Department of Pathology, College of Medicine, University of Iowa, 1161, Iowa, IA, 52242, USA.
Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa, IA, USA.
Head Neck Pathol. 2022 Sep;16(3):763-772. doi: 10.1007/s12105-022-01440-x. Epub 2022 Mar 25.
Interleukin-1 alpha (IL-1α) is a cytokine involved in the acute phase immune response and its expression is upregulated in a variety of solid tumors including head and neck squamous cell carcinomas (HNSCCs). Tumor expression of IL-1α is associated with increased tumor aggressiveness in HNSCCs, but this has yet to be studied in the context of human papilloma virus (HPV) status. This study is aimed at determining differences in tumor expression and subcellular localization of IL-1α in HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC tumors. Tissue microarrays (TMAs) containing HPV+ (n = 31) and HPV- (n = 47) primary and metastatic HNSCCs were analyzed for IL-1α expression using immunohistochemical (IHC) staining. HPV status was confirmed using p16 IHC staining and RNA in situ hybridization (RNA ISH). Differences in IL-1α protein expression and secretion in HPV+ and HPV- HNSCC cell lines were determined by western blot and ELISA respectively. Associations between tumor IL1A expression and survival outcomes were assessed in HPV+ and HPV- HNSCC patients from publicly available gene expression datasets. Tumor expression of IL-1α was significantly increased in HPV- tumors and cell lines (as detected by IHC and western blot respectively) compared to HPV+ tumors and cell lines. There was no difference in IL-1α release between HPV+ and HPV- cell lines. IL-1α was expressed in both nuclear and cytoplasmic compartments, with predominant expression in the nucleus. Gene expression of IL1A was significantly increased in HPV-tumors/cell lines compared to HPV+ tumors/cell lines. Lastly, increased IL1A gene expression was significantly associated with worse survival in HPV- tumors but not in HPV+ tumors. Overall IL-1α expression particularly in the nucleus may possess more prognostic significance in HPV- tumors rather than HPV+ tumors. This work warrants further investigation into the role of intracellular IL-1α ligand expression in HNSCCs and may have important implications in IL-1 pathway blockade as therapeutic strategy.
白细胞介素-1α（IL-1α）是一种参与急性期免疫反应的细胞因子，其表达在多种实体瘤中上调，包括头颈部鳞状细胞癌（HNSCCs）。肿瘤中 IL-1α 的表达与 HNSCCs 的肿瘤侵袭性增加有关，但这尚未在人乳头瘤病毒（HPV）状态的背景下进行研究。本研究旨在确定 HPV 阳性（HPV+）和 HPV 阴性（HPV-）HNSCC 肿瘤中 IL-1α 的肿瘤表达和亚细胞定位的差异。使用免疫组织化学（IHC）染色分析包含 HPV+（n=31）和 HPV-（n=47）原发性和转移性 HNSCC 的组织微阵列（TMA）中 IL-1α 的表达。使用 p16 IHC 染色和 RNA 原位杂交（RNA ISH）确认 HPV 状态。通过 Western blot 和 ELISA 分别确定 HPV+和 HPV-HNSCC 细胞系中 IL-1α 蛋白表达和分泌的差异。从公开的基因表达数据集评估 HPV+和 HPV-HNSCC 患者中肿瘤 IL1A 表达与生存结局之间的关联。与 HPV+肿瘤相比，HPV-肿瘤和细胞系中 IL-1α 的表达（分别通过 IHC 和 Western blot 检测）显著增加。HPV+和 HPV-细胞系之间的 IL-1α 释放没有差异。IL-1α 在核和细胞质区室中表达，主要在核中表达。与 HPV+肿瘤/细胞系相比，HPV-肿瘤/细胞系中 IL1A 的基因表达显著增加。最后，在 HPV-肿瘤中，增加的 IL1A 基因表达与生存不良显著相关，但在 HPV+肿瘤中则不然。总的来说，与 HPV+肿瘤相比，HPV-肿瘤中核内 IL-1α 的表达可能具有更大的预后意义。这项工作需要进一步研究 HNSCC 中细胞内 IL-1α 配体表达的作用，并且可能对 IL-1 途径阻断作为治疗策略具有重要意义。
