Abstract
BackgroundAccumulative evidence shows that an organoid is a more practical and reliable tool in cancer biology research. This study aimed to identify and validate crucial genes involved in non-small cell lung cancer carcinogenesis and development using the transcriptomic analysis of tumor tissues and organoids.MethodsGene set enrichment analysis (GSEA) of tumor tissues, tumor organoids, and normal tissues was performed to reveal the similar and different mechanisms involved in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) carcinogenesis and progression. Differentially expressed gene analysis, prognostic analysis, and gene co-expression network analysis were further used to identify hub genes involved in LUAD and LUSC carcinogenesis and development. Finally, LUAD cell lines and organoids were used to validate these findings.ResultsGSEA analysis was performed to reveal the similar mechanisms involved in LUAD and LUSC carcinogenesis and development, such as P53 signaling pathway, base mismatch repair, DNA replication, cAMP signaling pathway and PPAR pathway. However, comparing with LUSC organoids, LUAD organoids showed downregulation of immune-related pathways, inflammation-related pathways, MAPK signaling pathways, and Rap1 signaling pathways, although these pathways were downregulated in LUAD and LUSC tissues by comparing with normal lung tissues. Further gene co-expression network analysis and prognostic analysis indicated CDK1, CCNB2, and CDC25A as the hub tumor-promoting genes in LUAD but not in LUSC, which were further validated in other datasets. Using LUAD cell lines and organoid models, CDK1 and CCNB2 knockdown were found to suppress LUAD proliferation. However, CDC25A knockdown did not inhibit LUAD cell line proliferation but could effectively suppress LUAD organoid growth, indicating that an organoid could be used as an effective tool to study cancer biology in LUAD.ConclusionsThe results revealed CDK1, CCNB2, and CDC25A as the hub genes involved in LUAD carcinogenesis and development, which could be used as the potential biomarkers and targets for LUAD.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide, with an estimated 1.8 million deaths each year [1]
Comprehensive transcriptomic analysis of tumor tissues, tumor organoids, and normal tissues revealed the molecular mechanisms of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) Gene set enrichment analysis (GSEA) analysis was performed between paired LUAD and normal tissues (n = 58), and paired LUAD organoid and LUAD tissues (n = 6)
18 pathways enriched in LUAD tissues compared with normal tissues were obtained and simultaneously enriched in LUAD organoids compared with LUAD tissues (Fig. 1a)
Summary
Lung cancer is the leading cause of cancer-related death worldwide, with an estimated 1.8 million deaths each year [1]. Non-small cell lung cancer (NSCLC), the most common subtype with 85% of all cases, has an overall 5-year survival rate of 17.8%; more than half of patients die within. The treatment targeting somatic mutations and PD-L1/PD-1 improved survival, but most patients with NSCLC did not respond to or developed resistance to these treatments [5]. Organoids established from lung cancer tissues retain tumor histopathology as well as gene mutations, copy number aberrations, and gene expression profiles; they are used for therapeutic screening, including chemotherapy, FGFR and MEK-targeted therapies, and immune checkpoint inhibitors [6,7,8,9]. This study aimed to identify and validate crucial genes involved in non-small cell lung cancer carcinogenesis and development using the transcriptomic analysis of tumor tissues and organoids
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