2. Academic Validation
  3. Human menstrual blood-derived stem cells reverse sorafenib resistance in hepatocellular carcinoma cells through the hyperactivation of mitophagy

Human menstrual blood-derived stem cells reverse sorafenib resistance in hepatocellular carcinoma cells through the hyperactivation of mitophagy

  • Stem Cell Res Ther. 2023 Apr 1;14(1):58. doi: 10.1186/s13287-023-03278-8.
Sining Zhou # 1 2,  Yiming Liu # 1 3 2,  Qi Zhang # 1 2,  Huikang Xu 1 2,  Yangxin Fang 1 2,  Xin Chen 4,  Jiamin Fu 1 2,  Yin Yuan 1 2,  Yifei Li 1 2,  Li Yuan 5,  Charlie Xiang 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 2 Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China.
  • 3 Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
  • 4 Department of Haematology, Affiliated Hangzhou First People's Hospital, Zhejiang University, School of Medicine, Hangzhou, 310027, China.
  • 5 Innovative Precision Medicine (IPM) Group, Hangzhou, 311215, China.
  • 6 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. cxiang@zju.edu.cn.
  • 7 Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China. cxiang@zju.edu.cn.
  • # Contributed equally.
PMID: 37005657 DOI: 10.1186/s13287-023-03278-8
Abstract

Background: Sorafenib is a first-line drug targeting the RTK-MAPK signalling pathway used to treat advanced hepatocellular carcinoma (HCC). However, tumour cells readily develop sorafenib resistance, limiting long-term therapy with this drug. In our previous study, we found that human menstrual blood-derived stem cells (MenSCs) altered the expression of some sorafenib resistance-associated genes in HCC cells. Therefore, we wanted to further explore the feasibility of MenSC-based combination therapy in treating sorafenib-resistant HCC (HCC-SR) cells.

Methods: The therapeutic efficiency of sorafenib was determined using CCK-8 (Cell Counting Kit-8), Annexin V/PI and clone formation assays in vitro and a xenograft mouse model in vivo. DNA methylation was determined using RT‒PCR and methylated DNA immunoprecipitation (MeDIP). Autophagy was detected by measuring LC3-II degradation and autophagosome maturation. Transmission electron microscopy identified autophagosomes and mitochondria. Physiological functions of mitochondria were assessed by measuring the ATP content, Reactive Oxygen Species (ROS) generation, and mitochondrial membrane potential (MMP).

Results: The tumour suppressor genes BCL2 interacting protein 3 (BNIP3) and BCL2 interacting protein 3 like (BNIP3L) were silenced by promoter methylation and that BNIP3 and BNIP3L levels correlated negatively with sorafenib resistance in HCC-SR cells. Strikingly, MenSCs reversed sorafenib resistance. MenSCs upregulated BNIP3 and BNIP3L expression in HCC-SR cells via tet methylcytosine dioxygenase 2 (TET2)-mediated active demethylation. In HCC-SR cells receiving sorafenib and MenSC combination therapy, pressure from sorafenib and elevated BNIP3 and BNIP3L levels disrupted balanced Autophagy. Hyperactivation of Mitophagy significantly caused severe mitochondrial dysfunction and eventually led to the autophagic death of HCC-SR cells.

Conclusions: Our research suggests that combining sorafenib and MenSCs may be a potentially new strategy to reverse sorafenib resistance in HCC-SR cells.

Keywords

Combination therapy; Hepatocellular carcinoma; MenSCs; Sorafenib resistance.

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