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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 HCC and other liver diseases(A) HE and immunohistochemical staining for GLS1 and GLS2 in HCC tumor tissues (TT, n = 112), dysplastic nodule tissues (DN, n = 10), fibrotic liver tissues (FL, n = 44), hepatocellular adenoma tissues (HCA, n = 5), focal nodule hyperplastic tissues (FNH, n = 12), and normal liver tissues (NL, n = 20). Bars = 200 μm. (B) Quantitation of expression intensity and frequency of GLS1 (upper panel) and GLS2 (lower panel). Intensity was categorized into three grades: negative (−), weakly positive (+), and strongly positive (++); ***p < 0.001, N.S. not significant.
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Figure 2: Expression and biodistribution of GLS1 and GLS2 in HCC and other liver diseases(A) HE and immunohistochemical staining for GLS1 and GLS2 in HCC tumor tissues (TT, n = 112), dysplastic nodule tissues (DN, n = 10), fibrotic liver tissues (FL, n = 44), hepatocellular adenoma tissues (HCA, n = 5), focal nodule hyperplastic tissues (FNH, n = 12), and normal liver tissues (NL, n = 20). Bars = 200 μm. (B) Quantitation of expression intensity and frequency of GLS1 (upper panel) and GLS2 (lower panel). Intensity was categorized into three grades: negative (−), weakly positive (+), and strongly positive (++); ***p < 0.001, N.S. not significant.

Mentions: We wanted to determine the specificity and sensitivity of GLS1 as a marker for HCC. To this end, the expression and distribution of GLS1 and GLS2 were determined in a serial set of liver tissues including 20 normal liver (NL), 44 fibrotic liver (FL), 12 focal nodular hyperplasias (FNH), 5 hepatocellular adenoma (HCA), and 10 dysplastic nodules (DN) and compared to expression in 112 HCC samples. The histological features and immunohistochemical staining of GLS1 and GLS2 in these tissues are shown in Figure 2A and 2B and Supplementary Figure 2. Staining for GLS1 was positive in 94.64% of HCC samples (83/112 were strongly stained and 23/112 were weakly stained), 60% of DN (2/10 were strongly stained and 4/10 were weakly stained), 36.4% of fibrotic liver (1/44 was strongly stained and 15/44 were weakly stained), 20% of HCA (1/5 was weakly stained), 25% of FNH (3/12 were weakly stained), and 10% of normal liver samples (2/20 were weakly stained). We found that both positivity and intensity of GLS1 in HCC were significantly higher than in other liver diseases or normal liver tissues (p < 0.001, Figure 2A and 2B upper panel). Interestingly, GLS1 positivity in DN, a premalignant liver disease, was also significantly higher than in NL (p = 0.010) and FL (p = 0.069) (Figure 2B upper panel). We also evaluated the expression of GLS2 in these specimens. Similar to our previous observations, both positivity and intensity of GLS2 expression were significantly lower in HCC compared to DN, FL, FNH, and NL (p < 0.001, Figure 2A and 2B lower panel). Staining for GLS2 was positive in 37.5% of HCC samples (5/112 were strongly stained and 37/112 were weakly stained) and 80% or 100% in other liver diseases and normal liver tissue (Figure 2B lower panel).


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 HCC and other liver diseases(A) HE and immunohistochemical staining for GLS1 and GLS2 in HCC tumor tissues (TT, n = 112), dysplastic nodule tissues (DN, n = 10), fibrotic liver tissues (FL, n = 44), hepatocellular adenoma tissues (HCA, n = 5), focal nodule hyperplastic tissues (FNH, n = 12), and normal liver tissues (NL, n = 20). Bars = 200 μm. (B) Quantitation of expression intensity and frequency of GLS1 (upper panel) and GLS2 (lower panel). Intensity was categorized into three grades: negative (−), weakly positive (+), and strongly positive (++); ***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 2: Expression and biodistribution of GLS1 and GLS2 in HCC and other liver diseases(A) HE and immunohistochemical staining for GLS1 and GLS2 in HCC tumor tissues (TT, n = 112), dysplastic nodule tissues (DN, n = 10), fibrotic liver tissues (FL, n = 44), hepatocellular adenoma tissues (HCA, n = 5), focal nodule hyperplastic tissues (FNH, n = 12), and normal liver tissues (NL, n = 20). Bars = 200 μm. (B) Quantitation of expression intensity and frequency of GLS1 (upper panel) and GLS2 (lower panel). Intensity was categorized into three grades: negative (−), weakly positive (+), and strongly positive (++); ***p < 0.001, N.S. not significant.
Mentions: We wanted to determine the specificity and sensitivity of GLS1 as a marker for HCC. To this end, the expression and distribution of GLS1 and GLS2 were determined in a serial set of liver tissues including 20 normal liver (NL), 44 fibrotic liver (FL), 12 focal nodular hyperplasias (FNH), 5 hepatocellular adenoma (HCA), and 10 dysplastic nodules (DN) and compared to expression in 112 HCC samples. The histological features and immunohistochemical staining of GLS1 and GLS2 in these tissues are shown in Figure 2A and 2B and Supplementary Figure 2. Staining for GLS1 was positive in 94.64% of HCC samples (83/112 were strongly stained and 23/112 were weakly stained), 60% of DN (2/10 were strongly stained and 4/10 were weakly stained), 36.4% of fibrotic liver (1/44 was strongly stained and 15/44 were weakly stained), 20% of HCA (1/5 was weakly stained), 25% of FNH (3/12 were weakly stained), and 10% of normal liver samples (2/20 were weakly stained). We found that both positivity and intensity of GLS1 in HCC were significantly higher than in other liver diseases or normal liver tissues (p < 0.001, Figure 2A and 2B upper panel). Interestingly, GLS1 positivity in DN, a premalignant liver disease, was also significantly higher than in NL (p = 0.010) and FL (p = 0.069) (Figure 2B upper panel). We also evaluated the expression of GLS2 in these specimens. Similar to our previous observations, both positivity and intensity of GLS2 expression were significantly lower in HCC compared to DN, FL, FNH, and NL (p < 0.001, Figure 2A and 2B lower panel). Staining for GLS2 was positive in 37.5% of HCC samples (5/112 were strongly stained and 37/112 were weakly stained) and 80% or 100% in other liver diseases and normal liver tissue (Figure 2B lower panel).

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