Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice, its involvement in human hepatocellular carcinoma (HCC) has not been well investigated. FGF19, a member of the FGF family, has unique specificity for its receptor FGFR4. This study aimed to clarify the involvement of FGF19 in the development of HCC.</p> <p>Methods</p> <p>We investigated human FGF19 and FGFR4 expression in 40 hepatocellular carcinoma specimens using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. Moreover, we examined the expression and the distribution of FGF19 and FGFR4 in 5 hepatocellular carcinoma cell lines (HepG2, HuH7, HLE, HLF, and JHH7) using RT-PCR and immunohistochemistry. To test the role of the FGF19/FGFR4 system in tumor progression, we used recombinant FGF19 protein and small interfering RNA (siRNA) of <it>FGF19 </it>and <it>FGFR4 </it>to regulate their concentrations.</p> <p>Results</p> <p>We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (<it>P </it>< 0.05). Univariate and multivariate analyses revealed that the tumor <it>FGF19 </it>mRNA expression was an independent prognostic factor for overall and disease-free survival. Moreover, we found that the FGF19 recombinant protein could increase the proliferation (<it>P </it>< 0.01, <it>n </it>= 12) and invasion (<it>P </it>< 0.01, <it>n </it>= 6) capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (<it>P </it>< 0.01, <it>n </it>= 12). Inversely, decreasing <it>FGF19 </it>and <it>FGFR4 </it>expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (<it>P </it>< 0.01, <it>n </it>= 12). The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (<it>P </it>< 0.01, <it>n </it>= 29).</p> <p>Conclusions</p> <p>FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.</p

Flowering response of pearl millet to water stress during panicle development.

In pearl millet, severe water deficit during the period of panicle development delays flowering. The flowering response of both main shoot and tillers to water stress during panicle development was investigated using four hybrids. Panicle initiation of all tillers occurred in the three early genotypes despite water stress. In the late genotype, however, panicle initiation of tillers occurred only after the release of stress. The delay in flowering due to water stress was more pronounced in the tillers than in the main shoot. However, the proportion of tillers producing an inflorescence was increased by water stress. Grain yield losses on the main shoot by water stress were compensated by an increase in tiller grain yields. Delay in flowering and buffering by tillers provide an important adaptive mechanism to overcome a period of drought stress prior to flowering

Targeting FGFR4 Inhibits Hepatocellular Carcinoma in Preclinical Mouse Models

The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4–FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1). LD1 inhibited: 1) FGF1 and FGF19 binding to FGFR4, 2) FGFR4–mediated signaling, colony formation, and proliferation in vitro, and 3) tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease