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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

Glutamine metabolism is switched from GLS2 to GLS1 during oncogenic transformation to HCC(A) HE and immunohistochemical staining for GLS1 and GLS2 in normal liver tissues (NL, n = 20), fibrotic liver tissues from Grade I to V (S1–S4, n = 44), dysplastic nodule tissues (DN, n = 10), and HCC tumor tissues (TT, n = 112). Staining of representative sections are shown. Bars = 200 μm. (B) Quantitation of intensity and frequency of GLS1 (upper panel) and GLS2 (lower panel) expression. The intensity was scored as 2 (strongly positive), 1 (weakly positive), or 0 (negative). Brown lines indicate aggregate positivity in different tissues, calculated according to the frequency and intensity: ∑ Frequency × Intensity/2. ***p < 0.001.
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Figure 4: Glutamine metabolism is switched from GLS2 to GLS1 during oncogenic transformation to HCC(A) HE and immunohistochemical staining for GLS1 and GLS2 in normal liver tissues (NL, n = 20), fibrotic liver tissues from Grade I to V (S1–S4, n = 44), dysplastic nodule tissues (DN, n = 10), and HCC tumor tissues (TT, n = 112). Staining of representative sections are shown. Bars = 200 μm. (B) Quantitation of intensity and frequency of GLS1 (upper panel) and GLS2 (lower panel) expression. The intensity was scored as 2 (strongly positive), 1 (weakly positive), or 0 (negative). Brown lines indicate aggregate positivity in different tissues, calculated according to the frequency and intensity: ∑ Frequency × Intensity/2. ***p < 0.001.

Mentions: It has been shown that glutamine metabolism switches from GLS2 to GLS1 in MYC-induced mouse liver cancer [21]. It is unknown whether this metabolic switch also plays a role in human liver oncogenic transformation. To address this possibility, we evaluated the expression of GLS1 and GLS2 in a serial set of liver tissues mimicking HCC transformation; these included normal liver, fibrotic liver tissues from Grade I to IV, dysplasia nodule, and HCC tissues. The histological features and the immunohistochemical staining of GLS1 and GLS2 of fibrotic liver from grade I to IV are shown in Supplementary Figure 2 (D–G). GLS1 expression was low in normal liver tissues but was progressively upregulated in parallel with disease progression, and was high in HCC (p < 0.001, Figure 4A and 4B upper panel). Conversely, the intensity of GLS2 expression was high in normal liver and low-grade fibrotic liver tissues, and was low in HCC (p < 0.001, Figure 4A and 4B lower panel). We also investigated the correlation of GLS1 with c-MYC at gene level, and found that the expression of GLS1 in TT was associated with c-MYC expression (Supplementary Figure 3). These results suggest that glutamine metabolism may be switched from GLS2 to GLS1 during human HCC transformation.


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)

Glutamine metabolism is switched from GLS2 to GLS1 during oncogenic transformation to HCC(A) HE and immunohistochemical staining for GLS1 and GLS2 in normal liver tissues (NL, n = 20), fibrotic liver tissues from Grade I to V (S1–S4, n = 44), dysplastic nodule tissues (DN, n = 10), and HCC tumor tissues (TT, n = 112). Staining of representative sections are shown. Bars = 200 μm. (B) Quantitation of intensity and frequency of GLS1 (upper panel) and GLS2 (lower panel) expression. The intensity was scored as 2 (strongly positive), 1 (weakly positive), or 0 (negative). Brown lines indicate aggregate positivity in different tissues, calculated according to the frequency and intensity: ∑ Frequency × Intensity/2. ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Glutamine metabolism is switched from GLS2 to GLS1 during oncogenic transformation to HCC(A) HE and immunohistochemical staining for GLS1 and GLS2 in normal liver tissues (NL, n = 20), fibrotic liver tissues from Grade I to V (S1–S4, n = 44), dysplastic nodule tissues (DN, n = 10), and HCC tumor tissues (TT, n = 112). Staining of representative sections are shown. Bars = 200 μm. (B) Quantitation of intensity and frequency of GLS1 (upper panel) and GLS2 (lower panel) expression. The intensity was scored as 2 (strongly positive), 1 (weakly positive), or 0 (negative). Brown lines indicate aggregate positivity in different tissues, calculated according to the frequency and intensity: ∑ Frequency × Intensity/2. ***p < 0.001.
Mentions: It has been shown that glutamine metabolism switches from GLS2 to GLS1 in MYC-induced mouse liver cancer [21]. It is unknown whether this metabolic switch also plays a role in human liver oncogenic transformation. To address this possibility, we evaluated the expression of GLS1 and GLS2 in a serial set of liver tissues mimicking HCC transformation; these included normal liver, fibrotic liver tissues from Grade I to IV, dysplasia nodule, and HCC tissues. The histological features and the immunohistochemical staining of GLS1 and GLS2 of fibrotic liver from grade I to IV are shown in Supplementary Figure 2 (D–G). GLS1 expression was low in normal liver tissues but was progressively upregulated in parallel with disease progression, and was high in HCC (p < 0.001, Figure 4A and 4B upper panel). Conversely, the intensity of GLS2 expression was high in normal liver and low-grade fibrotic liver tissues, and was low in HCC (p < 0.001, Figure 4A and 4B lower panel). We also investigated the correlation of GLS1 with c-MYC at gene level, and found that the expression of GLS1 in TT was associated with c-MYC expression (Supplementary Figure 3). These results suggest that glutamine metabolism may be switched from GLS2 to GLS1 during human HCC transformation.

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