Up-Regulation of the Fibroblast Growth Factor 8 Subfamily in Human Hepatocellular Carcinoma for Cell Survival and Neoangiogenesis
Up-Regulation of the Fibroblast Growth Factor 8 Subfamily in Human Hepatocellular Carcinoma for Cell Survival and Neoangiogenesis
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DOI：
10.1002/hep.24099
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发表时间：
2011-03-01
期刊：
影响因子：
13.5
通讯作者：
Grasl-Kraupp, Bettina
中科院分区：
文献类型：
--
作者：
Gauglhofer, Christine;Sagmeister, Sandra;Grasl-Kraupp, Bettina
成纤维细胞生长因子（FGF）及其高亲和力受体[成纤维细胞生长因子受体（FGFR）]有助于几种非肝癌实体的自分泌和旁分泌生长刺激。在这里，我们报告说，至少有一个成员的FGF 8亚家族（FGF 8，FGF 17，和FGF 18）是上调，在59%的34人肝细胞癌（HCC）样本，我们调查。在绝大多数HCC病例中，相应受体（FGFR 2、FGFR 3和FGFR 4）的水平也升高。总体而言，82%的HCC病例显示至少一种FGF和/或FGFR过表达。通过模拟血液供应不足来研究去调节的FGF/FGFR系统的功能影响。当HCC-1.2、HepG 2或Hep 3B细胞经历血清戒断或缺氧模拟药物甲磺酸去铁胺时，FGF 8亚家族成员的表达显著增加。在血清饥饿的细胞中，细胞凋亡的发生率升高，而加入FGF 8，FGF 17，或FGF 18损害细胞凋亡，这与细胞外信号调节激酶1/2和核糖体蛋白S6的磷酸化有关。相反，通过小干扰RNA（siRNA）下调FGF 18显著降低肝癌细胞的活力。靶向FGF 18的siRNA也损害了细胞在低细胞密度或软琼脂中形成克隆的潜力。在肿瘤微环境方面，FGF 17和FGF 18刺激HCC来源的肌成纤维细胞的生长，并且FGF 8、FGF 17和FGF 18诱导肝内皮细胞的增殖和管形成。结论：FGF 8、FGF 17和FGF 18参与HCC中的自分泌和旁分泌信号传导，并增强肿瘤细胞在应激条件、恶性行为和新血管生成下的存活。因此，FGF 8亚家族支持肝细胞恶性肿瘤的发展和进展。（肝脏学2011;53：854-864）
Fibroblast growth factors (FGFs) and their high-affinity receptors [fibroblast growth factor receptors (FGFRs)] contribute to autocrine and paracrine growth stimulation in several non-liver cancer entities. Here we report that at least one member of the FGF8 subfamily (FGF8, FGF17, and FGF18) was up-regulated in 59% of 34 human hepatocellular carcinoma (HCC) samples that we investigated. The levels of the corresponding receptors (FGFR2, FGFR3, and FGFR4) were also elevated in the great majority of the HCC cases. Overall, 82% of the HCC cases showed overexpression of at least one FGF and/or FGFR. The functional implications of the deregulated FGF/FGFR system were investigated by the simulation of an insufficient blood supply. When HCC-1.2, HepG2, or Hep3B cells were subjected to serum withdrawal or the hypoxia-mimetic drug deferoxamine mesylate, the expression of FGF8 subfamily members increased dramatically. In the serum-starved cells, the incidence of apoptosis was elevated, whereas the addition of FGF8, FGF17, or FGF18 impaired apoptosis, which was associated with phosphorylation of extracellular signal-regulated kinase 1/2 and ribosomal protein S6. In contrast, down-modulation of FGF18 by small interfering RNA (siRNA) significantly reduced the viability of the hepatocarcinoma cells. siRNA targeting FGF18 also impaired the cells' potential to form clones at a low cell density or in soft agar. With respect to the tumor microenvironment, FGF17 and FGF18 stimulated the growth of HCC-derived myofibroblasts, and FGF8, FGF17, and FGF18 induced the proliferation and tube formation of hepatic endothelial cells. Conclusion: FGF8, FGF17, and FGF18 are involved in autocrine and paracrine signaling in HCC and enhance the survival of tumor cells under stress conditions, malignant behavior, and neoangiogenesis. Thus, the FGF8 subfamily supports the development and progression of hepatocellular malignancy. (HEPATOLOGY 2011;53:854-864)