Molecular subclasses of hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition.
Molecular subclasses of hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition.
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DOI：
10.1002/ijc.29893
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发表时间：
2016-03-15
影响因子：
6.4
通讯作者：
Fuchs BC
中科院分区：
文献类型：
--
作者：
Schmidt B;Wei L;DePeralta DK;Hoshida Y;Tan PS;Sun X;Sventek JP;Lanuti M;Tanabe KK;Fuchs BC
最近的肝细胞癌 (HCC) 基因表达分类包括称为 S2 的低生存亚类，约占临床系列中所有 HCC 的三分之一。 S2细胞表达E-钙粘蛋白和c-myc并分泌AFP。由于成纤维细胞生长因子受体 (FGFR) 的表达在 S2 和非 S2 HCC 之间存在差异，因此本研究调查了 HCC 的分子亚类是否可以预测对 FGFR 抑制的敏感性。 S2 细胞系对 FGFR 抑制剂 BGJ398 和 AZD4547 显着更敏感 (p<0.001)。 BGJ398 降低 S2 细胞系中的 MAPK 信号传导，但不降低非 S2 细胞系中的 MAPK 信号传导。所有细胞系均表达FGFR1和FGFR2，但仅S2细胞系表达FGFR3和FGFR4。 FGFR4 siRNA 使所有五种 S2 细胞系的增殖降低了 44% 或更多（每种细胞系 p<0.05），比通过 siRNA 转染敲低 FGFR1-3 所观察到的降低幅度显着更大。 FGFR4 敲低降低了 S2 细胞系中的 MAPK 信号传导，但敲低 FGFR1-3 几乎没有影响。总之，HCC 的 S2 分子亚类对 FGFR 抑制敏感。 FGFR4-MAPK 信号传导在驱动 HCC 分子亚类增殖中发挥着重要作用。该分类系统可能有助于识别最有可能从抑制该途径中受益的患者。
A recent gene expression classification of hepatocellular carcinoma (HCC) includes a poor survival subclass termed S2 representing about one third of all HCC in clinical series. S2 cells express E-cadherin, and c-myc and secrete AFP. As the expression of fibroblast growth factor receptors (FGFRs) differs between S2 and non-S2 HCC, this study investigated whether molecular subclasses of HCC predict sensitivity to FGFR inhibition. S2 cell lines were significantly more sensitive (p<0.001) to the FGFR inhibitors BGJ398 and AZD4547. BGJ398 decreased MAPK signaling in S2 but not in non-S2 cell lines. All cell lines expressed FGFR1 and FGFR2, but only S2 cell lines expressed FGFR3 and FGFR4. FGFR4 siRNA decreased proliferation by 44% or more in all five S2 cell lines (p<0.05 for each cell line), a significantly greater decrease than seen with knockdown of FGFR1-3 with siRNA transfection. FGFR4 knockdown decreased MAPK signaling in S2 cell lines, but little effect was seen with knockdown of FGFR1-3. In conclusion, the S2 molecular subclass of HCC is sensitive to FGFR inhibition. FGFR4-MAPK signaling plays an important role in driving proliferation of a molecular subclass of HCC. This classification system may help identify those patients who are most likely to benefit from inhibition of this pathway.