Mortensen Lindsey, Koenigsberg Cynthia K, Kimbrough Tyler G, Ping Jesse, Adeva Gema Souto, Wuertz Beverly R, Gaffney Patrick, Ondrey Frank G
Department of Otolaryngology, University of Minnesota, MMC396, 420 Delaware St SE, Minneapolis, MN 55455, USA.
Department of Otolaryngology, University of Minnesota, MMC396, 420 Delaware St SE, Minneapolis, MN 55455, USA.
Cancer Genet. 2025 Jan;290-291:61-71. doi: 10.1016/j.cancergen.2024.12.003. Epub 2024 Dec 26.
Studies of squamous cell carcinoma of the head and neck (HNSCC) have demonstrated the importance of nuclear receptors and their associated coregulators in the development and treatment of HNSCC. We sought to characterize members of the nuclear receptor super family through interrogation of RNA-Seq and microarray data.
TCGA RNA-Seq data within the cBioportal platform comparing HNSCC samples (n = 515 patients with RNA-Seq data) to normal tissue (n = 82 patients) was interrogated for significant differences in nuclear receptor expression. Affymetrix microarray analysis of HNSCC tumors relative to normal oral mucosa (41 tumor, 13 normal) was analyzed.
Of the 48 NR genes and 19 NR cofactors examined, 99 % of tumor samples in the TCGA had some form of NR gene 'alteration' compared to normal tissue. These alterations predominantly encompass expression changes. NR genes (PPARG) and (RORC), and the NR cofactor, (NCOA1), were differentially expressed and downregulated in tumors compared to normal tissue.
We have discovered significant decreases in PPARG expression with co-occurring changes in genes involved with lipid metabolism and cell cycle progression in HNSCC. We are targeting PPARγ with thiazolidinediones in a series of clinical trials to restore normal signaling via differentiation to hopefully reverse carcinogenesis. We also observed several receptors with differential expression associated with clinical factors that may become the focus of interest in future targeting efforts. These data provide evidence for nuclear receptors playing a role in the dysregulation of gene expression in HNSCC and illustrate the utility of current bioinformatic tools for interrogating complex, high throughput data sets.
头颈部鳞状细胞癌（HNSCC）研究表明核受体及其相关共调节因子在HNSCC的发生发展及治疗中具有重要作用。我们试图通过对RNA测序（RNA-Seq）和微阵列数据的分析来鉴定核受体超家族成员。
在cBioportal平台上，对TCGA的RNA-Seq数据进行分析，比较HNSCC样本（n = 515例有RNA-Seq数据的患者）与正常组织（n = 82例患者）中核受体表达的显著差异。对HNSCC肿瘤相对于正常口腔黏膜（41个肿瘤样本，13个正常样本）进行Affymetrix微阵列分析。
在所检测的48个核受体（NR）基因和19个NR辅因子中，与正常组织相比，TCGA中99%的肿瘤样本存在某种形式的NR基因“改变”。这些改变主要包括表达变化。与正常组织相比，NR基因（PPARG）和（RORC）以及NR辅因子（NCOA1）在肿瘤中差异表达且下调。
我们发现HNSCC中PPARG表达显著降低，同时脂质代谢和细胞周期进程相关基因也发生了变化。我们正在一系列临床试验中使用噻唑烷二酮类药物靶向PPARγ，以通过分化恢复正常信号传导，有望逆转癌变过程。我们还观察到几种受体的差异表达与临床因素相关，这些因素可能成为未来靶向治疗的关注焦点。这些数据为核受体在HNSCC基因表达失调中发挥作用提供了证据，并说明了当前生物信息学工具在分析复杂的高通量数据集方面的实用性。
