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Overexpression of Transferrin Receptor in Esophageal Squamous Cell Cancer Suggests Poor Prognosis and Potential Therapy

Naoki Ikenaga,Tsuyoshi Takahashi,Koji Tanaka,S. Serada,M. Fujimoto,K. Momose,K. Yamashita,T. Makino,Takuro Saito,Kazuyoshi Yamamoto,Y. Kurokawa,K. Nakajima,Tomomi Fujii,Eiichi Morii,T. Naka,H. Eguchi,Y. Doki

Published 2025 in Cancer Science

ABSTRACT

Despite recent advancements in multimodal therapies for esophageal squamous cell cancer (ESCC), the prognosis remains poor. Identifying suitable biomarkers for predicting prognosis and exploring new therapeutic targets are essential to improving treatment outcomes in ESCC. In this study, we utilized proteomic technology to identify the transferrin receptor (TfR), the main cellular iron importer, as a novel tumor antigen in ESCC. The clinicopathological characteristics of TfR were evaluated by immunohistochemistry using ESCC specimens, revealing that high TfR expression was associated with poor prognosis. Knockdown of TfR in ESCC cell lines resulted in a decrease in intracellular iron levels and suppressed the proliferation of ESCC cell lines, inducing cell cycle arrest in the G0/G1 phase by inhibiting cyclin D, cyclin E, and cyclin‐dependent kinase 2. Furthermore, the administration of deferoxamine (DFO), an oral iron chelator, induced a decrease in intracellular iron and suppressed the proliferation of ESCC cell lines and an increase in caspase 3 and 7 activity, indicating the induction of apoptosis. In an ESCC xenograft mouse model, the DFO‐treated group exhibited decreased serum iron levels and reduced tumor size. Finally, we confirmed that the deficiency of iron in ESCC cell lines induced an increase in TfR expression via upregulation of iron regulatory protein 2. These findings suggest that TfR is an independent prognostic factor in ESCC and that targeting iron metabolism may be a promising therapeutic approach for improving ESCC treatment outcomes.

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