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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 of GLS1and GLS2 correlate with survival times of HCC patients(A and B) Expression of GLS1 and GLS2 determined by immunohistochemical staining in tissue arrays containing tumor and paired adjacent non-tumor tissues from 90 HCC patients. Insets show higher magnifications of stainings of one set of paired tissues. Bars = 500 μm. Histograms show quantitation of expression and intensity of staining of all samples. Intensity of staining was classified into three grades: ++ strongly positive, + weakly positive, and − negative. (C and D) Survival curves of 90 HCC patients divided into 2 groups according to staining intensity. (C) GLS1 survival curves. Black line: low/non-expression (−/+); red line: high-expression (++). (D) GLS2 survival curves. Black line: non-expression (−); red line: expression (+/++). Kaplan–Meier survival curves were based on time to death from disease or on time to biochemical recurrence (BCR). (E) Survival curves of 90 HCC patients based on combined GLS1 and GLS2 expression. Black line: GLS1 −/+ and GLS2 +/++ (n = 13); red line: GLS1 −/+ and GLS2 − (n = 4); green line: GLS1 ++ and GLS2 +/++ (n = 40); blue line: GLS1 ++ and GLS2 − (n = 23). Kaplan–Meier survival curve based on time to death from disease or on time to biochemical recurrence (BCR).
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Figure 5: Expression of GLS1and GLS2 correlate with survival times of HCC patients(A and B) Expression of GLS1 and GLS2 determined by immunohistochemical staining in tissue arrays containing tumor and paired adjacent non-tumor tissues from 90 HCC patients. Insets show higher magnifications of stainings of one set of paired tissues. Bars = 500 μm. Histograms show quantitation of expression and intensity of staining of all samples. Intensity of staining was classified into three grades: ++ strongly positive, + weakly positive, and − negative. (C and D) Survival curves of 90 HCC patients divided into 2 groups according to staining intensity. (C) GLS1 survival curves. Black line: low/non-expression (−/+); red line: high-expression (++). (D) GLS2 survival curves. Black line: non-expression (−); red line: expression (+/++). Kaplan–Meier survival curves were based on time to death from disease or on time to biochemical recurrence (BCR). (E) Survival curves of 90 HCC patients based on combined GLS1 and GLS2 expression. Black line: GLS1 −/+ and GLS2 +/++ (n = 13); red line: GLS1 −/+ and GLS2 − (n = 4); green line: GLS1 ++ and GLS2 +/++ (n = 40); blue line: GLS1 ++ and GLS2 − (n = 23). Kaplan–Meier survival curve based on time to death from disease or on time to biochemical recurrence (BCR).

Mentions: Finally, we sought to determine if expression of GLS1 and GLS2 could be predictive biomarkers for clinical outcomes in HCC patients. To this end, we examined the expression of GLS1 and GLS2 in TMA (HLiv-HCC180Sur-01) with 90 paired NT and TT obtained from HCC patients, and analyzed the relationship between GLS1/GLS2 expression and patient survival. In line with our previous observation, immunoreactivity against GLS1 was observed primarily in the cytoplasm of HCC cells, and was strongly positive (++) in about 80% of HCC (72 of 90 cases), weak (+) in 16.67% (15/90), and was absent in 3.33% (3/90) cases. In paired adjacent non-tumor tissues, GLS1 immunoreactivity was absent in 33.3% (30/90) of cases, weak in 53.3% (48/90) of cases and strong in 13.3% (12/90) of cases (Figure 5A). Intensive GLS2 staining (++) was observed in 77.9% (67/86) of adjacent non-tumor tissues, and was observed in 20.9% (18/86) of tumor tissues (Figure 5B). Patients with high GLS1 expression (++) had a markedly shorter overall survival time (29.32 months vs. 44.56 months) compared to patients with absent or low GLS1 expression (−/+) (Figure 5C). We also evaluated the relationship between expression of GLS2 in tumor tissues and survival time. We found that the patients exhibiting GLS2 expression (+/++) in tumor tissues had a significantly prolonged survival time (35.60 months vs. 24.37 months) compared to patients without tumor GLS2 expression (Figure 5D). Consistently, patients with high tumor GLS1 but no tumoral GLS2 exhibited the shortest survival times (22.39 months), whereas patients with tumoral GLS2 (+/++) and low tumoral GLS1 (−/+) had significantly prolonged survival times (47.15 months). Patients with tumoral GLS2 (+/++) and high tumoral GLS1 (++) exhibited median survival times (31.85 months) (Figure 5E). Multivariate survival analysis showed that the scales for both GLS1 and GLS2 were independent indexes for survival time of HCC patients (p = 0.003). The clinical information of 90 HCC cases are summarized in Supplementary Table 2. We found that the expression of GLS1 correlated with age, while no correlation was found between GLS1 and gender, morphology, tumor number, clinical stage of the tumor (TNM), tumor size, or volume. Taken together, our results show that GLS1 and GLS2 are potential prognostic biomarkers for HCC.


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 of GLS1and GLS2 correlate with survival times of HCC patients(A and B) Expression of GLS1 and GLS2 determined by immunohistochemical staining in tissue arrays containing tumor and paired adjacent non-tumor tissues from 90 HCC patients. Insets show higher magnifications of stainings of one set of paired tissues. Bars = 500 μm. Histograms show quantitation of expression and intensity of staining of all samples. Intensity of staining was classified into three grades: ++ strongly positive, + weakly positive, and − negative. (C and D) Survival curves of 90 HCC patients divided into 2 groups according to staining intensity. (C) GLS1 survival curves. Black line: low/non-expression (−/+); red line: high-expression (++). (D) GLS2 survival curves. Black line: non-expression (−); red line: expression (+/++). Kaplan–Meier survival curves were based on time to death from disease or on time to biochemical recurrence (BCR). (E) Survival curves of 90 HCC patients based on combined GLS1 and GLS2 expression. Black line: GLS1 −/+ and GLS2 +/++ (n = 13); red line: GLS1 −/+ and GLS2 − (n = 4); green line: GLS1 ++ and GLS2 +/++ (n = 40); blue line: GLS1 ++ and GLS2 − (n = 23). Kaplan–Meier survival curve based on time to death from disease or on time to biochemical recurrence (BCR).
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Figure 5: Expression of GLS1and GLS2 correlate with survival times of HCC patients(A and B) Expression of GLS1 and GLS2 determined by immunohistochemical staining in tissue arrays containing tumor and paired adjacent non-tumor tissues from 90 HCC patients. Insets show higher magnifications of stainings of one set of paired tissues. Bars = 500 μm. Histograms show quantitation of expression and intensity of staining of all samples. Intensity of staining was classified into three grades: ++ strongly positive, + weakly positive, and − negative. (C and D) Survival curves of 90 HCC patients divided into 2 groups according to staining intensity. (C) GLS1 survival curves. Black line: low/non-expression (−/+); red line: high-expression (++). (D) GLS2 survival curves. Black line: non-expression (−); red line: expression (+/++). Kaplan–Meier survival curves were based on time to death from disease or on time to biochemical recurrence (BCR). (E) Survival curves of 90 HCC patients based on combined GLS1 and GLS2 expression. Black line: GLS1 −/+ and GLS2 +/++ (n = 13); red line: GLS1 −/+ and GLS2 − (n = 4); green line: GLS1 ++ and GLS2 +/++ (n = 40); blue line: GLS1 ++ and GLS2 − (n = 23). Kaplan–Meier survival curve based on time to death from disease or on time to biochemical recurrence (BCR).
Mentions: Finally, we sought to determine if expression of GLS1 and GLS2 could be predictive biomarkers for clinical outcomes in HCC patients. To this end, we examined the expression of GLS1 and GLS2 in TMA (HLiv-HCC180Sur-01) with 90 paired NT and TT obtained from HCC patients, and analyzed the relationship between GLS1/GLS2 expression and patient survival. In line with our previous observation, immunoreactivity against GLS1 was observed primarily in the cytoplasm of HCC cells, and was strongly positive (++) in about 80% of HCC (72 of 90 cases), weak (+) in 16.67% (15/90), and was absent in 3.33% (3/90) cases. In paired adjacent non-tumor tissues, GLS1 immunoreactivity was absent in 33.3% (30/90) of cases, weak in 53.3% (48/90) of cases and strong in 13.3% (12/90) of cases (Figure 5A). Intensive GLS2 staining (++) was observed in 77.9% (67/86) of adjacent non-tumor tissues, and was observed in 20.9% (18/86) of tumor tissues (Figure 5B). Patients with high GLS1 expression (++) had a markedly shorter overall survival time (29.32 months vs. 44.56 months) compared to patients with absent or low GLS1 expression (−/+) (Figure 5C). We also evaluated the relationship between expression of GLS2 in tumor tissues and survival time. We found that the patients exhibiting GLS2 expression (+/++) in tumor tissues had a significantly prolonged survival time (35.60 months vs. 24.37 months) compared to patients without tumor GLS2 expression (Figure 5D). Consistently, patients with high tumor GLS1 but no tumoral GLS2 exhibited the shortest survival times (22.39 months), whereas patients with tumoral GLS2 (+/++) and low tumoral GLS1 (−/+) had significantly prolonged survival times (47.15 months). Patients with tumoral GLS2 (+/++) and high tumoral GLS1 (++) exhibited median survival times (31.85 months) (Figure 5E). Multivariate survival analysis showed that the scales for both GLS1 and GLS2 were independent indexes for survival time of HCC patients (p = 0.003). The clinical information of 90 HCC cases are summarized in Supplementary Table 2. We found that the expression of GLS1 correlated with age, while no correlation was found between GLS1 and gender, morphology, tumor number, clinical stage of the tumor (TNM), tumor size, or volume. Taken together, our results show that GLS1 and GLS2 are potential prognostic biomarkers for HCC.

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