Cancer poses a significant global health burden, with approximately 19.3 million new cases reported annually. Lung cancer accounts for 11.4% of all cancer cases, and its mortality rate represents 18% of all cancer-related deaths, making it a leading cause of cancer-related fatalities [1]. Pathologically, lung cancer is categorized into two subtypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC comprises approximately 85% of all lung cancer cases, with squamous cell carcinoma (LUSC) representing 25–30%, adenocarcinoma (LUAD) representing approximately 40% of NSCLC cases, which is the most common subtype in NSCLC [2]. Currently, the vast majority of patients are usually diagnosed at advanced stages or have metastasis, palliative chemotherapy is the primary treatment approach for advanced non-small cell lung cancer, though immune checkpoint inhibitors and targeted therapy can further improve treatment outcomes and serve as consolidation treatment options after radiation and chemotherapy, they will not replace chemotherapy in future [3]. However, the emergence of drug resistance in many LUAD cases has led to final treatment failures, emphasizing the urgent need to uncover novel therapeutic targets that drive LUAD progression and chemotherapy resistance.
The ribosome, a molecular machine responsible for protein synthesis, consists of ribosomal RNA (rRNA) and ribosomal proteins. Eukaryotic cells harbor an 80S ribosome composed of a small 40S subunit and a large 60S subunit. The 40S subunit comprises the 18S rRNA and 33 distinct ribosomal proteins (RPS), while the 60S subunit contains the 28S, 5.8S, and 5S rRNA in addition to 47 ribosomal proteins (RPL) [4]. Under the drive of RNA polymerase I, ribosomal DNA (rDNA) is transcribed into 47S pre-rRNA (also known as 45S pre-rRNA), encoding 18S rRNA, 5.8S rRNA, and 28S rRNA [5]. Increasing evidence suggests that perturbations in human ribosome biogenesis can lead to various diseases, including cancer [6]. Notably, dysregulated ribosome biogenesis frequently occurs in tumor cells to sustain their rapid growth and high protein synthesis efficiency [7]. Significant progress has been made in both research and clinical treatment of tumors by targeting ribosome biogenesis. Several clinically approved drugs, including cisplatin, oxaliplatin, doxorubicin, mitoxantrone, and bleomycin, exert their therapeutic effects, at least in part, by inhibiting ribosome synthesis at the rRNA transcription level, while 5-fluorouracil and vincristine inhibit ribosome synthesis at the rRNA processing level [8]. These findings highlight the critical role of ribosome biogenesis in tumor progression and emphasize the importance of identifying additional regulators of ribosome biogenesis as potential therapeutic targets for cancer treatment.
In recent years, with the rapid development of next-generation sequencing technologies, high-throughput sequencing has emerged as an important tool for identifying tumor-related genes. In this study, we performed a bioinformatics analysis of differentially expressed genes from the lung cancer datasets GSE30219 and GSE102287, as well as ribosome biogenesis factors from the Gene Set Enrichment Analysis (GSEA) dataset, to identify key regulators of ribosome biogenesis potentially involved in lung cancer progression. Through comprehensive bioinformatics analysis and literature research, we identified C8ORF59 as a promising candidate gene. C8ORF59, located on chromosome 8, is a vertebrate-specific ribosome synthesis factor. A systematic nucleolar screening study has identified that C8ORF59 may be involved in the pre-rRNA processing [9]; Genome-wide RNAi Screening suggested its involvement in the biogenesis of the ribosomal 40S small subunit, and functional clustering analysis of molecules involved in 40S subunit synthesis revealed their participation in various biological processes and components, including ribosome biogenesis, ribosomal components, NPC transport, proteasome, transcription, translation, signal transduction, metabolism, and alternative splicing regulation [10]. The above two studies suggest that C8ORF59 may be related to the assembly of ribosomes, however, to date, there have been no reports investigating the functional role and mechanisms of C8ORF59 in relation to cancer.
In this study, we demonstrated for the first time that C8ORF59 is upregulated in lung cancer tissues. Knockdown of C8ORF59 significantly inhibited the in vitro growth, migration, and invasion potential of lung adenocarcinoma cells. Moreover, C8ORF59 depletion enhanced the inhibitory effect of the ribosome biogenesis-targeting drug CX-5461 on cell growth, as well as increased the sensitivity of lung adenocarcinoma cells to the chemotherapy drug gemcitabine. These findings identify C8ORF59 as a potential therapeutic target for lung adenocarcinoma and provide new insights into the development of combined gene and chemotherapy treatment strategies.