Abstract
BackgroundWe 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.ResultsQuantitative 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.ConclusionsElevated 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.
Highlights
With approximately 680,000 deaths in 2008, hepatocellular carcinoma (HCC) ranks third worldwide in cancerrelated mortalities [1]
We found no significant correlation of KLB gene expression with fibroblast growth factor receptor-4 (FGFR4) previously determined from the same patient population [12] (Spearman rank correlation: r = 0.032; P = 0.812)
To investigate the opposing effects that inhibiting FGFR4 signaling has on AFP protein and transcript levels, we considered the expression of AFP in hepatic progenitor cells and its role in development of stem-like features in HCC [20,21]
Summary
With approximately 680,000 deaths in 2008, hepatocellular carcinoma (HCC) ranks third worldwide in cancerrelated mortalities [1]. The majority of HCC patients present at advanced stages where curative surgical treatments are not applicable and face median survival of less than a year [2]. Traditional systemic chemotherapies have produced no significant survival benefit in advanced HCC patients [3]. The approval of sorafenib, a multi-targeted tyrosine kinase inhibitor, for the treatment of advanced-stage HCC patients in 2007 highlights the potential of such therapies in treating this complex neoplasia [4]. We had previously demonstrated overexpression of fibroblast growth factor receptor-4 (FGFR4) in hepatocellular carcinoma (HCC). Additional molecular mechanisms resulting in amplified FGFR4 signaling in HCC remain under-studied. We studied the mechanistic role of its co-receptor klotho-beta (KLB) in driving elevated FGFR4 activity in HCC progression
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