转铁蛋白受体通过影响铁积累调节肝癌衍生癌干细胞样细胞的恶性肿瘤和干性。
Transferrin receptor regulates malignancies and the stemness of hepatocellular carcinoma-derived cancer stem-like cells by affecting iron accumulation.
机构信息
Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
出版信息
PLoS One. 2020 Dec 22;15(12):e0243812. doi: 10.1371/journal.pone.0243812. eCollection 2020.
BACKGROUND
Iron metabolism is essential because it plays regulatory roles in various physiological and pathological processes. Disorders of iron metabolism balance are related to various cancers, including hepatocellular carcinoma. Cancer stem-like cells (CSCs) exert critical effects on chemotherapy failure, cancer metastasis, and subsequent disease recurrence and relapse. However, little is known about how iron metabolism affects liver CSCs. Here, we investigated the expression of transferrin receptor 1 (TFR1) and ferroportin (FPN), two iron importers, and an upstream regulator, iron regulatory protein 2 (IRP2), in liver hepatocellular carcinoma (LIHC) and related CSCs.
METHODS
The expression levels of TFR1, FPN and IRP2 were analysed using the GEPIA database. CSCs were derived from parental LIHC cells cultured in serum-free medium. After TFR1 knockdown, ROS accumulation and malignant behaviours were measured. The CCK-8 assay was performed to detect cell viability after TFR1 knockdown and erastin treatment.
RESULTS
TFR1 expression was upregulated in LIHC tissue and CSCs derived from LIHC cell lines, prompting us to investigate the roles of TFR1 in regulating CSCs. Knockdown of TFR1 expression decreased iron accumulation and inhibited malignant behaviour. Knockdown of TFR1 expression decreased reactive oxygen species (ROS) accumulation induced by erastin treatment and maintained mitochondrial function, indicating that TFR1 is critical in regulating erastin-induced cell death in CSCs. Additionally, knockdown of TFR1 expression decreased sphere formation by decreasing iron accumulation in CSCs, indicating a potential role for TFR1 in maintaining stemness.
CONCLUSION
These findings, which revealed TFR1 as a critical regulator of LIHC CSCs in malignant behaviour and stemness that functions by regulating iron accumulation, may have implications to improve therapeutic approaches.
背景
铁代谢对于各种生理和病理过程的调节都至关重要。铁代谢平衡紊乱与包括肝细胞癌（hepatocellular carcinoma）在内的各种癌症有关。癌症干细胞样细胞（cancer stem-like cells，CSCs）对化疗失败、癌症转移以及随后的疾病复发和再发起着关键作用。然而，铁代谢如何影响肝 CSCs 仍知之甚少。在这里，我们研究了转铁蛋白受体 1（transferrin receptor 1，TFR1）和铁输出蛋白（ferroportin，FPN）这两种铁摄取体以及上游调节因子铁调节蛋白 2（iron regulatory protein 2，IRP2）在肝细胞肝癌（liver hepatocellular carcinoma，LIHC）和相关 CSCs 中的表达。
方法
利用 GEPIA 数据库分析 TFR1、FPN 和 IRP2 的表达水平。CSCs 由无血清培养基中培养的亲本 LIHC 细胞衍生而来。在 TFR1 敲低后，测量 ROS 积累和恶性行为。进行 CCK-8 测定以检测 TFR1 敲低和 erastin 处理后细胞活力。
结果
TFR1 在 LIHC 组织和源自 LIHC 细胞系的 CSCs 中表达上调，促使我们研究 TFR1 在调节 CSCs 中的作用。TFR1 表达的敲低降低了铁积累并抑制了恶性行为。TFR1 表达的敲低降低了 erastin 处理诱导的活性氧（reactive oxygen species，ROS）积累并维持了线粒体功能，表明 TFR1 在调节 CSCs 中 erastin 诱导的细胞死亡中至关重要。此外，TFR1 表达的敲低通过减少 CSCs 中的铁积累降低了球体形成，表明 TFR1 在维持干细胞特性方面可能具有作用。
结论
这些发现表明，TFR1 作为 LIHC CSCs 恶性行为和干细胞特性的关键调节因子，通过调节铁积累起作用，可能对改善治疗方法具有意义。
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