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Klotho-β 和成纤维细胞生长因子 19 的表达与可切除肝细胞癌的早期复发相关。

Klotho-beta and fibroblast growth factor 19 expression correlates with early recurrence of resectable hepatocellular carcinoma.

机构信息

Department of Oncology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.

Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

出版信息

Liver Int. 2019 Sep;39(9):1682-1691. doi: 10.1111/liv.14055. Epub 2019 Jul 11.

DOI:10.1111/liv.14055

PMID:30698907

Abstract

BACKGROUND AND AIMS

Fibroblast growth factor 19 (FGF19) and fibroblast growth factor receptor 4 (FGFR4) signalling play critical roles in hepatocarcinogenesis. This study explored the potential of FGF19- and FGFR4-related biomarkers in predicting early tumour recurrence (ETR) and survival in patients with resectable hepatocellular carcinoma (HCC).

METHODS

We examined the mRNA expressions of FGF19, FGFR4, klotho-beta (KLB), cyclin D1 (CCND1) and FGF4 in 151 surgically resected, primary unifocal HCCs through quantitative real-time polymerase chain reaction. Generalized additive models were fitted to detect nonlinear effects of continuous covariates and define thresholds of biomarker expressions. Univariate and multivariate analyses were performed to evaluate prognostic values of these biomarkers for tumour recurrence and patient survival.

RESULTS

Overexpression of FGF19, FGFR4, KLB, CCND1 and FGF4 mRNA was detected in 40%, 32%, 26%, 15% and 35% of 151 tumours respectively. ETR was the strongest prognostic factor predicting worse overall survival (hazard ratio [HR], 5.678; 95% confidence interval, 3.7-8.713; P < 0.001). Furthermore, we revealed that mRNA expression levels of KLB (HR, 3.857; P = 0.021) and FGF19 (HR, 3.248; P = 0.017) were significantly associated with the occurrence of ETR.

CONCLUSIONS

Frequent overexpression of FGF19/FGFR4-related biomarkers was detected in resectable HCC. Expression levels of KLB and FGF19 may determine patient survival outcomes through their effects on ETR.

摘要

背景与目的

成纤维细胞生长因子 19（FGF19）和成纤维细胞生长因子受体 4（FGFR4）信号在肝癌发生中起着关键作用。本研究探讨了 FGF19 和 FGFR4 相关生物标志物在预测可切除肝细胞癌（HCC）患者早期肿瘤复发（ETR）和生存中的潜力。

方法

我们通过定量实时聚合酶链反应检测了 151 例手术切除的原发性单灶 HCC 中 FGF19、FGFR4、klotho-β（KLB）、细胞周期蛋白 D1（CCND1）和 FGF4 的 mRNA 表达。广义加性模型被拟合以检测连续协变量的非线性效应并定义生物标志物表达的阈值。进行单变量和多变量分析以评估这些生物标志物对肿瘤复发和患者生存的预后价值。

结果

在 151 个肿瘤中，FGF19、FGFR4、KLB、CCND1 和 FGF4 mRNA 的过表达分别为 40%、32%、26%、15%和 35%。ETR 是预测总生存较差的最强预后因素（风险比 [HR]，5.678；95%置信区间，3.7-8.713；P<0.001）。此外，我们发现 KLB（HR，3.857；P=0.021）和 FGF19（HR，3.248；P=0.017）的 mRNA 表达水平与 ETR 的发生显著相关。