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ORIGINAL RESEARCH article

Front. Oncol.
Sec. Cancer Molecular Targets and Therapeutics
Volume 14 - 2024 | doi: 10.3389/fonc.2024.1483660

Low miR-936-mediated upregulation of Pim-3 drives sorafenib resistance in liver cancer through ferroptosis inhibition by activating the ANKRD18A/Src/NRF2 pathway

Provisionally accepted
Qie Guo Qie Guo *Xiao Li Xiao Li Meng Na Cui Meng Na Cui Long Xu Long Xu
  • Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China

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

    Sorafenib, a multikinase inhibitor, is currently the standard treatment for advanced liver cancer. However, its application has become limited by the development of drug resistance. Exploring the mechanisms underlying the development of sorafenib resistance and identifying an effective strategy to overcome sorafenib resistance remain challenges.Here, we showed that upregulation of the provirus-integrating site for Moloney murine leukemia virus 3 (Pim-3) predicted poor response and unsatisfactory prognosis in sorafenib-treated liver cancer patients. Similarly, Pim-3 expression was positively associated with sorafenib resistance in liver cancer cells. Furthermore, microRNA-936 (miR-936) targeted the 3'-noncoding region (3'-UTR) of Pim-3 but exhibited lower expression in sorafenib-resistant liver cancer cells than in their parental cells. The high expression of Pim-3 mediated by miR-936 insufficiency activated the ANKRD18A/Src/NRF2 pathway which rearranged the expression of the indicated markers involved in iron distribution and lipid peroxidation homeostasis. MiR-936 overexpression and GV102-Pim-3-shRNA significantly attenuated the activity of the ANKRD18A/Src/NRF2 pathway to decrease the expression of Ankyrin repeat domain-containing protein 18A (ANKRD18A), Src, and Nuclear factor (erythroid-derived 2)-like 2 (NRF2), especially decreasing NRF2 nuclear retention and transcriptional activity. The transcriptional activity of NRF2 prompted cell ferroptosis because the transfection of miR-936 mimics, GV102-Pim-3-shRNA and GV102-NRF2-shRNA plasmid increased the expression of transferrin receptor 1 (TFR1) and divalent metal transporter 1 (DMT1) but decreased the expression of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1), thus facilitating the accumulation of intracellular Fe 2+ , lipid peroxides, and reactive oxygen species (ROS) but reducing the glutathione (GSH) level. Moreover, the elevated expression of Pim-3, resulting from the absence of miR-936 enhances sorafenib resistance in liver cancer by inhibiting cell ferroptosis. Overall, Pim-3 can be regarded as a target in the treatment of sorafenib-resistant liver cancer.

    Keywords: liver cancer, Sorafenib, Pim-3, miR-936, ferroptosis

    Received: 20 Aug 2024; Accepted: 07 Oct 2024.

    Copyright: © 2024 Guo, Li, Cui and Xu. 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: Qie Guo, Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.