FTH promotes the proliferation and renders the HCC cells specifically resist to ferroptosis by maintaining iron homeostasis

Cancer Cell International

Yancun Li¹  Ying Wang²  Chen Yuan³  Jiayu Hu³  Yi Zhou⁴  Huanjuan Li⁴  Jing Yang⁴  Hairui Wang⁴  Chen Yang⁴  Xueying Ren⁴  Jing Du⁴  Luyang Wang⁴  Wanye Hu⁵  Xiangmin Tong⁶  Chaoting Zhou⁷  Qiangan Jing⁷ 

[1] Department of Central Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, 310006, Hangzhou, Zhejiang, China;GCP Clinical Research Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, 310006, Hangzhou, Zhejiang, China;Department of Central Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, 310006, Hangzhou, Zhejiang, China;Graduate School, Bengbu Medical College, 233030, Bengbu, Anhui, China;Laboratory Medicine Center, Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, 310014, Hangzhou, Zhejiang, China;Laboratory Medicine Center, Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, 310014, Hangzhou, Zhejiang, China;GCP Clinical Research Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, 310006, Hangzhou, Zhejiang, China;Graduate School, Bengbu Medical College, 233030, Bengbu, Anhui, China;Laboratory Medicine Center, Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, 310014, Hangzhou, Zhejiang, China;Graduate School, Bengbu Medical College, 233030, Bengbu, Anhui, China;School of Pharmacy, Zhejiang University of Technology, 310014, Hangzhou, Zhejiang, China;School of Pharmacy, Zhejiang University of Technology, 310014, Hangzhou, Zhejiang, China;

关键词: FTH;    Hepatocellular carcinoma;    Ferroptosis;    Iron homeostasis;    Mitochondria;   

DOI  :  10.1186/s12935-021-02420-x

来源: Springer

【 摘 要 】

BackgroundFerroptosis is a newly identified type of programmed cell death, which preferentially targets iron-rich cancer cells such as hepatocellular carcinoma (HCC). Ferritin heavy chain (FTH) is a major iron storing nanocage to store redox-inactive iron, and harbors ferroxidase activity to prevent the iron-mediated production of ROS. Our previous studies have demonstrated that FTH acts as a protective role to increase the cellular resistance to ferroptosis. However, the specific role of FTH in the development of HCC and ferroptosis resistance remains unclear.MethodsThe indicated databases were used for bioinformatics analysis. The abilities of cell proliferation, migration were measured by cell proliferation assay, transwell assay and wound healing assay. The levels of reactive oxygen species (ROS), lipid peroxide, free iron, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were determined by DCF-DA, C11-BODIPY, mitoSOX, mitoTracker, JC-10 and TMRM staining, respectively. The mitochondrial oxygen consumption rate was monitored by the Seahorse XF24 Analyzer.ResultsThe pan-cancer analysis was performed and showed that FTH expression is upregulated in multiple cancers, such as LIHC, CHOL, HNSC, compared to corresponding normal tissues. In addition, the level of serum ferritin is positively associated with the progression of hepatitis, cirrhosis liver and hepatocellular carcinoma. Further investigation shed light on the strong correlation between FTH expression and tumor grades, cancer stages and prognosis of HCC. Importantly, the proteins interaction network elucidated that FTH is involved in iron homeostasis maintenance and lysosomal-dependent degradation. Enforced expression of FTH accelerates proliferation, migration and endows HCC cells specifically resistant to ferroptosis, but does not protect against cell death caused by cytotoxic compounds like oxaliplatin, irinotecan, and adriamycin. Mechanically, FTH reconstituted cells exhibit diminished peroxides accumulation, reduce mitochondrial ROS level, attenuate the impaired mitochondrial respiratory and rescue the mitochondrial homeostasis. Notably, FTH expression boosts tumorigenic potential in vivo with increased PCNA staining and lesser lipid peroxides generation.ConclusionThese results provide new insights that FTH acts as an oncogene in the carcinogenesis and progression of HCC, and is hopeful to be a potential target for therapeutic intervention through ferroptosis.

【 授权许可】

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