The Association of Transferrin Receptor with Prognosis and Biologic Role in Intrahepatic Cholangiocarcinoma.

BACKGROUND

Ferroptosis is a cell death caused by iron-dependent accumulation of lipid peroxidation. Transferrin receptor (TFR) is a ferroptosis-related protein responsible for iron transport. The detailed biologic role of TFR in intrahepatic cholangiocarcinoma (ICC) is not fully elucidated.

METHODS

The study enrolled 92 ICC patients who had undergone hepatic resection. Immunohistochemistry (IHC) assays were performed for TFR protein expression. The regulation of malignant activity and the effect on sensitivity to the ferroptosis-inducer artesunate by TFR were investigated in vitro.

RESULTS

Using IHC staining, 23 patients were categorized as TFR-positive. The TFR-positive group had a significantly larger tumor size and more microscopic vascular invasion. In the multivariate analysis, TFR positivity was an independent poor prognostic factor. In vitro TFR-knockdown (KD) significantly decreased the intracellular iron levels and the cell proliferation, migration, and invasion rates. Artesunate treatment significantly decreased cell viability, whereas cisplatin promoted ferroptosis. When iron transport into cells was inhibited by TFR-KD, ferroptosis was significantly suppressed. Expression of PD-L1 was induced by cisplatin, with a further increase observed when artesunate and cisplatin were used in combination.

CONCLUSIONS

Transferrin receptor is a poor prognostic factor for ICC and contributes to sensitivity to ferroptosis.