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Kidney-type glutaminase (GLS1) is a biomarker for pathologic diagnosis and prognosis of hepatocellular carcinoma.

Yu D, Shi X, Meng G, Chen J, Yan C, Jiang Y, Wei J, Ding Y - Oncotarget (2015)

Bottom Line: We found that GLS1 was highly expressed in HCC; whereas, expression of GLS2 was mainly confined to non-tumor hepatocytes.We found that high expression of GLS1 and low expression of GLS2 in HCC correlated with survival time of HCC patients.These findings indicate that GLS1 expression is a sensitive and specific biomarker for pathological diagnosis and prognosis of HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210093, China.

ABSTRACT
The lack of sensitive and specific biomarkers hinders pathological diagnosis and prognosis for hepatocellular carcinoma (HCC). Since glutaminolysis plays a crucial role in carcinogenesis and progression, we sought to determine if the expression of kidney-type and liver-type glutaminases (GLS1 and GLS2) were informative for pathological diagnosis and prognosis of HCC. We compared the expression of GLS1 and GLS2 in a large set of clinical samples including HCC, normal liver, and other liver diseases. We found that GLS1 was highly expressed in HCC; whereas, expression of GLS2 was mainly confined to non-tumor hepatocytes. The sensitivity and specificity of GLS1 for HCC were 96.51% and 75.21%, respectively. A metabolic switch from GLS2 to GLS1 was observed in a series of tissues representing progressive pathologic states mimicking HCC oncogenic transformation, including normal liver, fibrotic liver, dysplasia nodule, and HCC. We found that high expression of GLS1 and low expression of GLS2 in HCC correlated with survival time of HCC patients. Expression of GLS1 and GLS2 were independent indexes for survival time; however, prognosis was predominantly determined by the level of GLS1 expression. These findings indicate that GLS1 expression is a sensitive and specific biomarker for pathological diagnosis and prognosis of HCC.

No MeSH data available.


Related in: MedlinePlus

Expression and biodistribution of GLS1 and GLS2 in hepatocellular carcinoma(A) GLS1 and GLS2 were detected by immunohistochemical staining in 112 tumor tissues (TT) and paired non-tumor tissues (NT) from HCC patients. Representative staining of GLS1 and GLS2, and corresponding hematoxylin and eosin (HE) staining are shown (left panel). Bars = 200 μm. The expression and intensity of total samples were evaluated and classified into three grades: ++ strongly positive, + weakly positive; − negative (right panel). (B) The expression and distribution of GLS1and GLS2 in mesenchymal cells (black arrows) were evaluated by immunohistochemical staining in 60 paired TT and NT from HCC patients comprising a random subset of the 112 paired TT and NT samples from panel A. Representative staining of GLS1 and GLS2, and corresponding HE staining are shown (left panel). The expression and intensity of total specimens were evaluated (right panel). Bars = 100 μm. (C) GLS1 concentration in serum obtained from 9 normal healthy donors (NL) and 10 HCC patients was determined by ELISA. (D) Expression of GLS1 and GLS2 in 98 HCC tumors and paired adjacent non-tumor tissues was determined by quantitative RT-PCR. (E) Enzyme activity of GLS1 in TT and paired NT (n = 4, left panel), and in a non-malignant hepatic cell line (L-O2) and HCC cell lines (Hep3B, 7402, MHCC97-H, HepG2) (right panel); *p < 0.05, **p < 0.01, ***p < 0.001, N.S. not significant.
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Figure 1: Expression and biodistribution of GLS1 and GLS2 in hepatocellular carcinoma(A) GLS1 and GLS2 were detected by immunohistochemical staining in 112 tumor tissues (TT) and paired non-tumor tissues (NT) from HCC patients. Representative staining of GLS1 and GLS2, and corresponding hematoxylin and eosin (HE) staining are shown (left panel). Bars = 200 μm. The expression and intensity of total samples were evaluated and classified into three grades: ++ strongly positive, + weakly positive; − negative (right panel). (B) The expression and distribution of GLS1and GLS2 in mesenchymal cells (black arrows) were evaluated by immunohistochemical staining in 60 paired TT and NT from HCC patients comprising a random subset of the 112 paired TT and NT samples from panel A. Representative staining of GLS1 and GLS2, and corresponding HE staining are shown (left panel). The expression and intensity of total specimens were evaluated (right panel). Bars = 100 μm. (C) GLS1 concentration in serum obtained from 9 normal healthy donors (NL) and 10 HCC patients was determined by ELISA. (D) Expression of GLS1 and GLS2 in 98 HCC tumors and paired adjacent non-tumor tissues was determined by quantitative RT-PCR. (E) Enzyme activity of GLS1 in TT and paired NT (n = 4, left panel), and in a non-malignant hepatic cell line (L-O2) and HCC cell lines (Hep3B, 7402, MHCC97-H, HepG2) (right panel); *p < 0.05, **p < 0.01, ***p < 0.001, N.S. not significant.

Mentions: To investigate the expression and biodistribution of GLS1 and GLS2 in HCC, we performed immunohistochemical staining for GLS1 and GLS2 on the first group of paired tumor tissues (TT) and adjacent none tumor tissues (NT) from HCC patients. In the analysis of 112 cases, strongly positive staining against GLS1 in HCC tumor cells was observed in 83 cases (74.11%), weakly positive staining was found in 23 cases (20.54%), and negative staining was found in 6 cases (5.36%) (Figure 1A). Conversely, among adjacent NT hepatocytes from 110 cases analyzed, negative GLS1 staining was found in 103 cases (93.64%), and weakly positive staining was found in 7 cases (6.36%). These data suggest that GLS1 is highly expressed by HCC cells. We found negative staining for GLS2 in 70 of 112 HCC cases (62.5%), and positive staining in 103 of 111 cases in NT hepatocytes of NT (92.7%) (Figure 1A). Statistically, the expression of GLS1 in TT was significantly higher than in NT, while expression of GLS2 in TT was significantly lower than in NT. Additional immunohistochemical staining of GLS1 and GLS2 in TT and NT at a serial of magnifications is shown in Supplementary Figure 2A and 2B. We analyzed the available clinical information of the cases studied. We found that tumor capsule invaded was the only parameter showing clinical significance associated with differential expression of GLS1 and GLS2 (Supplementary Table 1). We found positive GLS1 staining in some mesenchymal cells in TT and NT. Among stained mesenchymal cells, no differences in expression intensity showed were observed. No GLS2 staining was observed in mesenchymal cells in TT or NT (Figure 1B). To determine if serum levels of GLS1 correlated with GLS1 staining of HCC cells, we analyzed sera from 10 HCC patients from group 1 and 9 healthy volunteers from group 2. GLS1 protein was detected a relative high levels in serum (about 100 ng/ml), but there was no difference between HCC patients and controls (Figure 1C).


Kidney-type glutaminase (GLS1) is a biomarker for pathologic diagnosis and prognosis of hepatocellular carcinoma.

Yu D, Shi X, Meng G, Chen J, Yan C, Jiang Y, Wei J, Ding Y - Oncotarget (2015)

Expression and biodistribution of GLS1 and GLS2 in hepatocellular carcinoma(A) GLS1 and GLS2 were detected by immunohistochemical staining in 112 tumor tissues (TT) and paired non-tumor tissues (NT) from HCC patients. Representative staining of GLS1 and GLS2, and corresponding hematoxylin and eosin (HE) staining are shown (left panel). Bars = 200 μm. The expression and intensity of total samples were evaluated and classified into three grades: ++ strongly positive, + weakly positive; − negative (right panel). (B) The expression and distribution of GLS1and GLS2 in mesenchymal cells (black arrows) were evaluated by immunohistochemical staining in 60 paired TT and NT from HCC patients comprising a random subset of the 112 paired TT and NT samples from panel A. Representative staining of GLS1 and GLS2, and corresponding HE staining are shown (left panel). The expression and intensity of total specimens were evaluated (right panel). Bars = 100 μm. (C) GLS1 concentration in serum obtained from 9 normal healthy donors (NL) and 10 HCC patients was determined by ELISA. (D) Expression of GLS1 and GLS2 in 98 HCC tumors and paired adjacent non-tumor tissues was determined by quantitative RT-PCR. (E) Enzyme activity of GLS1 in TT and paired NT (n = 4, left panel), and in a non-malignant hepatic cell line (L-O2) and HCC cell lines (Hep3B, 7402, MHCC97-H, HepG2) (right panel); *p < 0.05, **p < 0.01, ***p < 0.001, N.S. not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480704&req=5

Figure 1: Expression and biodistribution of GLS1 and GLS2 in hepatocellular carcinoma(A) GLS1 and GLS2 were detected by immunohistochemical staining in 112 tumor tissues (TT) and paired non-tumor tissues (NT) from HCC patients. Representative staining of GLS1 and GLS2, and corresponding hematoxylin and eosin (HE) staining are shown (left panel). Bars = 200 μm. The expression and intensity of total samples were evaluated and classified into three grades: ++ strongly positive, + weakly positive; − negative (right panel). (B) The expression and distribution of GLS1and GLS2 in mesenchymal cells (black arrows) were evaluated by immunohistochemical staining in 60 paired TT and NT from HCC patients comprising a random subset of the 112 paired TT and NT samples from panel A. Representative staining of GLS1 and GLS2, and corresponding HE staining are shown (left panel). The expression and intensity of total specimens were evaluated (right panel). Bars = 100 μm. (C) GLS1 concentration in serum obtained from 9 normal healthy donors (NL) and 10 HCC patients was determined by ELISA. (D) Expression of GLS1 and GLS2 in 98 HCC tumors and paired adjacent non-tumor tissues was determined by quantitative RT-PCR. (E) Enzyme activity of GLS1 in TT and paired NT (n = 4, left panel), and in a non-malignant hepatic cell line (L-O2) and HCC cell lines (Hep3B, 7402, MHCC97-H, HepG2) (right panel); *p < 0.05, **p < 0.01, ***p < 0.001, N.S. not significant.
Mentions: To investigate the expression and biodistribution of GLS1 and GLS2 in HCC, we performed immunohistochemical staining for GLS1 and GLS2 on the first group of paired tumor tissues (TT) and adjacent none tumor tissues (NT) from HCC patients. In the analysis of 112 cases, strongly positive staining against GLS1 in HCC tumor cells was observed in 83 cases (74.11%), weakly positive staining was found in 23 cases (20.54%), and negative staining was found in 6 cases (5.36%) (Figure 1A). Conversely, among adjacent NT hepatocytes from 110 cases analyzed, negative GLS1 staining was found in 103 cases (93.64%), and weakly positive staining was found in 7 cases (6.36%). These data suggest that GLS1 is highly expressed by HCC cells. We found negative staining for GLS2 in 70 of 112 HCC cases (62.5%), and positive staining in 103 of 111 cases in NT hepatocytes of NT (92.7%) (Figure 1A). Statistically, the expression of GLS1 in TT was significantly higher than in NT, while expression of GLS2 in TT was significantly lower than in NT. Additional immunohistochemical staining of GLS1 and GLS2 in TT and NT at a serial of magnifications is shown in Supplementary Figure 2A and 2B. We analyzed the available clinical information of the cases studied. We found that tumor capsule invaded was the only parameter showing clinical significance associated with differential expression of GLS1 and GLS2 (Supplementary Table 1). We found positive GLS1 staining in some mesenchymal cells in TT and NT. Among stained mesenchymal cells, no differences in expression intensity showed were observed. No GLS2 staining was observed in mesenchymal cells in TT or NT (Figure 1B). To determine if serum levels of GLS1 correlated with GLS1 staining of HCC cells, we analyzed sera from 10 HCC patients from group 1 and 9 healthy volunteers from group 2. GLS1 protein was detected a relative high levels in serum (about 100 ng/ml), but there was no difference between HCC patients and controls (Figure 1C).

Bottom Line: We found that GLS1 was highly expressed in HCC; whereas, expression of GLS2 was mainly confined to non-tumor hepatocytes.We found that high expression of GLS1 and low expression of GLS2 in HCC correlated with survival time of HCC patients.These findings indicate that GLS1 expression is a sensitive and specific biomarker for pathological diagnosis and prognosis of HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210093, China.

ABSTRACT
The lack of sensitive and specific biomarkers hinders pathological diagnosis and prognosis for hepatocellular carcinoma (HCC). Since glutaminolysis plays a crucial role in carcinogenesis and progression, we sought to determine if the expression of kidney-type and liver-type glutaminases (GLS1 and GLS2) were informative for pathological diagnosis and prognosis of HCC. We compared the expression of GLS1 and GLS2 in a large set of clinical samples including HCC, normal liver, and other liver diseases. We found that GLS1 was highly expressed in HCC; whereas, expression of GLS2 was mainly confined to non-tumor hepatocytes. The sensitivity and specificity of GLS1 for HCC were 96.51% and 75.21%, respectively. A metabolic switch from GLS2 to GLS1 was observed in a series of tissues representing progressive pathologic states mimicking HCC oncogenic transformation, including normal liver, fibrotic liver, dysplasia nodule, and HCC. We found that high expression of GLS1 and low expression of GLS2 in HCC correlated with survival time of HCC patients. Expression of GLS1 and GLS2 were independent indexes for survival time; however, prognosis was predominantly determined by the level of GLS1 expression. These findings indicate that GLS1 expression is a sensitive and specific biomarker for pathological diagnosis and prognosis of HCC.

No MeSH data available.


Related in: MedlinePlus