OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Clin Cancer Res. 2019 May 15;25(10):3152-3163. doi: 10.1158/1078-0432.CCR-18-2951. Epub 2019 Jan 22.
The heavy chain of the CD98 protein (CD98hc) is encoded by the gene. Together with the light subunit LAT1, CD98hc constitutes a heterodimeric transmembrane amino acid transporter. High 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 (TCD) 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 and 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.
CD98 蛋白的重链（CD98hc）由 基因编码。CD98hc 与轻链 LAT1 一起构成异二聚体跨膜氨基酸转运蛋白。高 mRNA 表达水平与接受放化疗治疗的头颈部鳞状细胞癌（HNSCC）患者的预后不良相关。关于 CD98hc 蛋白介导的肿瘤放射抵抗的分子机制知之甚少。
在 HNSCC 异种移植模型中，将 CD98hc 蛋白表达水平与相应的肿瘤控制剂量 50（TCD）相关联。通过 siRNA 或 CRISPR/Cas9 基因编辑调节 HNSCC 细胞中的 CD98hc 和 LAT1 的表达水平。通过转录谱分析、质膜蛋白质组学、代谢分析和信号通路激活来表征 HNSCC 细胞表型。通过对接受原发放化疗（RCTx）治疗的局部晚期 HNSCC 患者的肿瘤组织进行 IHC 分析来检查 CD98hc 和 LAT1 蛋白的表达水平。主要终点是局部区域肿瘤控制（LRC）。
CD98hc 的高表达水平导致 mTOR 通路激活、氨基酸代谢和 DNA 修复增加，以及氧化应激和自噬下调。在 HNSCC 模型中，CD98hc 和 LAT1 蛋白的高表达水平显著相关，并与放射抵抗性增加相关。在接受 RCTx 治疗的局部晚期 HNSCC 患者中，两种蛋白的高表达均确定了预后不良亚组。
我们发现 CD98hc 相关的信号机制在调节 HNSCC 放射抵抗中起核心作用，可能是肿瘤放射增敏的有前途的靶点。
