Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma.
Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma.
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DOI：
10.1186/1476-4598-11-14
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发表时间：
2012-03-23
期刊：
影响因子：
37.3
通讯作者：
Ho HK
中科院分区：
文献类型：
--
作者：
Poh W;Wong W;Ong H;Aung MO;Lim SG;Chua BT;Ho HK
我们先前已经证实了成纤维细胞生长因子受体4（FGFR 4）在肝细胞癌（HCC）中的过表达。然而，导致HCC中FGFR4信号传导增强的其他分子机制仍未得到充分研究。在这里，我们研究了其共受体klotho-β（KLB）在HCC进展中驱动FGFR 4活性升高的机制作用。定量实时PCR分析发现，相对于匹配的非肿瘤组织，HCC肿瘤中KLB基因表达频繁升高，其中超过两倍的增加与患者中多种肿瘤的发展相关。Huh7细胞中的KLB沉默降低细胞增殖并抑制FGFR 4下游信号传导。虽然KLB-FGFR4信号传导的瞬时抑制降低了甲胎蛋白（AFP）（HCC诊断标志物）的蛋白质表达，但延长的抑制富集了表现出增加的肝干细胞的抗性HCC细胞。HCC组织中KLB表达升高进一步证实了FGFR4信号传导增加在HCC进展中的致癌作用，并代表了一种新的生物标志物，可用于鉴定其他适合抗FGFR4治疗的患者。KLB的限制性组织表达谱，连同KLB沉默观察到的抗增殖作用，也使其有资格作为HCC患者的特异性和有效的治疗靶点。响应于延长的KLB-FGFR4抑制的肝干细胞样群体的富集需要进一步研究以靶向耐药性的发展。
We had previously demonstrated overexpression of fibroblast growth factor receptor-4 (FGFR4) in hepatocellular carcinoma (HCC). However, additional molecular mechanisms resulting in amplified FGFR4 signaling in HCC remain under-studied. Here, we studied the mechanistic role of its co-receptor klotho-beta (KLB) in driving elevated FGFR4 activity in HCC progression. Quantitative real-time PCR analysis identified frequent elevation of KLB gene expression in HCC tumors relative to matched non-tumor tissue, with a more than two-fold increase correlating with development of multiple tumors in patients. KLB-silencing in Huh7 cells decreased cell proliferation and suppressed FGFR4 downstream signaling. While transient repression of KLB-FGFR4 signaling decreased protein expression of alpha-fetoprotein (AFP), a HCC diagnostic marker, prolonged inhibition enriched for resistant HCC cells exhibiting increased liver stemness. Elevated KLB expression in HCC tissues provides further credence to the oncogenic role of increased FGFR4 signaling in HCC progression and represents a novel biomarker to identify additional patients amenable to anti-FGFR4 therapy. The restricted tissue expression profile of KLB, together with the anti-proliferative effect observed with KLB-silencing, also qualifies it as a specific and potent therapeutic target for HCC patients. The enrichment of a liver stem cell-like population in response to extended KLB-FGFR4 repression necessitates further investigation to target the development of drug resistance.
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DOI：
10.1073/pnas.0701600104
发表时间：
2007-05-01
影响因子：
11.1
作者：
Ogawa, Yasushi;Kurosu, Hiroshi;Kuro-o, Makoto
通讯作者：
Kuro-o, Makoto
影响因子：
13.5
作者：
Llovet, Josep M.;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
29.4
作者：
Llovet, Josep M.;Chen, Yingbei;Friedman, Scott L.
通讯作者：
Friedman, Scott L.
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
14.5
作者：
Abelev, GI;Eraiser, TL
通讯作者：
Eraiser, TL