胆管癌中长链非编码 RNA 相关预后标志物的建立和验证。
Establishment and validation of lncRNA-related prognostic signatures in cholangiocarcinoma.
机构信息
Department of Hepatic Surgery II, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
Changzheng Hospital, Naval Medical University, Shanghai, China.
出版信息
Genomics. 2023 May;115(3):110621. doi: 10.1016/j.ygeno.2023.110621. Epub 2023 Apr 15.
BACKGROUND
The prognosis of CCA is extremely poor, making it one of the most lethal cancers. Therefore, there is a need to elucidate the pathogenic mechanisms of CCA. In this study, we aimed at identifying lncRNA-related prognostic signatures for CCA through bioinformatics analysis and further validated their functions in CCA tumorigenesis and progression.
METHODS
The RNA-seq data of CCA were downloaded from public databases. Differentially expressed lncRNAs (DElncRNAs) were screened. Then, candidate OS- and DFS-related DElncRNAs were selected through Kaplan-Meier survival analysis. Furthermore, LASSO regression was performed to establish the OS and DFS signatures, respectively. Multivariate COX models and nomograms for overall survival (OS) and disease-free survival (DFS) were established based on OS/DFS signature and clinical data. Hub lncRNAs were identified and enrichment analyses were performed to explore their potential functions. Finally, in vitro and in vivo models were used to validate the effects of the hub lncRNAs in CCA tumorigenesis and progression.
RESULTS
A total of 925 DElncRNAs were selected, of which six candidate OS-related lncRNAs and 15 candidate DFS-related lncRNAs were identified. The OS and DFS signatures were then established using four lncRNAs, respectively. We found that the OS signature and vascular invasion were independent risk factors for the OS of CCA, while the DFS signature, vascular invasion, and CA19-9 were independent risk factors for the DFS of CCA. Then, nomograms were established to achieve personalized CCA recurrence and death prediction. Furthermore, our study uncovered that MIR4435-2HG and GAPLINC might play crucial roles in CCA progression and be selected as hub lncRNAs. GO and KEGG enrichment analyses revealed that the two hub lncRNAs were closely related to CCA tumorigenesis. Finally, we demonstrated that MIR4435-2HG and GAPLINC can stimulate CCA proliferation and migration in vitro and in vivo.
CONCLUSIONS
The established OS and DFS signatures are independent risk factors for OS and DFS of CCA patients, respectively. MIR4435-2HG and GAPLINC were identified as hub lncRNAs. In vitro and in vivo models revealed that MIR4435-2HG and GAPLINC can prompt CCA progression, which might be novel prognostic biomarkers and therapeutic targets for CCA.
背景
CCA 的预后极差，使其成为最致命的癌症之一。因此，需要阐明 CCA 的发病机制。在本研究中，我们旨在通过生物信息学分析鉴定与 CCA 相关的 lncRNA 预后特征，并进一步验证其在 CCA 肿瘤发生和进展中的功能。
方法
从公共数据库中下载 CCA 的 RNA-seq 数据。筛选差异表达的 lncRNAs（DElncRNAs）。然后，通过 Kaplan-Meier 生存分析选择候选 OS 和 DFS 相关 DElncRNAs。进一步通过 LASSO 回归分别建立 OS 和 DFS 特征。基于 OS/DFS 特征和临床数据，建立多变量 COX 模型和用于总生存期（OS）和无病生存期（DFS）的列线图。鉴定出核心 lncRNAs 并进行富集分析以探索其潜在功能。最后，在体外和体内模型中验证了核心 lncRNAs 在 CCA 肿瘤发生和进展中的作用。
结果
共筛选出 925 个 DElncRNAs，其中鉴定出 6 个候选 OS 相关 lncRNAs 和 15 个候选 DFS 相关 lncRNAs。然后分别使用四个 lncRNAs 建立了 OS 和 DFS 特征。我们发现 OS 特征和血管侵犯是 CCA 患者 OS 的独立危险因素，而 DFS 特征、血管侵犯和 CA19-9 是 CCA 患者 DFS 的独立危险因素。然后，建立了列线图以实现个性化 CCA 复发和死亡预测。此外，我们的研究表明，MIR4435-2HG 和 GAPLINC 可能在 CCA 进展中发挥关键作用，并被选为核心 lncRNAs。GO 和 KEGG 富集分析表明，这两个核心 lncRNAs 与 CCA 肿瘤发生密切相关。最后，我们证明 MIR4435-2HG 和 GAPLINC 可以在体外和体内刺激 CCA 的增殖和迁移。
结论
建立的 OS 和 DFS 特征分别是 CCA 患者 OS 和 DFS 的独立危险因素。鉴定出 MIR4435-2HG 和 GAPLINC 作为核心 lncRNAs。体外和体内模型表明，MIR4435-2HG 和 GAPLINC 可以促进 CCA 进展，可能成为 CCA 的新的预后生物标志物和治疗靶点。
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