Huang Xinqiang, Yu Chundong, Jin Chengliu, Yang Chaofeng, Xie Rui, Cao Dongdong, Wang Fen, McKeehan Wallace L
Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030, USA.
Mol Carcinog. 2006 Dec;45(12):934-42. doi: 10.1002/mc.20241.
Inappropriate fibroblast growth factor (FGF) signaling is involved in most tissue-specific pathologies including cancer. Previously we showed that inappropriate expression and chronic activity of FGF receptor (FGFR) 1 in hepatocytes accelerated diethylnitrosamine (DEN)-initiated hepatocarcinogenesis. Here we showed that although widely expressed FGF1 and FGF2 are frequently upregulated in hepatocellular carcinoma (HCC), germline deletion of both FGF1 and FGF2 had no effect on DEN-initiated hepatocarcinogenesis. Thus overexpression of FGF1 or FGF2 may be a consequence rather than contributor to hepatoma progression. FGF21 is the first of 22 homologues whose expression has been reported to be preferentially in the liver. We showed that similar to FGF1 and FGF2, FGF21 mRNA was upregulated in neoplastic and regenerating liver after partial hepatectomy (PH) and CCl4 administration. In situ hybridization analysis confirmed that in contrast to FGF1 and FGF2, expression of FGF21 mRNA was limited to hepatocytes. Forced overexpression of FGF21 in hepatocytes by gene targeting had no apparent impact on normal liver development and compensatory response to injury. Surprisingly, overexpression of FGF21 delayed the appearance of DEN-induced liver tumors. At 8 and 10 mo, only 10% and 30% of transgenic mice, respectively, developed adenomas compared to 50% (all adenomas) and 80% (60% adenoma/20% HCC) in the wild-type (WT) mice. However, the incidence and burden of HCC at 10 mo and later was equal in the FGF21 transgenic and WT mice. We propose that FGF21 may delay development of adenomas through activation of resident hepatocyte FGFR4 at early times, but counteracts the delay by acceleration of progression to HCC through interaction with ectopic FGFR1 once it appears in hepatoma cells. This indicates a dual function of FGF21 that may reflect changes in FGFR isotype during progression of differentiated hepatoma cells.
不适当的成纤维细胞生长因子（FGF）信号传导参与了包括癌症在内的大多数组织特异性病理过程。此前我们发现，肝细胞中FGF受体（FGFR）1的不适当表达和慢性激活加速了二乙基亚硝胺（DEN）引发的肝癌发生。在此我们发现，尽管广泛表达的FGF1和FGF2在肝细胞癌（HCC）中经常上调，但FGF1和FGF2的种系缺失对DEN引发的肝癌发生没有影响。因此，FGF1或FGF2的过表达可能是肝癌进展的结果而非促成因素。FGF21是已报道其表达优先在肝脏中的22个同源物中的第一个。我们发现，与FGF1和FGF2相似，FGF21 mRNA在部分肝切除（PH）和给予四氯化碳后肿瘤性和再生性肝脏中上调。原位杂交分析证实，与FGF1和FGF2不同，FGF21 mRNA的表达仅限于肝细胞。通过基因靶向在肝细胞中强制过表达FGF21对正常肝脏发育和对损伤的代偿反应没有明显影响。令人惊讶的是，FGF21的过表达延迟了DEN诱导的肝肿瘤的出现。在8个月和10个月时，分别只有10%和30%的转基因小鼠发生腺瘤，而野生型（WT）小鼠中这一比例分别为50%（均为腺瘤）和80%（60%腺瘤/20% HCC）。然而，10个月及以后FGF21转基因小鼠和WT小鼠中HCC的发生率和负担是相等的。我们提出，FGF21可能在早期通过激活驻留肝细胞FGFR4来延迟腺瘤的发展，但一旦其在肝癌细胞中出现，就会通过与异位FGFR1相互作用加速向HCC的进展来抵消这种延迟。这表明FGF21的双重功能可能反映了分化型肝癌细胞进展过程中FGFR亚型的变化。
