Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, 450052, China.
Affiliated People's Hospital of Zhengzhou University, Zhengzhou, China.
J Transl Med. 2022 Feb 14;20(1):88. doi: 10.1186/s12967-022-03282-1.
The effect of the cytochrome P450 oxidoreductase (POR) rs10954732 (G > A) polymorphism on hepatocellular carcinoma (HCC) susceptibility is unknown. Here we found that A allele carriers showed a 69% decrease in susceptibility to HCC with overall survival (OS) prolonged to 199%, accompanied by lower activity for cytochrome P450 2E1. A total of 222 differentially expressed proteins were mainly enriched in neutrophil and T cell activation and involved in the immune and inflammatory responses, constituting the altered immune tumor microenvironment related with A allele by proteomics analysis. Hepsin (HPN) showed significant down-regulation in HCC and up-regulation in A allele carriers. A lower HPN level was associated with increased susceptibility to HCC and a worse prognosis. Moreover, HPN is a potential independent prognostic biomarker for HCC and is strongly associated with clinicopathological features, tumor-infiltrating status of immune cells both in our discovery cohort and database surveys. Our findings provide a new potential mechanism by which HPN may play an important role in the susceptibility of rs10954732 A allele carriers to HCC and their prognosis through tumor immune infiltration, thus offering potential insights for future studies on tumor immunotherapy.
细胞色素 P450 氧化还原酶（POR）rs10954732（G > A）多态性对肝细胞癌（HCC）易感性的影响尚不清楚。在这里，我们发现 A 等位基因携带者 HCC 的易感性降低了 69%，总生存率（OS）延长至 199%，同时细胞色素 P450 2E1 的活性降低。通过蛋白质组学分析，共鉴定到 222 个差异表达蛋白，主要富集在中性粒细胞和 T 细胞激活，并参与免疫和炎症反应，构成与 A 等位基因相关的改变的免疫肿瘤微环境。在 HCC 中 Hepsin（HPN）明显下调，而 A 等位基因携带者中上调。HPN 水平较低与 HCC 的易感性增加和预后较差相关。此外，HPN 是 HCC 的潜在独立预后生物标志物，与临床病理特征、肿瘤浸润免疫细胞状态密切相关，在我们的发现队列和数据库调查中均如此。我们的研究结果提供了一个新的潜在机制，即 HPN 可能通过肿瘤免疫浸润在 rs10954732 A 等位基因携带者 HCC 的易感性及其预后中发挥重要作用，从而为肿瘤免疫治疗的未来研究提供了潜在的思路。
