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

Miura S, Mitsuhashi N, Shimizu H, Kimura F, Yoshidome H, Otsuka M, Kato A, Shida T, Okamura D, Miyazaki M - BMC Cancer (2012)

Bottom Line: We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P < 0.05).Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P < 0.01, n = 12).The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P < 0.01, n = 29).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-0856, Japan.

ABSTRACT

Background: 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.

Methods: 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 FGF19 and FGFR4 to regulate their concentrations.

Results: We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P < 0.05). Univariate and multivariate analyses revealed that the tumor FGF19 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 (P < 0.01, n = 12) and invasion (P < 0.01, n = 6) capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (P < 0.01, n = 12). Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P < 0.01, n = 12). The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P < 0.01, n = 29).

Conclusions: FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.

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Real-time quantitative RT-PCR analysis, immunohistochemical staining of representative specimens from HCC patients of 40 HCC samples. (A): Ratio of average FGF19/GAPDH expression in HCC (T) compared with corresponding noncancerous hepatic tissues (N). The average FGF19/GAPDH level in HCCs. (B): The average FGFR4/GAPDH level in HCCs. (C): Immunohistochemistry using anti-FGF19 monoclonal antibodies; HCC tissue (lower) and noncancerous hepatocytes (upper). (D): Immunohistochemistry using anti-FGFR4 monoclonal antibodies; HCC tissue (lower) and noncancerous tissue (upper). (Original magnifications: ×40 (upper); ×40 (lower)). RT-PCR; reverse transcription polymerase chain reaction; HCC, hepatocellular carcinoma.
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Figure 1: Real-time quantitative RT-PCR analysis, immunohistochemical staining of representative specimens from HCC patients of 40 HCC samples. (A): Ratio of average FGF19/GAPDH expression in HCC (T) compared with corresponding noncancerous hepatic tissues (N). The average FGF19/GAPDH level in HCCs. (B): The average FGFR4/GAPDH level in HCCs. (C): Immunohistochemistry using anti-FGF19 monoclonal antibodies; HCC tissue (lower) and noncancerous hepatocytes (upper). (D): Immunohistochemistry using anti-FGFR4 monoclonal antibodies; HCC tissue (lower) and noncancerous tissue (upper). (Original magnifications: ×40 (upper); ×40 (lower)). RT-PCR; reverse transcription polymerase chain reaction; HCC, hepatocellular carcinoma.

Mentions: We examined 40 HCC samples and corresponding noncancerous hepatic tissues for FGF19 mRNA expression using real-time quantitative RT-PCR. The average FGF19/GAPDH level in HCCs was significantly higher than that in noncancerous tissues. (Figure 1A; P = 0.015), whereas FGFR4 was not significantly overexpressed in HCCs compared to noncancerous tissues (Figure 1B, P = 0.055). An immunohistochemical study using anti-FGF19 monoclonal antibodies was performed to determine whether FGF19 protein was expressed in HCC specimens. FGF19 protein was detectable in both cancer and noncancerous tissues Figure 1C). FGF19 staining was observed in the cytoplasm of tumor cells and noncancerous hepatocytes, and tended to be greater in the tumor cells. FGFR4 staining was not significantly greater in the membranes of tumor cells as compared to those of cells from corresponding noncancerous tissue (Figure 1D).


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

Miura S, Mitsuhashi N, Shimizu H, Kimura F, Yoshidome H, Otsuka M, Kato A, Shida T, Okamura D, Miyazaki M - BMC Cancer (2012)

Real-time quantitative RT-PCR analysis, immunohistochemical staining of representative specimens from HCC patients of 40 HCC samples. (A): Ratio of average FGF19/GAPDH expression in HCC (T) compared with corresponding noncancerous hepatic tissues (N). The average FGF19/GAPDH level in HCCs. (B): The average FGFR4/GAPDH level in HCCs. (C): Immunohistochemistry using anti-FGF19 monoclonal antibodies; HCC tissue (lower) and noncancerous hepatocytes (upper). (D): Immunohistochemistry using anti-FGFR4 monoclonal antibodies; HCC tissue (lower) and noncancerous tissue (upper). (Original magnifications: ×40 (upper); ×40 (lower)). RT-PCR; reverse transcription polymerase chain reaction; HCC, hepatocellular carcinoma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3293719&req=5

Figure 1: Real-time quantitative RT-PCR analysis, immunohistochemical staining of representative specimens from HCC patients of 40 HCC samples. (A): Ratio of average FGF19/GAPDH expression in HCC (T) compared with corresponding noncancerous hepatic tissues (N). The average FGF19/GAPDH level in HCCs. (B): The average FGFR4/GAPDH level in HCCs. (C): Immunohistochemistry using anti-FGF19 monoclonal antibodies; HCC tissue (lower) and noncancerous hepatocytes (upper). (D): Immunohistochemistry using anti-FGFR4 monoclonal antibodies; HCC tissue (lower) and noncancerous tissue (upper). (Original magnifications: ×40 (upper); ×40 (lower)). RT-PCR; reverse transcription polymerase chain reaction; HCC, hepatocellular carcinoma.
Mentions: We examined 40 HCC samples and corresponding noncancerous hepatic tissues for FGF19 mRNA expression using real-time quantitative RT-PCR. The average FGF19/GAPDH level in HCCs was significantly higher than that in noncancerous tissues. (Figure 1A; P = 0.015), whereas FGFR4 was not significantly overexpressed in HCCs compared to noncancerous tissues (Figure 1B, P = 0.055). An immunohistochemical study using anti-FGF19 monoclonal antibodies was performed to determine whether FGF19 protein was expressed in HCC specimens. FGF19 protein was detectable in both cancer and noncancerous tissues Figure 1C). FGF19 staining was observed in the cytoplasm of tumor cells and noncancerous hepatocytes, and tended to be greater in the tumor cells. FGFR4 staining was not significantly greater in the membranes of tumor cells as compared to those of cells from corresponding noncancerous tissue (Figure 1D).

Bottom Line: We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P < 0.05).Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P < 0.01, n = 12).The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P < 0.01, n = 29).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-0856, Japan.

ABSTRACT

Background: 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.

Methods: 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 FGF19 and FGFR4 to regulate their concentrations.

Results: We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P < 0.05). Univariate and multivariate analyses revealed that the tumor FGF19 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 (P < 0.01, n = 12) and invasion (P < 0.01, n = 6) capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (P < 0.01, n = 12). Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P < 0.01, n = 12). The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P < 0.01, n = 29).

Conclusions: FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.

Show MeSH
Related in: MedlinePlus