Abstract
IntroductionLDH-A, the enzyme responsible for transforming pyruvate into lactate, has been demonstrated to be up-regulated in many types of cancer and to give rise to more aggressive behavior by regulating proliferation and anti-apoptosis. However, its expression in gastric cancer (GC) has not been characterized thoroughly. The purpose of this study was to clarify the expression and potential impact of LDH-A in GC.MethodsWe examined LDH-A expression by immunohistochemistry on GC tissue microarray (TMA) and using Western blot on fresh GC tissues and cell lines. Prognostic value and correlation with other clinicopathologic factors were evaluated. We transfected siRNA into GC cells against LDH-A. LDH-A was analyzed by Western blotting and real-time RT-PCR. Cell growth was evaluated in vitro and in vivo. Lactate and ATP production by cells were determined.ResultsThere was significantly higher LDH-A expression in carcinoma than in non-neoplastic mucosa (NNM). There was a positive correlation of LDH-A expression with age, histological type and Lymph node metastases. Survival analysis demonstrated that high expression of LDH-A in GC was associated with lower overall survival (OS). When stratified by Lauren grade and histological classification, significance appeared in diffuse type and undifferentiated type GC. In multivariate analysis, the LDH-A expression in GC was an independent prognostic risk factor for OS (hazard ratio = 1.829, 95%CI 1.375–2.433,P<0.0001). Specific siRNA against LDH-A in GC cell line retarded cell growth both in vitro and in mouse models. LDH-A knockdown also reduced lactate and ATP production in GC cells.ConclusionsOur study indicated the oncogenic role of LDH-A in GC. LDH-A expression is an independent prognostic risk factor in GC patients and up-regulated expression of LDH-A could be predictive of poor outcomes in diffuse type and undifferentiated type GC. Our results suggested that LDH-A might be a potential therapeutic target in gastric cancer.
Highlights
LDH-A, the enzyme responsible for transforming pyruvate into lactate, has been demonstrated to be upregulated in many types of cancer and to give rise to more aggressive behavior by regulating proliferation and antiapoptosis
Our results demonstrate that the expression of LDH-A was up-regulated in the clinical gastric cancer samples, and protein expression was correlated to age and histological classification
Our study revealed the oncogenic function of LDH-A in gastric cancer and suggested LDH-A as a new potential prognostic factor and a potential therapeutic target
Summary
LDH-A, the enzyme responsible for transforming pyruvate into lactate, has been demonstrated to be upregulated in many types of cancer and to give rise to more aggressive behavior by regulating proliferation and antiapoptosis. The metabolic properties of cancer cells diverge significantly from those of normal cells, as cancer cells preferentially utilize glycolysis instead of mitochondrial oxidative phosphorylation even in the presence of oxygen; this phenomenon is known as the Warburg effect [1][2,3]. The surprisingly high rate of taking up glucose and lactate production in tumors in the presence of oxygen led Warburg to speculate that aberrant metabolism could be the cause of many cancers [2]. The advantage of the metabolic transformation confers to cancer cells remains unclear [4,5]. Cancer metabolism has been under extensive exploration in the hope of discovering new effective therapies for cancer
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