Bone Max, Schreyer Daniel, Treanor-Taylor Mairi, Proby Charlotte M, Harwood Catherine A, Leigh Irene M, Bailey Peter, Inman Gareth J
School of Cancer Sciences, University of Glasgow, UK.
Cancer Research UK Scotland Institute, Glasgow, UK.
Br J Dermatol. 2025 Mar 27. doi: 10.1093/bjd/ljaf108.
Cutaneous squamous cell carcinoma (cSCC) is a common cancer with high morbidity and poor prognosis for metastatic disease. Disease may progress from pre-malignant Actinic Keratosis (AK) to invasive and metastatic cSCC but perhaps is best characterised as a disease continuum progressing from a differentiated to a progenitor like state. The critical molecular mediators of this process remain poorly defined. Long non-coding RNAs (lncRNAs), a relatively unexplored class of RNA molecules over 200 nucleotides long, are likely to have important functional roles in cSCC.
Here we wished to provide a comprehensive landscape of lncRNA expression during the cSCC continuum and identify potentially functional lncRNA drivers of disease progression.
We interrogated bulk RNA sequencing data from 110 patient samples, encompassing normal sun-exposed skin (n=26), Actinic Keratosis (n=14), primary cSCC (n=66), and metastases (n=4)1 to identify changes in lncRNA expression during disease progression. We developed a bioinformatics pipeline to infer lncRNA function based on co-expression patterns and generated a lncRNA signature score which we validated in head and neck squamous cell carcinoma (HNSC), and pancreatic adenocarcinoma (PAAD). We performed bulk RNA sequencing on 15 patient-derived cell lines and integrated this data to identify tumour cell specific lncRNAs and validated our findings in multiple other cSCC gene expression cohorts. Using in-vitro knockdown approaches we investigated the functional role of LINC00941.
We characterised the landscape of lncRNAs during cSCC disease progression and revealed that lncRNA expression alone is sufficient to identify disease states and progression along the disease continuum. Correlation analysis revealed potentially functionally relevant lncRNAs and the processes that they may regulate. We developed a 267 lncRNA signature that correlates with a progenitor like state and predicts poor prognosis in HNSC and PAAD. Bulk RNA sequencing of patient derived cell lines (PDCLs) revealed tumour cell specific lncRNAs and knockdown of LINC00941 indicated that this is required for cell proliferation and colony formation in vitro.
Our findings provide a comprehensive description of lncRNA transcriptomic changes in cSCC and demonstrate their functional relevance as both biomarkers and drivers of disease progression in this and potentially other cancers.
皮肤鳞状细胞癌（cSCC）是一种常见癌症，发病率高，转移性疾病预后差。疾病可能从癌前日光性角化病（AK）发展为侵袭性和转移性cSCC，但或许最好将其描述为一个从分化状态发展为祖细胞样状态的疾病连续体。这一过程的关键分子介质仍未明确界定。长链非编码RNA（lncRNA）是一类长度超过200个核苷酸、相对未被充分探索的RNA分子，可能在cSCC中发挥重要功能作用。
在此，我们希望描绘cSCC疾病连续体中lncRNA表达的全貌，并确定疾病进展中潜在的功能性lncRNA驱动因素。
我们分析了110例患者样本的大量RNA测序数据，包括正常暴露于阳光下的皮肤（n = 26）、日光性角化病（n = 14）、原发性cSCC（n = 66）和转移灶（n = 4），以确定疾病进展过程中lncRNA表达的变化。我们开发了一个生物信息学流程，根据共表达模式推断lncRNA功能，并生成了一个lncRNA特征评分，我们在头颈部鳞状细胞癌（HNSC）和胰腺腺癌（PAAD）中对其进行了验证。我们对15个患者来源的细胞系进行了大量RNA测序，并整合这些数据以鉴定肿瘤细胞特异性lncRNA，并在多个其他cSCC基因表达队列中验证了我们的发现。使用体外敲低方法，我们研究了LINC00941的功能作用。
我们描绘了cSCC疾病进展过程中lncRNA的全貌，并揭示仅lncRNA表达就足以识别疾病状态以及沿疾病连续体的进展情况。相关性分析揭示了潜在的功能相关lncRNA及其可能调控的过程。我们开发了一个由267个lncRNA组成的特征，其与祖细胞样状态相关，并预测HNSC和PAAD的预后不良。患者来源细胞系（PDCLs）的大量RNA测序揭示了肿瘤细胞特异性lncRNA，并且敲低LINC00941表明这是体外细胞增殖和集落形成所必需的。
我们的研究结果全面描述了cSCC中lncRNA转录组的变化，并证明了它们作为生物标志物和疾病进展驱动因素在这种癌症以及可能的其他癌症中的功能相关性。
