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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Molecular Cancer 1/2012

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

Zeitschrift:
Molecular Cancer > Ausgabe 1/2012
Autoren:
Weijie Poh, Winnie Wong, Huimin Ong, Myat Oo Aung, Seng Gee Lim, Boon Tin Chua, Han Kiat Ho
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1476-4598-11-14) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

WP carried out the molecular genetic studies and drafted the manuscript. WW and HO assisted with in vitro experiments and data analysis. MO and SL processed the patient liver samples and collected clinical information. HH and BC conceived of the study, participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

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.
Zusatzmaterial
Additional file 1: Table S1 Clinicopathological parameters of HCC patients. (DOC 67 KB)
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Additional file 3: Figure S2 Upregulation of CYP7A1 mRNA in KLB-silenced Huh7 cells. 48 h post siRNA transfection in Huh7 cells, CYP7A1 gene expression was measured by qRT-PCR and normalized to GAPDH. Results are indicated with SD converted to fold changes as error bars. (DOC 87 KB)
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Additional file 4: Figure S3 Decreased KLB and FGFR4 expression with RNAi silencing. 48 h post siRNA silencing of (A) KLB and (B) FGFR4 in Huh7 cells, gene expression of KLB and FGFR4 were measured by qRT-PCR and normalized to GAPDH. Results are indicated with SD converted to fold changes as error bars. (DOC 55 KB)
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Authors’ original file for figure 1
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Literatur
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