Transcriptomic analysis reveals key lnc RNAs associated with ribosomal biogenesis and epidermis differentiation in head and neck squamous cell carcinoma

头颈部肿瘤转录组分析揭示与核糖体生物合成和表皮分化相关的关键长链非编码RNA（英文）

Objective： In this study, we aimed to expand current knowledge of head and neck squamous cell carcinoma （HNSCC）-associated long noncoding RNAs （IncRNAs）, and to discover potential IncRNA prognostic biomarkers for HNSCC based on next-generation RNA-seq. Methods： RNA-seq data of 546 samples from patients with HNSCC were downloaded from The Cancer Genome Atlas （TCGA）, including 43 paired samples of tumor tissue and adjacent normal tissue. An integrated analysis incorporating differential expression, weighted gene co-expression networks, functional enrichment, clinical parameters, and survival analysis was conducted to discover HNSCC-associated IncRNAs. The function of CYTOR was verified by cell-based experiments. To further identify IncRNAs with prognostic significance, a multivariate Cox proportional hazard regression analysis was performed. The identified IncRNAs were validated with an independent cohort using clinical feature relevance analysis and multivariate Cox regression analysis. Results： We identified nine HNSCC-relevant IncRNAs likely to play pivotal roles in HNSCC onset and development. By functional enrichment analysis, we revealed that CYTOR might participate in the multistep pathological processes of cancer, such as ribosome biogenesis and maintenance of genomic stability. CY-I-OR was identified to be positively correlated with lymph node metastasis, and significantly negatively correlated with overall survival （OS） and disease free survival （DFS） of HNSCC patients. Moreover, CYTOR inhibited cell apoptosis following treatment with the chemotherapeutic drug diamminedichloroplatinum （DDP）. HCG22, the most dramatically down-regulated IncRNA in tumor tissue, may function in epidermis differentiation. It was also significantly associated with several clinical features of patients with HNSCC, and positively correlated with patient survival. CYTOR and HCG22 maintained their prognostic values in- dependent of several clinical features in multivariate Cox hazards analysis. Notably, validation either based on an independent HNSCC cohort or by laboratory experiments confirmed these findings. Conclusions： Our transcriptomic analysis suggested that dysregulation of these HNSCC-associated IncRNAs might be involved in HNSCC oncogenesis and progression. Moreover, CYTOR and HCG22 were confirmed as two independent prognostic factors for HNSCC patient survival, providing new insights into the roles of these IncRNAs in HNSCC as well as clinical applications.

目的:研究长链非编码RNA(lncRNA)与头颈部肿瘤发生、发展及预后的关系。创新点:通过使用整合的转录组分析方法筛选出与头颈部肿瘤密切相关的lncRNA,其中CYTOR和HCG22在头颈部肿瘤发生发展中具有重要的生物学功能和临床预后价值,为制定新的治疗策略和探索新的预后标记分子提供参考。方法:从癌症基因组数据集(The Cancer Genome Atlas)中获得RNA-seq数据。结合差异表达分析和共表达网络分析的方法发掘出与头颈部鳞状细胞癌相关的lnc RNA,探讨其与头颈部肿瘤临床病理变化和预后的关系,进一步利用外部数据集以及细胞水平进行验证。结论:发现9个与头颈部肿瘤发生发展密切相关的lncRNA,其中CYTOR可能参与核糖体的生物合成,与病人生存率呈负相关。HCG22可能参与细胞表皮分化过程,与病人生存率呈正相关。此外,CYTOR和HCG22可作为头颈部鳞状细胞癌独立的预后标记物。