Cidem Abdulkadir, Chang Gary Ro-Lin, Yen Chih-Ching, Chen Ming-Shan, Yang Shang-Hsun, Chen Chuan-Mu
Department of Life Sciences, College of Life Sciences, National Chung Hsing University, Kuo Kuang Rd., Taichung, 402, Taiwan.
Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, 25250, Turkey.
Sci Rep. 2024 Dec 28;14(1):31210. doi: 10.1038/s41598-024-82514-4.
Hepatocellular carcinoma (HCC) constitutes 90% of liver cancer cases and ranks as the third leading cause of cancer-related mortality, necessitating urgent development of alternative therapies. Lactoferrin (LF), a natural iron-binding glycoprotein with reported anticancer effects, is investigated for its potential in liver cancer treatment, an area with limited existing studies. This study focuses on evaluating LF's anti-liver cancer effects on HCC cells and assessing the preventive efficacy of oral LF administration in a murine model. Data showed that LF exerted anti-proliferative effects on HepG2, Hep3B, and SK-Hep1 cells while having no cytotoxicity on healthy liver cells (FL83B). Mechanistically, LF induces mitochondrial-mediated apoptosis and G0/G1 cell cycle arrest in HepG2 cells, associated with increased phosphorylation of p38 MAPK and JNK for apoptosis, and ERK phosphorylation for cell cycle arrest. Intelectin-1 (INTL1) is identified as the receptor facilitating LF endocytosis in HepG2 cells, and downregulation of INTL1 inhibits LF-induced signaling pathways. Notably, oral LF administration prevents HCC development in nude mice with orthotopic HepG2 cell injection. This study unveils the mechanistic basis of LF action in HepG2 cells, showcasing its potential in HCC prevention. Importantly, we report the novel identification of INTL1 as the LF receptor in HepG2 cells, providing valuable insights for future exploration of LF and its derivatives in liver cancer therapy.
肝细胞癌（HCC）占肝癌病例的90%，是癌症相关死亡的第三大主要原因，因此迫切需要开发替代疗法。乳铁蛋白（LF）是一种具有抗癌作用报道的天然铁结合糖蛋白，其在肝癌治疗中的潜力正在被研究，而该领域现有研究有限。本研究重点评估LF对肝癌细胞的抗肝癌作用，并在小鼠模型中评估口服LF给药的预防效果。数据显示，LF对HepG2、Hep3B和SK-Hep1细胞具有抗增殖作用，而对健康肝细胞（FL83B）无细胞毒性。机制上，LF诱导HepG2细胞中线粒体介导的凋亡和G0/G1细胞周期阻滞，这与凋亡相关的p38 MAPK和JNK磷酸化增加以及细胞周期阻滞相关的ERK磷酸化有关。识别出Intlectin-1（INTL1）是促进LF在HepG2细胞中内吞作用的受体，INTL1的下调抑制LF诱导的信号通路。值得注意的是，口服LF给药可预防原位注射HepG2细胞的裸鼠发生HCC。本研究揭示了LF在HepG2细胞中的作用机制，展示了其在肝癌预防中的潜力。重要的是，我们报道了在HepG2细胞中首次鉴定出INTL1作为LF受体，为未来探索LF及其衍生物在肝癌治疗中的应用提供了有价值的见解。
