American Association for Cancer Research
10780432ccr182951-sup-208415_2_supp_5271199_pl4q2d.pdf (13.51 MB)

Supplementary Data from The CD98 Heavy Chain Is a Marker and Regulator of Head and Neck Squamous Cell Carcinoma Radiosensitivity

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journal contribution
posted on 2023-03-31, 20:27 authored by David Digomann, Ina Kurth, Anna Tyutyunnykova, Oleg Chen, Steffen Löck, Ielizaveta Gorodetska, Claudia Peitzsch, Ira-Ida Skvortsova, Giulia Negro, Bertram Aschenbrenner, Graeme Eisenhofer, Susan Richter, Stephan Heiden, Joseph Porrmann, Barbara Klink, Christian Schwager, Adam A. Dowle, Linda Hein, Leoni A. Kunz-Schughart, Amir Abdollahi, Fabian Lohaus, Mechthild Krause, Michael Baumann, Annett Linge, Anna Dubrovska

Supplementary discussion; Supplementary methods; Supplementary tables S1-S8; Supplementary figures S1-S8.


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The heavy chain of the CD98 protein (CD98hc) is encoded by the SLC3A2 gene. Together with the light subunit LAT1, CD98hc constitutes a heterodimeric transmembrane amino acid transporter. High SLC3A2 mRNA expression levels are associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy. Little is known regarding the CD98hc protein–mediated molecular mechanisms of tumor radioresistance. CD98hc protein expression levels were correlated with corresponding tumor control dose 50 (TCD50) in HNSCC xenograft models. Expression levels of CD98hc and LAT1 in HNSCC cells were modulated by siRNA or CRISPR/Cas9 gene editing. HNSCC cell phenotypes were characterized by transcription profiling, plasma membrane proteomics, metabolic analysis, and signaling pathway activation. Expression levels of CD98hc and LAT1 proteins were examined by IHC analysis of tumor tissues from patients with locally advanced HNSCC treated with primary radiochemotherapy (RCTx). Primary endpoint was locoregional tumor control (LRC). High expression levels of CD98hc resulted in an increase in mTOR pathway activation, amino acid metabolism, and DNA repair as well as downregulation of oxidative stress and autophagy. High expression levels of CD98hc and LAT1 proteins were significantly correlated and associated with an increase in radioresistance in HNSCC in vitro and in vivo models. High expression of both proteins identified a poor prognosis subgroup in patients with locally advanced HNSCC after RCTx. We found that CD98hc-associated signaling mechanisms play a central role in the regulation of HNSCC radioresistance and may be a promising target for tumor radiosensitization.

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