Department of Medical Oncology, The First Affiliated Hospital of Hainan Medical University, Haikou, 570102, China.
Department of Radiology, Wenzhou Central Hospital, The Second Affiliated Hospital of Shanghai University, Wenzhou, 325000, China.
Mol Biol Rep. 2024 Aug 12;51(1):905. doi: 10.1007/s11033-024-09826-6.
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.
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.
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.
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.
肝细胞癌（HCC）是一种侵袭性很强的癌症，治疗选择有限。缺氧是肿瘤微环境的一个常见特征，据报道它促进了肿瘤的发生。长链非编码 RNA（lncRNA）是一类具有多种功能的调节分子，在癌症生物学中。本研究旨在鉴定与 HCC 相关的缺氧诱导的 lncRNA，并评估其作为预后和治疗生物标志物的潜力。
我们采用微阵列和癌症基因组图谱（TCGA）数据鉴定 HCC 中的缺氧诱导的 lncRNA。随后，我们专注于候选 lncRNA CTD-2510F5.4，通过基因本体论（GO）和关联推断（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 Huh7 和 HepG2 细胞缺氧下的表达。进行 CCK8、划痕愈合和 Transwell 测定等功能测定，以评估 CTD-2510F5.4 过表达对 HCC 细胞增殖、侵袭和转移潜能的影响。此外，我们研究了 CTD-2510F5.4 表达与患者预后、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之间的关系。
我们的数据表明，CTD-2510F5.4 的表达在缺氧时显著上调。功能富集分析表明，CTD-2510F5.4 参与细胞周期调控、E2F 靶标、G2M 检查点控制和 MYC 信号通路。功能上，CTD-2510F5.4 的过表达促进了 HCC 细胞的增殖、侵袭和转移。高 CTD-2510F5.4 表达的患者预后较差，TP53 突变更为常见，免疫抑制性调节 T 细胞浸润增加，免疫检查点分子表达升高，TIDE 评分较高，表明免疫功能障碍和排除。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更敏感，而高表达的患者对化疗反应更好。
我们的研究结果表明，CTD-2510F5.4 在 HCC 进展和免疫调节中起着关键作用。其作为预后生物标志物和治疗反应预测因子的潜力需要进一步研究，以制定 HCC 患者的个体化治疗策略。
