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

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.With approximately 680,000 deaths in 2008, hepatocellular carcinoma (HCC) ranks third worldwide in cancer-related 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]. Moreover, traditional systemic chemotherapies have produced no significant survival benefit in advanced HCC patients [3]. Consequently, novel therapies for unresectable HCC are urgently needed to address this grim prognosis.Recently, there has been increasing interest in developing molecular-targeted therapies that can discriminate between cancer cells and their non-neoplastic counterparts by targeting proteins overexpressed in tumors. The approval of sorafenib, a multi-targeted tyrosine kinase inhibitor, for the treatment of advance