CENPF/CDK1 信号通路通过调节 G2/M 期细胞周期促进肾上腺皮质癌的进展。

BACKGROUND: Adrenocortical carcinoma (ACC) is an aggressive and rare malignant tumor and is prone to local invasion and metastasis. And, overexpressed Centromere Protein F (CENPF) is closely related to the oncogenesis of various neoplasms, including ACC. However, the prognosis and exact biological function of CENPF in ACC remains largely unclear. METHODS: In the present essay, the expression patterns and prognostic value of CENPF in ACC were investigated in clinical specimens and public cancer databases, including GEO and TCGA. The potential signaling mechanism of CENPF in ACC was studied based on gene-set enrichment analysis (GSEA). Furthermore, a small RNA interference experiment was conducted to probe the underlying biological function of CENPF in the human ACC cell line, SW13 cells. Lastly, two available therapeutic strategies, including immunotherapy and chemotherapy, have been further explored. RESULTS: The expression of CENPF in human ACC samples, GEO, and TCGA databases depicted that CENPF was overtly hyper-expressed in ACC patients and positively correlated with tumor stage. The aberrant expression of CENPF was significantly correlated with unfavorable overall survival (OS) in ACC patients. Then, the GSEA analysis declared that CENPF was mainly involved in the G2/M-phase mediated cell cycle and p53 signaling pathway. Further, the in vitro experiment demonstrated that the interaction between CENPF and CDK1 augmented the G2/M-phase transition of mitosis, cell proliferation and might induce p53 mediated anti-tumor effect in human ACC cell line, SW13 cells. Lastly, immune infiltration analysis highlighted that ACC patients with high CENPF expression harbored significantly different immune cell populations, and high TMB/MSI score. The gene-drug interaction network stated that CENPF inhibitors, such as Cisplatin, Sunitinib, and Etoposide, might serve as potential drugs for the therapy of ACC. CONCLUSION: The result points out that CENPF is significantly overexpressed in ACC patients. The overexpressed CENPF predicts a poor prognosis of ACC and might augment the progress of ACC. Thus, CENPF and related genes might serve as a novel prognostic biomarker or latent therapeutic target for ACC patients.

背景：肾上腺皮质癌（ACC）是一种侵袭性和罕见的恶性肿瘤，容易发生局部侵犯和转移。并且，过度表达的着丝粒蛋白 F（CENPF）与包括 ACC 在内的各种肿瘤的发生密切相关。然而，CENPF 在 ACC 中的预后和确切的生物学功能在很大程度上仍不清楚。

方法：本研究通过临床标本和包括 GEO 和 TCGA 在内的公共癌症数据库，研究了 CENPF 在 ACC 中的表达模式和预后价值。基于基因集富集分析（GSEA）研究了 CENPF 在 ACC 中的潜在信号机制。此外，还进行了小 RNA 干扰实验，以探讨 CENPF 在人 ACC 细胞系 SW13 中的潜在生物学功能。最后，进一步探讨了两种可行的治疗策略，包括免疫治疗和化疗。

结果：在人类 ACC 样本、GEO 和 TCGA 数据库中，CENPF 的表达表明 CENPF 在 ACC 患者中明显过表达，并与肿瘤分期呈正相关。CENPF 的异常表达与 ACC 患者的不良总生存（OS）显著相关。然后，GSEA 分析表明 CENPF 主要参与 G2/M 期介导的细胞周期和 p53 信号通路。进一步的体外实验表明，CENPF 与 CDK1 的相互作用增强了有丝分裂的 G2/M 期转变、细胞增殖，并可能在人 ACC 细胞系 SW13 中诱导 p53 介导的抗肿瘤作用。最后，免疫浸润分析强调，CENPF 高表达的 ACC 患者具有显著不同的免疫细胞群体和高 TMB/MSI 评分。基因-药物相互作用网络表明，CENPF 抑制剂，如顺铂、舒尼替尼和依托泊苷，可能作为 ACC 治疗的潜在药物。

结论：结果表明 CENPF 在 ACC 患者中显著过表达。过表达的 CENPF 预测 ACC 的预后不良，并可能加速 ACC 的进展。因此，CENPF 及其相关基因可能成为 ACC 患者的一种新的预后生物标志物或潜在治疗靶标。