TfR associated with cervical cancer with or without neoadjuvant chemotherapy

The objectives of this study was to examine the role of transferrin receptor (TfR) in the treatment of cervical cancer. Demographic and cancer-specific data were collected prospectively. Cancerous and adjacent mucosa tissues with neoadjuvant chemotherapy (NACT) or surgery alone were collected. TfR mRNA and protein expression was measured by Quantitative reverse transcription PCR (RT-qPCR) and immunoblots. We measured the cell viability by the MTT (3- [4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay with or without TfR-siRNA transfection. All 42 patients aged 49.31 ± 6.30 years with locally advanced cervical cancer were included: NACT (n = 22), surgery alone (n = 20). Quantitative results showed that the levels of TfR mRNA & protein in cancerous tissues were higher than those in adjacent mucosal tissues. We also demonstrated that the levels of TfR mRNA and protein were lower in tumor tissues collected from patients with NACT than in those collected from patients without NACT. We also observed that silencing of the TfR gene suppressed the survival of HeLa cells (48 h, p < 0.05). Our findings suggest a potential value for TfR as a diagnosis or evaluation marker for cervical cancer. The present study suggests that si-TfR may have an antitumou effect against cervical cancer cells, probably by limiting cell proliferation and reducing the TfR mRNA and protein levels.

Neoadjuvant chemotherapy; Transferrin receptor; Cervical cancer; Clinical characteristics

[1] Zou W, Han Y, Zhang Y, Hu C, Feng Y, Zhang H, et al. Neoadjuvant chemotherapy plus surgery versus concurrent chemoradiotherapy in stage IB2-IIB cervical cancer: a systematic review and meta-analysis. Plos One. 2019; 14: e0225264.

[2] Marchetti C, Fagotti A, Tombolini V, Scambia G, De Felice F. Survival and toxicity in neoadjuvant chemotherapy plus surgery versus definitive chemoradiotherapy for cervical cancer: a systematic review and meta-analysis. Cancer Treatment Reviews. 2020; 83: 101945.

[3] de la Torre M. Neoadjuvant chemotherapy in woman with early or locally advanced cervical cancer. Reports of Practical Oncology & Radiotherapy. 2018; 23: 528–532.

[4] Vici P, Buglioni S, Sergi D, Pizzuti L, Di Lauro L, Antoniani B, et al. DNA damage and repair biomarkers in cervical cancer patients treated with neoadjuvant chemotherapy: an exploratory analysis. PLoS One. 2016; 11: e0149872.

[5] Mallmann P, Mallmann C. Neoadjuvant and adjuvant chemotherapy of cervical cancer. Oncology Research and Treatment. 2016; 39: 522–524.

[6] Greene CJ, Attwood K, Sharma NJ, Gross KW, Smith GJ, Xu B, et al. Transferrin receptor 1 upregulation in primary tumor and downregulation in benign kidney is associated with progression and mortality in renal cell carcinoma patients. Oncotarget. 2017; 8: 107052–107075.

[7] Tang T, Xia Q, Xi M. Dihydroartemisinin and its anticancer activity against endometrial carcinoma and cervical cancer: involvement of apoptosis, autophagy and transferrin receptor. Singapore Medical Journal. 2021; 62: 96–103.

[8] Testi C, Boffi A, Montemiglio LC. Structural analysis of the transferrin receptor multifaceted ligand(s) interface. Biophysical Chemistry. 2019; 254: 106242.

[9] Tortorella S, Karagiannis TC. Transferrin receptor-mediated endocytosis: a useful target for cancer therapy. The Journal of Membrane Biology. 2014; 247: 291–307.

[10] Dufes C, Al Robaian M, Somani S. Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells. Therapeutic Delivery. 2013; 4: 629–640.

[11] Shen Y, Li X, Dong D, Zhang B, Xue Y, Shang P. Transferrin receptor 1 in cancer: a new sight for cancer therapy. American Journal of Cancer Research. 2018; 8: 916–931.

[12] Rohner F, Namaste SM, Larson LM, Addo OY, Mei Z, Suchdev PS, et al. Adjusting soluble transferrin receptor concentrations for inflammation: biomarkers reflecting inflammation and nutritional determinants of anemia (BRINDA) project. The American Journal of Clinical Nutrition. 2017; 106: 372S–382S.

[13] Klyuchko KO, Gargin VV. Influence of neoadjuvant chemoradiotherapy for locally advanced cervical cancer. Polish Medical Journal. 2020; 48: 406–409.

[14] Xu X, Liu T, Wu J, Wang Y, Hong Y, Zhou H. Transferrin receptor-involved HIF-1 signaling pathway in cervical cancer. Cancer Gene Therapy. 2019; 26: 356–365.

[15] Adachi M, Kai K, Yamaji K, Ide T, Noshiro H, Kawaguchi A, et al. Transferrin receptor 1 overexpression is associated with tumour de‐differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma. Histopathology. 2019; 75: 63–73.

[16] Gammella E, Buratti P, Cairo G, Recalcati S. The transferrin receptor: the cellular iron gate. Metallomics. 2017; 9: 1367–1375.

[17] Kawabata H. Transferrin and transferrin receptors update. Free Radical Biology & Medicine. 2019; 133: 46–54.

[18] Jabara HH, Boyden SE, Chou J, Ramesh N, Massaad MJ, Benson H, et al. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nature Genetics. 2016; 48: 74–78.

[19] Fu M, He Q, Guo Z, Zhou X, Li H, Zhao L, et al. Therapeutic bispecific T- cell engager antibody targeting the transferrin receptor. Frontiers in Immunology. 2019; 10: 1396.

[20] Wortham AM, Goldman DC, Chen J, Fleming WH, Zhang A, Enns CA. Extrahepatic deficiency of transferrin receptor 2 is associated with increased erythropoiesis independent of iron overload. Journal of Biological Chemistry. 2020; 295: 3906–3917.