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Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma.

Liu X, Chi X, Gong Q, Gao L, Niu Y, Chi X, Cheng M, Si Y, Wang M, Zhong J, Niu J, Yang W - PLoS ONE (2015)

Bottom Line: Hepatocellular carcinoma (HCC) and liver cirrhosis are associated with high mortality worldwide.Serum GDF15 levels did not significantly differ between the high-AFP and low-AFP groups.GDF15 protein expression in HCC was significantly higher than that in the corresponding adjacent paracarcinomatous tissue and normal liver.

View Article: PubMed Central - PubMed

Affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

ABSTRACT
Hepatocellular carcinoma (HCC) and liver cirrhosis are associated with high mortality worldwide. Currently, alpha-fetoprotein (AFP) is used as a standard serum marker for the detection of HCC, but its sensitivity and specificity are unsatisfactory, and optimal diagnostic markers for cirrhosis are lacking. We previously reported that growth differentiation factor 15 (GDF15) was significantly induced in HCV-infected hepatocytes. This study aimed to investigate GDF15 expression and its correlation with hepatitis virus-related liver diseases. A total of 412 patients with various liver diseases were studied. Healthy and Mycobacterium tuberculosis-infected subjects were included as controls. Serum and tissue GDF15 levels were measured. Serum GDF15 levels were significantly increased in patients with HCC (6.66±0.67 ng/mL, p<0.0001) and cirrhosis (6.51±1.47 ng/mL, p<0.0001) compared with healthy controls (0.31±0.01 ng/mL), though the GDF15 levels in HBV and HCV carriers were moderately elevated (1.34±0.19 ng/mL and 2.13±0.53 ng/mL, respectively). Compared with HBV or HCV carriers, GDF15 had a sensitivity of 63.1% and a specificity of 86.6% at the optimal cut-off point of 2.463 ng/mL in patients with liver cirrhosis or HCC. In HCC patients, the area under the receiver operating curve was 0.84 for GDF15 and 0.76 for AFP, but 0.91 for the combined GDF15 and AFP. Serum GDF15 levels did not significantly differ between the high-AFP and low-AFP groups. GDF15 protein expression in HCC was significantly higher than that in the corresponding adjacent paracarcinomatous tissue and normal liver. Using a combination of GDF15 and AFP will improve the sensitivity and specificity of HCC diagnosis. Further research and the clinical implementation of serum GDF15 measurement as a biomarker for HCC and cirrhosis are recommended.

No MeSH data available.


Related in: MedlinePlus

GDF15 protein expression in HCC, adjacent paracarcinomatous liver (PCL) and normal liver (NL) tissues.(A) Normal liver and HCC with different grades of malignancy were prepared for IHC with anti-GDF15 or isotype antibodies, respectively. Representative results are shown. (B) GDF15 protein expression in HCC (T) and PCL (P) lysates was determined by Western blotting. An antibody against β-Actin was used as a loading control. (C) Quantification of Western Blot described in Fig 4B with Image J.
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pone.0127518.g005: GDF15 protein expression in HCC, adjacent paracarcinomatous liver (PCL) and normal liver (NL) tissues.(A) Normal liver and HCC with different grades of malignancy were prepared for IHC with anti-GDF15 or isotype antibodies, respectively. Representative results are shown. (B) GDF15 protein expression in HCC (T) and PCL (P) lysates was determined by Western blotting. An antibody against β-Actin was used as a loading control. (C) Quantification of Western Blot described in Fig 4B with Image J.

Mentions: In this study, we showed evidence that the serum level of GDF15 was significantly elevated in the patients with HCC and cirrhosis. However, the sources of this up-regulated GDF15 were still unclear. It may be produced from either malignant tissues or systematic stress. Therefore, to identify whether the expression of GDF15 was also increased in HCC, IHC and Western blotting were performed on normal and malignant tissues. Twenty HCC biopsy tissues, 10 HBV-positive and 10 HCV-positive, were used for IHC with an antibody against GDF15. Normal liver tissues were used as control. Grading of HCC was based on the tumor differentiation according to Edmondson and Steiner system. Basically, performance of the antibody for IHC was not satisfactory very well. Only 5 of 20 (25%) samples were positively stained at various intensities. The representative data were shown in Fig 5A. Expression of GDF15 was increased in relatively moderate (HCC-II) or severe (HCC-III) malignant HCCs, but not in the normal liver (Fig 5A). To further confirm the IHC data, Western blotting was performed, and 12 pairs of HCC (T) and PCL (P) were prepared from the same resection specimen to eliminate the effects of differences in the genetic background. GDF15 protein levels were consistently increased in 9 of 12 (75%) HCC samples (Fig 5B). In addition, we did quantification of GDF15 levels of Western blotting films by analyzing the band density with image J software and the results were shown in Fig 5C. These results suggest that the elevated serum GDF15 level may result from GDF15 production by HCC tissues.


Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma.

Liu X, Chi X, Gong Q, Gao L, Niu Y, Chi X, Cheng M, Si Y, Wang M, Zhong J, Niu J, Yang W - PLoS ONE (2015)

GDF15 protein expression in HCC, adjacent paracarcinomatous liver (PCL) and normal liver (NL) tissues.(A) Normal liver and HCC with different grades of malignancy were prepared for IHC with anti-GDF15 or isotype antibodies, respectively. Representative results are shown. (B) GDF15 protein expression in HCC (T) and PCL (P) lysates was determined by Western blotting. An antibody against β-Actin was used as a loading control. (C) Quantification of Western Blot described in Fig 4B with Image J.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440744&req=5

pone.0127518.g005: GDF15 protein expression in HCC, adjacent paracarcinomatous liver (PCL) and normal liver (NL) tissues.(A) Normal liver and HCC with different grades of malignancy were prepared for IHC with anti-GDF15 or isotype antibodies, respectively. Representative results are shown. (B) GDF15 protein expression in HCC (T) and PCL (P) lysates was determined by Western blotting. An antibody against β-Actin was used as a loading control. (C) Quantification of Western Blot described in Fig 4B with Image J.
Mentions: In this study, we showed evidence that the serum level of GDF15 was significantly elevated in the patients with HCC and cirrhosis. However, the sources of this up-regulated GDF15 were still unclear. It may be produced from either malignant tissues or systematic stress. Therefore, to identify whether the expression of GDF15 was also increased in HCC, IHC and Western blotting were performed on normal and malignant tissues. Twenty HCC biopsy tissues, 10 HBV-positive and 10 HCV-positive, were used for IHC with an antibody against GDF15. Normal liver tissues were used as control. Grading of HCC was based on the tumor differentiation according to Edmondson and Steiner system. Basically, performance of the antibody for IHC was not satisfactory very well. Only 5 of 20 (25%) samples were positively stained at various intensities. The representative data were shown in Fig 5A. Expression of GDF15 was increased in relatively moderate (HCC-II) or severe (HCC-III) malignant HCCs, but not in the normal liver (Fig 5A). To further confirm the IHC data, Western blotting was performed, and 12 pairs of HCC (T) and PCL (P) were prepared from the same resection specimen to eliminate the effects of differences in the genetic background. GDF15 protein levels were consistently increased in 9 of 12 (75%) HCC samples (Fig 5B). In addition, we did quantification of GDF15 levels of Western blotting films by analyzing the band density with image J software and the results were shown in Fig 5C. These results suggest that the elevated serum GDF15 level may result from GDF15 production by HCC tissues.

Bottom Line: Hepatocellular carcinoma (HCC) and liver cirrhosis are associated with high mortality worldwide.Serum GDF15 levels did not significantly differ between the high-AFP and low-AFP groups.GDF15 protein expression in HCC was significantly higher than that in the corresponding adjacent paracarcinomatous tissue and normal liver.

View Article: PubMed Central - PubMed

Affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

ABSTRACT
Hepatocellular carcinoma (HCC) and liver cirrhosis are associated with high mortality worldwide. Currently, alpha-fetoprotein (AFP) is used as a standard serum marker for the detection of HCC, but its sensitivity and specificity are unsatisfactory, and optimal diagnostic markers for cirrhosis are lacking. We previously reported that growth differentiation factor 15 (GDF15) was significantly induced in HCV-infected hepatocytes. This study aimed to investigate GDF15 expression and its correlation with hepatitis virus-related liver diseases. A total of 412 patients with various liver diseases were studied. Healthy and Mycobacterium tuberculosis-infected subjects were included as controls. Serum and tissue GDF15 levels were measured. Serum GDF15 levels were significantly increased in patients with HCC (6.66±0.67 ng/mL, p<0.0001) and cirrhosis (6.51±1.47 ng/mL, p<0.0001) compared with healthy controls (0.31±0.01 ng/mL), though the GDF15 levels in HBV and HCV carriers were moderately elevated (1.34±0.19 ng/mL and 2.13±0.53 ng/mL, respectively). Compared with HBV or HCV carriers, GDF15 had a sensitivity of 63.1% and a specificity of 86.6% at the optimal cut-off point of 2.463 ng/mL in patients with liver cirrhosis or HCC. In HCC patients, the area under the receiver operating curve was 0.84 for GDF15 and 0.76 for AFP, but 0.91 for the combined GDF15 and AFP. Serum GDF15 levels did not significantly differ between the high-AFP and low-AFP groups. GDF15 protein expression in HCC was significantly higher than that in the corresponding adjacent paracarcinomatous tissue and normal liver. Using a combination of GDF15 and AFP will improve the sensitivity and specificity of HCC diagnosis. Further research and the clinical implementation of serum GDF15 measurement as a biomarker for HCC and cirrhosis are recommended.

No MeSH data available.


Related in: MedlinePlus