title: Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma.
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 alpha-fetoprotein (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.
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Weijie
authors.initials: W
authors.lastname: Poh
authors.forename: Winnie
authors.initials: W
authors.lastname: Wong
authors.forename: Huimin
authors.initials: H
authors.lastname: Ong
authors.forename: Myat Oo
authors.initials: MO
authors.lastname: Aung
authors.forename: Seng Gee
authors.initials: SG
authors.lastname: Lim
authors.forename: Boon Tin
authors.initials: BT
authors.lastname: Chua
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D000090265:Klotho Proteins; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D051499:Receptor, Fibroblast Growth Factor, Type 4; D005966:Glucuronidase; D000090265:Klotho Proteins