan Zhao  3
Affiliations
  • 1. Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China.
  • 2. Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China.
  • 3. Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China. Electronic address: [email protected].
PMID: 37517671 DOI: 10.1016/j.cellsig.2023.110828
Abstract

Background: Lenvatinib is a common systemic treatment for advanced hepatocellular carcinoma (HCC), the resistance to which presents a great challenge. However, the mechanism of lenvatinib resistance in HCC remains unclear. Therefore, elucidating the underlying and key regulatory molecular mechanisms of lenvatinib resistance is urgently needed.

Methods: Bioinformatic enrichment analysis was used to investigate the gene associated with lenvatinib resistance. RT-PCR, Western blot, immunohistochemistry, and luciferase assays were used to explore the mechanisms of lenvatinib resistance. The effects of the FGD5-AS1/miR-5590-3p/PINK1 axis on lenvatinib resistance were evaluated by colony formation assay, cell viability, Apoptosis, mitochondrial homeostasis, and morphology analyses.

Results: Higher expression of PINK1 was observed in lenvatinib-resistant cells and tissues. PINK1 could be activated by increased FGD5-AS1 expression, thereby maintaining the mitochondrial structure and function and promoting the antioxidative stress response. FGD5-AS1/miR-5590-3p showed competitive regulation of PINK1, which affected lenvatinib sensitivity through regulation of mitochondrial structure and antioxidative stress.

Conclusions: PINK1 was identified as a key gene leading to lenvatinib resistance by maintaining the mitochondrial structure and function. The FGD5-AS1/miR-5590-3p/PINK1 axis may be a promising strategy to overcome lenvatinib resistance in treatment-negative patients.

Keywords
FGD5-AS1; Hepatocellular carcinoma; Lenvatinib; PINK1; Resistance; miR-5590-3p.
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