TY - JOUR
T1 - The CD98 heavy chain is a marker and regulator of head and neck squamous cell carcinoma radiosensitivity
AU - Digomann, David
AU - Kurth, Ina
AU - Tyutyunnykova, Anna
AU - Chen, Oleg
AU - Lock, Steffen
AU - Gorodetska, Ielizaveta
AU - Peitzsch, Claudia
AU - Skvortsova, Ira Ida
AU - Negro, Giulia
AU - Aschenbrenner, Bertram
AU - Eisenhofer, Graeme
AU - Richter, Susan
AU - Heiden, Stephan
AU - Porrmann, Joseph
AU - Klink, Barbara
AU - Schwager, Christian
AU - Dowle, Adam A.
AU - Hein, Linda
AU - Kunz-Schughart, Leoni A.
AU - Abdollahi, Amir
AU - Lohaus, Fabian
AU - Krause, Mechthild
AU - Baumann, Michael
AU - Linge, Annett
AU - Dubrovska, Anna
N1 - Funding Information:
The authors thank Vasyl Lukiyanchuk for analysis of gene expression data, TCGA datasets and Celigo imaging, co-localization analysis, PCR analysis of DNA repair genes as well as for design and cloning of sgRNAs, screening for clones with SLC3A2 deletion, and their genotyping. They thank Liane Stolz-Kieslich for her technical assistance with IHC staining. They thank Lydia Koi (DKTK) for providing the HNSCC cell samples and Aliona Bogdanova (MPI-CBG, Dresden) for providing the Cas9-HF1 plasmid construct. They also thank the DKTK-ROG for providing access to the tumor material and to the clinical data of the subset of patients from previously published work (11). Work in the Dubrovska laboratory was partially supported by grants from the Deutsche Forschungsgemeinschaft (DFG; 273676790, 401326337, and 416001651), from Wilhelm Sander-Stiftung (2017.106.1), the DLR Project Management Agency (01DK17047), and the German Federal Ministry of Education and Science (BMBF; 03Z1NN11). D. Digomann was supported by the Preiss Daimler foundation Medical Equipment and Research and by the Else Kr€oner-Promotionskolleg. The York Centre of Excellence in Mass Spectrometry was created thanks to a major capital investment through Science City York, supported by Yorkshire Forward with funds from the Northern Way Initiative, and subsequent support from EPSRC (EP/K039660/1; EP/M028127/1). Work in Baumann and Krause laboratories was supported by German Federal Ministry of Education and Science (BMBF, Oncoray), the German Cancer Consortium DKTK, and by the Deutsche Forschungsgemeinschaft (DFG) grants BA 1433/5-2 and BA 1433/6.
Funding Information:
M. Baumann attended an advisory board meeting of Merck KGaA (Darm-stadt), for which the University of Dresden received a travel grant; received funding for his research projects and for educational grants to the University of Dresden by Teutopharma GmbH, IBA, Bayer AG, Merck KGaA, and Medipan GmbH; as former chair of OncoRay (Dresden) and present CEO and Scientific Chair of the German Cancer Research Center (DKFZ, Heidelberg), signed/s contracts for his institute(s) and for the staff for research funding and collaborations with a multitude of companies worldwide; and for the German Cancer Research Center (DKFZ, Heidelberg), is on the supervisory boards of HI-STEM gGmbH (Heidelberg). None of these funding sources were involved in the study design or materials used, nor in the collection, analysis and interpretation of data nor in the writing of the paper.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - Purpose: 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. Experimental Design: 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). Results: 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. Conclusions: 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.
AB - Purpose: 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. Experimental Design: 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). Results: 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. Conclusions: 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.
UR - http://www.scopus.com/inward/record.url?scp=85065778899&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-2951
DO - 10.1158/1078-0432.CCR-18-2951
M3 - Article
C2 - 30670494
AN - SCOPUS:85065778899
SN - 1078-0432
VL - 25
SP - 3152
EP - 3163
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -