Equipe CHIMERE, EA 7516, Université de Picardie Jules Verne, 80054 Amiens, France.
Laboratoire de Biochimie, Centre de Biologie Humaine, CHU Sud, 80054 Amiens, France.
Oncol Rep. 2019 Mar;41(3):2041-2050. doi: 10.3892/or.2018.6922. Epub 2018 Dec 10.
Sorafenib is the standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, identifying secreted biomarkers that predict sorafenib efficacy in all HCC patients remains challenging. It was recently reported that sorafenib interferes with protein homeostasis and inhibits global translation in tumour cells. A likely consequence of this inhibition would be the interruption of autocrine loops. The aim of the present study was to investigate the effect of sorafenib on two growth factors implicated in autocrine loops and HCC tumour invasion: amphiregulin (AREG) and vascular endothelial growth factor (VEGF). ELISA, quantitative polymerase chain reaction analysis, western blotting and a cytokine array were performed on HCC cell lines and the prognostic role of these two biomarkers in HCC patients was evaluated. Serum AREG and VEGF levels were assayed by ELISA in 55 patients with advanced HCC treated with sorafenib. It was observed that sorafenib decreased AREG, VEGF and cytokine expression at the transcriptional and post‑transcriptional levels. All HCC patients in our cohort had detectable concentrations of AREG and VEGF both at baseline and after sorafenib treatment. The decreased serum levels of AREG and VEGF after 15 days of sorafenib treatment were significantly associated with better overall and progression‑free survival. The results of the multivariate analysis demonstrated that a decrease in AREG was an independent prognostic indicator of overall survival (hazard ratio, 0.208; 95% confidence interval, 0.173‑0.673; P=0.0003). These results suggest that sorafenib inhibits auto-crine loops and that early decrease in serum AREG or VEGF levels predicts sorafenib efficacy in HCC patients.
索拉非尼是治疗晚期肝细胞癌（HCC）的标准治疗方法。然而，确定可预测所有 HCC 患者索拉非尼疗效的分泌生物标志物仍然具有挑战性。最近有报道称，索拉非尼会干扰蛋白质稳态并抑制肿瘤细胞中的全局翻译。这种抑制的可能后果将是中断自分泌环。本研究旨在研究索拉非尼对两种参与自分泌环和 HCC 肿瘤侵袭的生长因子：表皮生长因子受体（AREG）和血管内皮生长因子（VEGF）的影响。对 HCC 细胞系进行 ELISA、定量聚合酶链反应分析、Western blot 和细胞因子阵列分析，并评估这两种生物标志物在 HCC 患者中的预后作用。对 55 例接受索拉非尼治疗的晚期 HCC 患者进行了 ELISA 检测血清 AREG 和 VEGF 水平。结果观察到，索拉非尼在转录和转录后水平降低了 AREG、VEGF 和细胞因子的表达。我们队列中的所有 HCC 患者在基线和索拉非尼治疗后均检测到 AREG 和 VEGF 的可检测浓度。索拉非尼治疗 15 天后血清 AREG 和 VEGF 水平降低与总生存期和无进展生存期显著相关。多变量分析的结果表明，AREG 减少是总生存期的独立预后指标（危险比，0.208；95%置信区间，0.173-0.673；P=0.0003）。这些结果表明，索拉非尼抑制自分泌环，而血清 AREG 或 VEGF 水平的早期降低可预测 HCC 患者对索拉非尼的疗效。
