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

• Published in: Molecular cancer Vol. 11; no. 1; p. 14
• Main Authors: Poh, Weijie, Wong, Winnie, Ong, Huimin, Aung, Myat Oo, Lim, Seng Gee, Chua, Boon Tin, Ho, Han Kiat
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 23-03-2012; BioMed Central; BMC
• Subjects: Cancer; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; Cell Proliferation; FGFR4; Glucuronidase - genetics; Glucuronidase - metabolism; Hep G2 Cells; Hepatocellular carcinoma; Humans; Immunoblotting; Kinases; KLB; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver stemness; Proteins; Real-Time Polymerase Chain Reaction; Receptor, Fibroblast Growth Factor, Type 4 - genetics; Receptor, Fibroblast Growth Factor, Type 4 - metabolism; RNA, Small Interfering; Rodents; Tumors
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-11-14

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.