Background. CYP39A1 is a poorly characterized metabolic enzyme that has been investigated in a few tumors. However, the role of CYP39A1 in hepatocellular carcinoma (HCC) has not yet been clarified. In this study, the expression and clinical significance of CYP39A1 in HCC were explored. Methods. CYP39A1 protein expression was detected in Akt/c-Met-induced HCC mice and 14 paired fresh HCC samples as well as another 159 HCC and matched noncancerous tissues. Meanwhile, the mRNA expression was analyzed by GEO and TCGA analysis and validated in 14 paired fresh HCC tissues. Furthermore, the relationships between CYP39A1 expression and clinicopathologic features as well as prognosis were analyzed. HCC cell growth changes were analyzed by cell viability assays after CYP39A1 overexpression and then validated after CYP39A1 knockout by DepMap database analysis. Results. CYP39A1 protein expression was lower expressed in HCC mouse models, and its mRNA and protein expression were also downregulated in HCC compared with noncancerous liver tissues. Higher CYP39A1 expression was associated with well differentiation. Moreover, survival analysis indicated that lower CYP39A1 expression was associated with poorer overall survival. In addition, HepG2 and SMMC-7721 cell viability were inhibited after CYP39A1 overexpression. Genome-wide CRISPR/Cas9 proliferation screening indicated that knockout of CYP39A1 could promote HCC cell growth. Likewise, p-NF-κB and Nrf2 were suppressed after CYP39A1 overexpression. It is worth mentioning that total bile acid, total bilirubin, and direct bilirubin were significantly increased in the patients with low CYP39A1 expression. Conclusions. Downregulation of CYP39A1 is associated with HCC carcinogenesis, tumor differentiation, and poor overall survival, suggesting that CYP39A1 may serve as a tumor suppressor gene and novel biomarker for HCC patients.

中文翻译：

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CYP39A1 的下调可作为临床结果更差的肝细胞癌的新型生物标志物

背景。CYP39A1 是一种特征不佳的代谢酶，已在少数肿瘤中进行了研究。然而，CYP39A1 在肝细胞癌 (HCC) 中的作用尚未阐明。本研究探讨 CYP39A1 在 HCC 中的表达及临床意义。方法. 在 Akt/c-Met 诱导的 HCC 小鼠和 14 对新鲜 HCC 样本以及另外 159 个 HCC 和匹配的非癌组织中检测到 CYP39A1 蛋白表达。同时，通过 GEO 和 TCGA 分析分析 mRNA 表达，并在 14 对新鲜 HCC 组织中进行验证。此外，分析了CYP39A1表达与临床病理特征以及预后之间的关系。在 CYP39A1 过表达后通过细胞活力测定分析 HCC 细胞生长变化，然后在 CYP39A1 敲除后通过 DepMap 数据库分析进行验证。结果. CYP39A1 蛋白在 HCC 小鼠模型中表达较低，与非癌性肝组织相比，其 mRNA 和蛋白表达在 HCC 中也下调。较高的 CYP39A1 表达与良好分化相关。此外，生存分析表明，较低的 CYP39A1 表达与较差的总体生存率相关。此外，在 CYP39A1 过表达后，HepG2 和 SMMC-7721 细胞活力受到抑制。全基因组 CRISPR/Cas9 增殖筛选表明敲除 CYP39A1 可促进 HCC 细胞生长。同样，在 CYP39A1 过表达后p-NF- κ B 和 Nrf2 被抑制。值得一提的是，CYP39A1低表达患者的总胆汁酸、总胆红素和直接胆红素显着升高。结论. CYP39A1 的下调与 HCC 癌变、肿瘤分化和较差的总生存期有关，这表明 CYP39A1 可能作为 HCC 患者的肿瘤抑制基因和新型生物标志物。