Unraveling the gender-specific molecular landscape of lung squamous cell carcinoma progression

Lung squamous cell carcinoma (LUSC) is a type of non-small cell lung cancer that is the most common and deadly type of lung cancer, originating from the cells lining the bronchi. The progression of LUSC is influenced by various factors, such as genetic, viral, environmental and hormonal factors, immune system response, and smoking history. Despite extensive studies aimed at improving patient survival, the role of gender-specific molecular variants in LUSC progression remains unclear. Using a systems biology approach, combining differential gene expression, network analysis, and machine learning, aberrant mRNA and ncRNAs implicated in LUSC have been identified to improve patient survival, stratify patients and develop novel prognostic strategies. Furthermore, a systematic analysis of the prognostic implications and functional annotations of the molecular variants results in the filtering of key protein-coding genes and non-coding RNAs that are involved in tumor progression. We found several common molecular variants in both genders, including 4 mRNA, 4 miRNAs, and 27 lncRNAs. Among the shared lncRNAs, 5 were novel for both genders. These were found to have a poor prognostic performance in patients with lung cancer. The key players are involved in DNA replication, nucleotide excision repair, complement and coagulation cascades, and estrogen signaling pathways. In this study, we report lncRNAs (PVT1, FAM13A-AS1, LINC00461, NAV2-AS5, PRICKLE2-AS1, and VCAN-AS1) that may function as oncogenes or tumor suppressors by regulating the expression of coding genes, such as RAB24, HECW2, LGR4, and FKBP5. These lncRNAs and coding genes may play important roles in LUSC development and progression.肺鳞状细胞癌（Lung squamous cell carcinoma, LUSC）是非小细胞肺癌的一类，也是最为常见且致死率最高的肺癌亚型，起源于支气管黏膜上皮细胞。肺鳞状细胞癌的进展受多种因素调控，包括遗传、病毒、环境与激素因素、免疫系统应答以及吸烟史等。尽管学界已开展大量旨在提升患者生存率的研究，但性别特异性分子变异在肺鳞状细胞癌进展中的作用仍未明确。本研究采用系统生物学方法，结合差异基因表达分析、网络分析与机器学习技术，筛选出与肺鳞状细胞癌相关的异常信使RNA（mRNA）与非编码RNA（ncRNAs），以期改善患者生存率、实现患者分层并开发新型预后策略。此外，通过对分子变异的预后意义与功能注释进行系统性分析，本研究筛选出参与肿瘤进展的关键蛋白编码基因与非编码RNA。研究发现两类性别共有的多种分子变异，包括4种信使RNA、4种微小RNA（miRNAs）以及27种长链非编码RNA（lncRNAs）。在共有的长链非编码RNA中，有5种为两类性别均未被报道的新型分子。上述分子在肺癌患者中均表现出不良预后相关性。关键调控分子参与的生物学通路包括DNA复制、核苷酸切除修复、补体与凝血级联反应以及雌激素信号通路。本研究还报道了数条长链非编码RNA（PVT1、FAM13A-AS1、LINC00461、NAV2-AS5、PRICKLE2-AS1及VCAN-AS1），它们可通过调控RAB24、HECW2、LGR4及FKBP5等蛋白编码基因的表达，发挥癌基因或抑癌基因的功能。上述长链非编码RNA与蛋白编码基因可能在肺鳞状细胞癌的发生与进展中发挥重要作用。