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

Decai Yu,Gang Meng,Xianbiao Shi,Jiwu Wei,Yong Jiang,Jun Chen,Yitao Ding,Chen Yan

doi:10.18632/oncotarget.3196

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.

Highlights

hepatocellular carcinoma (HCC) occurs mainly in patients with chronic liver disease such as hepatitis B or C infection
These findings indicate that GLS1 expression is a sensitive and specific biomarker for pathological diagnosis and prognosis of HCC
GLS1 expression is preferentially upregulated in HCC tumor cells and GLS2 is preferentially expressed in normal hepatocytes

Summary

Introduction

HCC occurs mainly in patients with chronic liver disease such as hepatitis B or C infection. It is challenging to distinguish early stage HCC from cirrhotic or dysplastic nodules in pathological biopsy material. Several markers for early malignant HCC are used in clinic. Glutamine synthetase (GS), glypican-3 (GPC3), and heat shock protein 70 (HSP70) have been validated, and can be used for histopathological diagnosis [1, 2]. Increased aerobic glycolysis ( known as the Warburg effect) and glutaminolysis are commonly found in many malignancies [5, 6]. During malignancy development and progression, the glutamine (Gln) pathway provides a variety of essential products to sustain biological function and cell proliferation, such as ATP generation and macromolecules for biosynthesis [6,7,8]

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