Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth receptor-4 signaling in hepatocellular carcinoma

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Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth receptor-4 signaling in hepatocellular carcinoma
Title:
Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth receptor-4 signaling in hepatocellular carcinoma
Journal Title:
Molecular Cancer
Keywords:
Publication Date:
23 March 2012
Citation:
Poh et al.: Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma. Molecular Cancer 2012 11:14.
Abstract:
Background: 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. Results: 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 alphafetoprotein (AFP), a HCC diagnostic marker, prolonged inhibition enriched for resistant HCC cells exhibiting increased liver stemness. Conclusions: 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. Keywords: FGFR4, Hepatocellular carcinoma, KLB, Liver stemness
License type:
http://creativecommons.org/licenses/by/3.0/
Funding Info:
Description:
ISSN:
1476-4598
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