Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.
Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.
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DOI：
10.1186/1471-2407-12-56
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发表时间：
2012-02-06
期刊：
影响因子：
3.8
通讯作者：
Miyazaki M
中科院分区：
文献类型：
--
作者：
Miura S;Mitsuhashi N;Shimizu H;Kimura F;Yoshidome H;Otsuka M;Kato A;Shida T;Okamura D;Miyazaki M
尽管成纤维细胞生长因子 19 (FGF19) 可以促进小鼠肝癌发生，但其与人类肝细胞癌 (HCC) 的关系尚未得到充分研究。 FGF19 是 FGF 家族的成员，对其受体 FGFR4 具有独特的特异性。本研究旨在阐明 FGF19 在 HCC 发展中的参与。我们使用定量实时逆转录聚合酶链反应 (RT-PCR) 分析和免疫组织化学研究了 40 份肝细胞癌标本中的人 FGF19 和 FGFR4 表达。此外，我们使用 RT-PCR 和免疫组化检测了 5 种肝细胞癌细胞系（HepG2、HuH7、HLE、HLF 和 JHH7）中 FGF19 和 FGFR4 的表达和分布。为了测试 FGF19/FGFR4 系统在肿瘤进展中的作用，我们使用重组 FGF19 蛋白以及 FGF19 和 FGFR4 的小干扰 RNA (siRNA) 来调节它们的浓度。我们发现，与相应的非癌性肝组织相比，FGF19 在 HCC 中显着过表达（P < 0.05）。单变量和多变量分析显示，肿瘤 FGF19 mRNA 表达是总体生存率和无病生存率的独立预后因素。此外，我们发现FGF19重组蛋白可以增加人肝癌细胞系的增殖（P < 0.01，n = 12）和侵袭（P < 0.01，n = 6）能力，并抑制其凋亡（P < 0.01，n = 12）。相反，通过 siRNA 减少 FGF19 和 FGFR4 表达可显着抑制 JHH7 细胞的增殖并增加凋亡（P < 0.01，n = 12）。 HCC患者术后血清FGF19水平显着低于术前水平（P < 0.01，n = 29）。 FGF19 在 HCC 的发展中发挥着重要作用。靶向 FGF19 抑制是 HCC 的一种有吸引力的潜在治疗策略。
Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice, its involvement in human hepatocellular carcinoma (HCC) has not been well investigated. FGF19, a member of the FGF family, has unique specificity for its receptor FGFR4. This study aimed to clarify the involvement of FGF19 in the development of HCC. We investigated human FGF19 and FGFR4 expression in 40 hepatocellular carcinoma specimens using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. Moreover, we examined the expression and the distribution of FGF19 and FGFR4 in 5 hepatocellular carcinoma cell lines (HepG2, HuH7, HLE, HLF, and JHH7) using RT-PCR and immunohistochemistry. To test the role of the FGF19/FGFR4 system in tumor progression, we used recombinant FGF19 protein and small interfering RNA (siRNA) of FGF19 and FGFR4 to regulate their concentrations. We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P < 0.05). Univariate and multivariate analyses revealed that the tumor FGF19 mRNA expression was an independent prognostic factor for overall and disease-free survival. Moreover, we found that the FGF19 recombinant protein could increase the proliferation (P < 0.01, n = 12) and invasion (P < 0.01, n = 6) capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (P < 0.01, n = 12). Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P < 0.01, n = 12). The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P < 0.01, n = 29). FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.
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