Abstract
Background
Lung adenocarcinoma (LUAD) has high morbidity and mortality. Despite substantial advances in treatment, the prognosis of patients with LUAD remains unfavorable. The ceRNA axis has been reported to play an important role in the pathogenesis of LUAD. In addition, cuproptosis is considered an important factor in tumorigenesis. The expression of CBX2 has been associated with the development of multiple tumors, including LUAD. However, the precise molecular mechanisms through which the cuproptosis-related ceRNA network regulates CBX2 remain unclear.
Methods
The DEGs between tumor and normal samples of LUAD were identified in TCGA database. The “ConsensusClusterPlus” R package was used to perform consensus clustering based on the mRNA expression matrix and cuproptosis-related gene expression profile. Then, LASSO-COX regression analysis was performed to identify potential prognostic biomarkers associated with cuproptosis, and the ceRNA network was constructed. Finally, the mechanisms of ceRNA in LUAD was studied by cell experiments.
Results
In this study, the AC144450.1/miR-424-5p axis was found to promote the progression of LUAD by acting on CBX2. The expression of AC144450.1 and miR-424-5p can be altered to regulate CBX2 and is correlated with cell proliferation and cell cycle of LUAD. Mechanistically, AC144450.1 affects the expression of CBX2 by acting as the ceRNA of miR-424-5p. In addition, a cuproptosis-related model were constructed in this study to predict the prognosis of LUAD.
Conclusions
This study is the first to demonstrate that the AC144450.1/miR-424-5p/CBX2 axis is involved in LUAD progression and may serve as a novel target for its diagnosis and treatment.
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Background
Lung adenocarcinoma (LUAD), particularly in advanced stages, is highly malignant and has an unfavorable prognosis [1]. Despite substantial advancements in treatment, the 5-year survival rate of patients with LUAD is 12–15% [2]. Currently available diagnostic methods, such as imaging, biopsy, and molecular testing, have limitations, including the high likelihood of false-negative results and the inability to detect early-stage LUAD [3]. In contrast, novel diagnostic techniques such as next-generation sequencing and companion diagnostics have demonstrated great potential in identifying genomic alterations and biomarkers that can facilitate early detection and prompt personalized treatment [4]. Additionally, novel techniques for detecting early-stage cancer and understanding its progression are under development [5]. Traditional therapeutic strategies such as surgery, chemotherapy, and radiation therapy have disadvantages, including side effects, drug resistance, and the inability to treat advanced-stage LUAD [6]. However, novel therapies such as immunotherapy and targeted therapy, have shown beneficial effects in the treatment of LUAD. Therefore, develo** more effective diagnostic and treatment methods is necessary for improving the prognosis of patients with LUAD.
MicroRNAs (miRNAs) modulate gene expression by binding to the 3´-untranslated region (UTR) of target mRNAs. They are small non-coding RNA (ncRNAs) that can either degrade the target mRNA or inhibit translation [7]. miRNAs play a crucial role in regulating the cell cycle, metastasis, angiogenesis, metabolism, and apoptosis, thus influencing tumorigenesis [8]. In lung cancer, miRNAs act as both tumor suppressors and oncomirs, regulating the expression of target mRNAs to influence tumor cell proliferation, angiogenesis, and metastasis [9]. miR-424-5p, a distinct miRNA variant, is involved in regulating gene expression and the progression of several cancer types [10]. For instance, it can hinder the proliferative, migratory, and invasive capabilities of lung cancer cells [11]. Long non-coding RNAs (lncRNAs) are RNA transcripts that exceed 200 nucleotides in length and lack protein-coding ability but play a pivotal role in gene regulation [12]. lncRNAs can interact with DNA, RNA, and proteins to regulate chromatin structure, transcription, post-transcriptional processes, and translation [13]. They act as molecular decoys for miRNAs and regulate splicing, mRNA decay, translation, and protein stability [14]. In addition, they are involved in the development of various types of cancers, including LUAD [15]. For example, the lncRNA MALAT1 induces tumor cell proliferation and metastasis by regulating downstream genes in LUAD [16], and the lncRNA HOTAIR induces tumor cell proliferation and invasion by regulating downstream genes in LUAD [17]. lncRNAs can be used as biomarkers for the diagnosis and treatment of LUAD. The lncRNA AC144450.1, also known as ENSG00000228613, is involved in various biological processes, including cancer development [19]. It involves lncRNA acting as an endogenous sponge to effect mRNA expression via sinking miRNA [20]. ceRNAs have been reported to play a vital role in the initiation and development of LUAD [21]. lncRNAs and miRNAs that are inversely related to each other may serve as biomarkers for the diagnosis, prognosis, and treatment of cancer [22].
The presence of excessive copper can induce cell death. The mechanisms underlying copper-induced cell death remained elusive until the identification of cuproptosis [Full size image