Transferrin receptor uptakes iron from tumor-associated neutrophils to regulate invasion patterns of OSCC.

Background: Transferrin receptor (TFRC) uptakes iron-loaded transferrin (TF) to acquire iron and regulates tumor development. Nonetheless, the clinical values and the precise functions of TF-TFRC axis in the development of oral squamous cell carcinoma (OSCC) were still undiscovered, especially the impacts of their regional heterogeneous expression.

Methods: Immunohistochemistry (IHC) was used to analyze the expression of TFRC in 106 OSCC patients. Then the prognostic value of TFRC was compared between high and low worst pattern of invasion (WPOI) patients. OSCC cells with low or high expression of TFRC were constructed, and functional experiments were performed to elucidate the effects of TFRC on the migration and proliferation of OSCC cells. Multi-immunofluorescence was applied to stain TF and tumor-associated neutrophils (TANs). The stimulating effects of TF were compared between normal and high TFRC cells in vitro and across different OSCC patients' subgroups in our sample bank and TCGA database.

Results: Higher TFRC was expressed at invasive tumor front (ITF) in OSCC and correlated with WPOI. Only at ITF in patients with WPOI 4-5, TFRC was a prognostic factor. High TFRC promoted migration and proliferation of cancer cells. Additionally, TANs secreted TF outside. Exogenous TF promoted migration and proliferation of cells with high expression of TFRC. Compared to the TANs^lowTFRC^low OSCC patients, TANs^highTFRC^high OSCC patients had poorer clinical outcomes.

Conclusions: Higher expression of TFRC at ITF and TANs-TF-TFRC axis promoted OSCC invasion at ITF by facilitating cell migration and proliferation, which may result from increased cellular iron uptake through regulating iron metabolism.