Purpose: Transcatheter arterial chemoembolization (TACE) is commonly used in the treatment of hepatocellular carcinoma (HCC). However, not all patients respond to this treatment. TACE typically leads to hypoxia in the tumor microenvironment. Therefore, we aimed to construct a prognostic model based on hypoxia-related differentially expressed microRNA (miRNAs) in hepatocellular carcinoma (HCC) and to investigate the potential target mRNAs for predicting TACE response.
Methods: The hypoxia-related miRNAs (HRMs) were identified in liver cancer cells, then global test was performed to further select the miRNAs which were associated with recurrence and vascular invasion. A prognostic model was constructed based on multivariate Cox regression analysis; qRT-PCR analysis was used to validate the differentially expressed miRNAs in HCC cell lines under hypoxic condition. We further identified the putative target genes of the miRNAs and investigate the relationship between the target genes and TACE response, immune cells infiltration.
Results: We established a HRMs prognostic model for HCC patients, containing two miRNAs (miR-638, miR-501-5p), the patients with high-HRMs score showed worse survival in discovery and validation cohort; qRT-PCR analysis confirmed that these two miRNAs are up-regulated in hepatoma cells under hypoxic condition. Furthermore, four putative target genes of these two miRNAs were identified (ADH1B, CTH, FTCD, RCL1), which were significantly associated with TACE response, immune score, immunosuppressive immune cells infiltration, PDCD1 and CTLA4.
Conclusion: The HCC-HRMs signature may be utilized as a promising prognostic factor and may have implications for guiding TACE and immune therapy.

Keywords: hypoxia, miRNA, signature, hepatocellular carcinoma, prognosis


中文翻译：

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缺氧相关 miRNA-mRNA 特征用于预测肝细胞癌经导管动脉化疗栓塞的反应和预后

目的：经导管动脉化疗栓塞（TACE）常用于治疗肝细胞癌（HCC）。然而，并非所有患者都对这种治疗有反应。TACE 通常会导致肿瘤微环境缺氧。因此，我们的目的是构建一个基于肝细胞癌（HCC）缺氧相关差异表达的microRNA（miRNA）的预后模型，并研究预测TACE反应的潜在靶标mRNA。
方法：鉴定肝癌细胞中与缺氧相关的miRNA（HRM），然后进行整体测试，进一步筛选与复发和血管侵犯相关的miRNA。基于多元Cox回归分析构建预后模型；qRT-PCR 分析用于验证缺氧条件下 HCC 细胞系中差异表达的 miRNA。我们进一步鉴定了 miRNA 的假定靶基因，并研究了靶基因与 TACE 反应、免疫细胞浸润之间的关系。
结果：我们建立了 HCC 患者的 HRM 预后模型，包含两种 miRNA（miR-638、miR-501-5p），HRM 评分高的患者在发现和验证队列中表现出较差的生存率；qRT-PCR分析证实这两种miRNA在低氧条件下肝癌细胞中表达上调。此外，还鉴定了这两种 miRNA 的四个假定靶基因（ADH1B、CTH、FTCD、RCL1），它们与 TACE 反应、免疫评分、免疫抑制性免疫细胞浸润、PDCD1 和 CTLA4 显着相关。
结论： HCC-HRM 特征可用作有希望的预后因素，并可能对指导 TACE 和免疫治疗具有影响。

关键词:缺氧, miRNA, 特征, 肝细胞癌, 预后