<br>HIF 羟化酶 PHD2/EGLN1 和 PHD3/EGLN3 的低核表达与透明细胞肾细胞癌无复发生存率差相关,Cancer Medicine

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HIF 羟化酶 PHD2/EGLN1 和 PHD3/EGLN3 的低核表达与透明细胞肾细胞癌无复发生存率差相关
Cancer Medicine ( IF 2.9 ) Pub Date : 2024-02-24 , DOI: 10.1002/cam4.6998
Lassi Luomala ₁ , Kalle Mattila _{2,

3} , Paula Vainio ₄ , Harry Nisén ₁ , Teijo Pellinen ₅ , Jouni Lohi ₆ , Teemu D Laajala _{6,

7} , Petrus Järvinen ₁ , Anna-Riina Koskenniemi ₄ , Panu Jaakkola ₂ , Tuomas Mirtti _{6,

7,

8}

Affiliation

背景缺氧诱导因子 HIF-1α 和 HIF-2α 及其主要调节因子脯氨酰羟化酶结构域蛋白 (PHD) 介导细胞对缺氧的反应，并有助于透明细胞肾细胞癌 (ccRCC) 的肿瘤进展。这些生物标志物可能会提高传统组织病理学特征在预测局限性 ccRCC 肾切除术后疾病进展方面的价值，并指导患者选择辅助治疗。患者和方法在本研究中，我们分析了 PHD2 和 PHD3 与肿瘤组织病理学特征和无复发生存期的关联(RFS) 对 173 名在芬兰赫尔辛基大学医院 (HUH) 接受过局部 ccRCC 手术的患者进行的回顾性队列研究。来自芬兰图尔库大学医院 (TUH) 的 191 名患者的外部验证队列。使用原发肿瘤样本构建组织微阵列（TMA）。从电子病历中获取2006年至2019年的临床参数和随访信息。基于免疫组织化学染色对 PHD2 和 PHD3 的细胞质和核表达进行评分，并评估其与组织病理学特征和 RFS 的关联。结果与阴性细胞核相比，癌细胞中的核 PHD2 和 PHD3 表达与较低的 pT 分期和 Fuhrman 分级相关。与肿瘤阴性的患者相比，癌细胞中 PHD2 和 PHD3 核表达阳性的患者具有良好的 RFS。在多变量分析中，PHD2 的核表达与 RCC 疾病复发或死亡风险降低独立相关。在两个队列中都观察到了这些结果。结论 ccRCC 中核 PHD2 和 PHD3 表达的缺失与较差的 RFS 相关，无论其他已知的组织病理学预后因素如何，PHD2 的核表达可预测 RFS。核 PHD2 和 PHD3 是局限性 ccRCC 患者潜在的预后生物标志物，应在前瞻性研究中进一步研究和验证。

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Low nuclear expression of HIF‐hydroxylases PHD2/EGLN1 and PHD3/EGLN3 are associated with poor recurrence‐free survival in clear cell renal cell carcinoma

BackgroundHypoxia inducible factors, HIF‐1α and HIF‐2α, and their main regulators, the prolyl hydroxylase domain proteins (PHDs), mediate cellular response to hypoxia and contribute to tumor progression in clear cell renal cell carcinoma (ccRCC). These biomarkers may improve the value of traditional histopathological features in predicting disease progression after nephrectomy for localized ccRCC and guide patient selection for adjuvant treatments.Patients and MethodsIn this study, we analyzed the associations of PHD2 and PHD3 with histopathological tumor features and recurrence‐free survival (RFS) in a retrospective cohort of 173 patients who had undergone surgery for localized ccRCC at Helsinki University Hospital (HUH), Finland. An external validation cohort of 191 patients was obtained from Turku University Hospital (TUH), Finland. Tissue‐microarrays (TMA) were constructed using the primary tumor samples. Clinical parameters and follow‐up information from 2006 to 2019 were obtained from electronic medical records. The cytoplasmic and nuclear expression of PHD2, and PHD3 were scored based on immunohistochemical staining and their associations with histopathological features and RFS were evaluated.ResultsNuclear PHD2 and PHD3 expression in cancer cells were associated with lower pT‐stage and Fuhrman grade compared with negative nuclei. Patients with positive nuclear expression of PHD2 and PHD3 in cancer cells had favorable RFS compared with patients having negative tumors. The nuclear expression of PHD2 was independently associated with a decreased risk of disease recurrence or death from RCC in multivariable analysis. These results were observed in both cohorts.ConclusionsThe absence of nuclear PHD2 and PHD3 expression in ccRCC was associated with poor RFS and the nuclear expression of PHD2 predicted RFS regardless of other known histopathological prognostic factors. Nuclear PHD2 and PHD3 are potential prognostic biomarkers in patients with localized ccRCC and should be further investigated and validated in prospective studies.

更新日期：2024-02-24

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