HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells.

Dan-Lei Chen,Hai-Feng Wei,Cheng-Hao Shao,Xin-Gang Cui,Dian-Wen Song,Jing Wang,Yuan-Ming Chen,Xing-Da Wu,Tielong Liu,Ning Su,Ting Wang,Zhi-Tao Han,Jianru Xiao,Shao-Hui He,Wang-Jun Yan,Tian-Rui Chen,Xing-Hai Yang

doi:10.18632/oncotarget.15266

Abstract

Glycolysis is a typical conduit for energy metabolism in pancreatic cancer (PC) due to the hypoxic microenviroment. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate and is considered to be a key checkpoint of anaerobic glycolysis. The aim of the present study was to explore the mechanism of interactions between hypoxia, HIF-1/2α and LDHA, and the function of LDHA on PC cells by analyzing 244 PC and paratumor specimens. It was found that LDHA was over-expressed and related to tumor stages. The result of in vitro study demonstrated that hypoxia induced LDHA expression. To explore the relationship between HIF and LDHA, chromatin immunoprecipitation assay and luciferase assay were performed. The result showed that HIF-1/2α bound to LDHA at 89bp under the hypoxic condition. Furthermore, knockdown of endogenous HIF-1α and HIF-2α decreased the LDHA expression even in the hypoxic condition, which was accompanied with a significant decrease in lactate production and glucose utilization (p < 0.01). Immunofluorescence in the 244 specimens showed that HIF-1/2α was over-expressed and associated with LDHA over-expression (p < 0.0001). Forced expression of LDHA promoted the growth and migration of PC cells, while knocking down the expression of LDHA inhibited the cell growth and migration markedly. In summary, the present study proved that HIF1/2α could activate LDHA expression in human PC cells, and high expression of LDHA promoted the growth and migration of PC cells.

Highlights

Pancreatic cancer (PC) is one of the most common malignant tumors in the digestive system, with high incidence and mortality worldwide [1]
Knowing that the expression level of Lactate dehydrogenase A (LDHA) is increased in human pancreatic cancer (PC) and related to tumor stages [11], we detected the expression of LDHA in the 244 primary PC and paired para-tumor normal tissues by IHC staining (Figure 1)
The results showed that LDHA was mainly expressed in the cytoplasm of tumor cells and significantly up-regulated in PC tissues as compared with the controls

Summary

Introduction

Pancreatic cancer (PC) is one of the most common malignant tumors in the digestive system, with high incidence and mortality worldwide [1]. Despite improvements in early diagnosis, surgical technology and systemic chemotherapy for PC in recent years, the overall 5-year survival rate remains below 5% [3]. This disappointing survival rate even after margin-negative pancreatectomy indicates the high grade of malignancy of this disease. The expression of LDHA was found to be increased in various types of human cancers [9, 10], including PC [11]. Previous studies [11, 12] found that increased LDHA expression could promote PC cell proliferation, migration and invasion. The expression level of LDHA was closely associated with tumor size, TNM stage and prognosis in PC patients [12], indicating that LDHA may be a potential prognostic marker and therapeutic target of PC

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Conclusion