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

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

Molecular Cancer

10.1186/1476-4598-11-14

http://www.molecular-cancer.com/content/11/1/14

Weijie Poh, Winnie Wong, Huimin Ong, Myat Oo Aung, Seng Gee Lim, Boon Tin Chua, Han Kiat Ho

23 March 2012

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.

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

http://creativecommons.org/licenses/by/3.0/

https://oar.a-star.edu.sg/communities-collections/articles/11816

1476-4598

Institute of Medical Biology