背景:肝细胞癌(HCC)是一种高度侵袭性的癌症,治疗选择有限。缺氧是据报道促进肿瘤发生的肿瘤微环境的共同特征。长链非编码RNA(lncRNA)是一类在癌症生物学中具有多种功能的调控分子。本研究旨在鉴定缺氧诱导的与HCC相关的lncRNAs,并评估其作为预后和治疗性生物标志物的潜力。
方法:我们使用微阵列和癌症基因组图谱(TCGA)数据来鉴定缺氧诱导的肝癌中的lncRNAs。随后,我们专注于CTD-2510F5.4,一种候选lncRNA,并使用基因本体论(GO)和内疚(GBA)分析预测其在HCC中的功能作用。我们使用RT-PCR验证了其在缺氧下在Huh7和HepG2细胞中的表达。功能测定,包括CCK8,伤口愈合,和transwell分析,进行评估CTD-2510F5.4过表达对HCC细胞增殖的影响,入侵,和转移潜力。此外,我们调查了CTD-2510F5.4表达与患者预后之间的关系,肿瘤突变特征,免疫微环境特征,以及对不同治疗方式的治疗反应。
结果:我们的数据表明,在缺氧反应中CTD-2510F5.4表达显著上调。功能富集分析显示CTD-2510F5.4参与细胞周期调节,E2F目标,G2M检查点控制,和MYC信号通路。功能上,CTD-2510F5.4过表达促进肝癌细胞增殖,入侵,和转移。CTD-2510F5.4高表达的患者预后较差,TP53突变的患病率较高,免疫抑制调节性T细胞浸润增加,免疫检查点分子的表达升高,和更高的TIDE评分表明免疫功能障碍和排斥。值得注意的是,低CTD-2510F5.4表达的患者对免疫治疗和抗血管生成治疗表现出更高的敏感性,而高表达的患者对化疗反应更好。
结论:我们的研究结果表明,CTD-2510F5.4在HCC进展和免疫调节中起关键作用。其作为预后生物标志物和治疗反应的预测因子的潜力值得进一步研究肝癌患者的个性化治疗策略。
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive cancer with limited therapeutic options. Hypoxia is a common feature of the tumor microenvironment that reportedly promotes tumorigenesis. Long non-coding RNAs (lncRNAs) are a class of regulatory molecules with diverse functions in cancer biology. This study aimed to identify hypoxia-induced lncRNAs associated with HCC and evaluate their potential as prognostic and therapeutic biomarkers.
METHODS: We employed microarray and The Cancer Genome Atlas (TCGA) data to identify hypoxia-induced lncRNAs in HCC. Subsequently, we focused on CTD-2510F5.4, a candidate lncRNA, and predicted its functional roles in HCC using Gene Ontology (GO) and Guilt-by-Association (GBA) analyses. We validated its expression under hypoxia in Huh7 and HepG2 cells using RT-PCR. Functional assays, including CCK8, wound-healing, and transwell assays, were performed to assess the effects of CTD-2510F5.4 overexpression on HCC cell proliferation, invasion, and metastasis potential. Furthermore, we investigated the association between CTD-2510F5.4 expression and patient prognosis, tumor mutation signature, immune microenvironment characteristics, and therapeutic response to different treatment modalities.
RESULTS: Our data demonstrated a significant upregulation of CTD-2510F5.4 expression in response to hypoxia. Functional enrichment analyses revealed the involvement of CTD-2510F5.4 in cell cycle regulation, E2F targets, G2M checkpoint control, and MYC signaling pathways. Functionally, CTD-2510F5.4 overexpression promoted HCC cell proliferation, invasion, and metastasis. Patients with high CTD-2510F5.4 expression exhibited a worse prognosis, a higher prevalence of TP53 mutations, increased infiltration by immunosuppressive regulatory T cells, elevated expression of immune checkpoint molecules, and higher TIDE scores indicative of immune dysfunction and exclusion. Notably, patients with low CTD-2510F5.4 expression displayed greater sensitivity to immunotherapy and antiangiogenic therapy, while those with high expression responded better to chemotherapy.
CONCLUSIONS: Our findings suggest that CTD-2510F5.4 plays a critical role in HCC progression and immune modulation. Its potential as a prognostic biomarker and a predictor of therapeutic response warrants further investigation for personalized treatment strategies in HCC patients.