HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells.
HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells.
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HIF1/2α 介导人胰腺癌细胞缺氧诱导的 LDHA 表达
DOI：
10.18632/oncotarget.15266
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发表时间：
2017-04-11
期刊：
影响因子：
--
通讯作者：
Xiao J
中科院分区：
文献类型：
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作者：
Cui XG;Han ZT;He SH;Wu XD;Chen TR;Shao CH;Chen DL;Su N;Chen YM;Wang T;Wang J;Song DW;Yan WJ;Yang XH;Liu T;Wei HF;Xiao J
糖酵解是胰腺癌(PC)在低氧微环境下能量代谢的典型途径。乳酸脱氢酶A(LDHA)催化丙酮酸转化为乳酸，被认为是厌氧糖酵解的关键关卡。本研究的目的是通过对244例PC及癌旁组织标本的分析，探讨低氧、低氧诱导因子-1/2α与低氧血症相互作用的机制，以及低氧血症对PC细胞的作用。研究发现，LDHA的过度表达与肿瘤的分期有关。体外实验结果表明，低氧可诱导LDHA的表达。为探讨HIF与LDHA的关系，采用染色质免疫沉淀法和荧光素酶测定法。结果表明，在低氧条件下，HIF-1/2α与乳酸脱氢酶结合的碱基长度为89bp。此外，抑制内源性低氧诱导因子-1α和低氧诱导因子-2α的表达，即使在低氧条件下也能降低乳酸生成和葡萄糖利用率(p<；0.01)。免疫荧光显示HIF-1/2α高表达，且与LDHA高表达相关(p<；0.0001)。强迫表达LDHA可促进PC细胞的生长和迁移，而下调LDHA的表达则显著抑制PC细胞的生长和迁移。综上所述，本研究证实了HIF1/2α能够激活人PC细胞LDHA的表达，并且LDHA的高表达促进了PC细胞的生长和迁移。
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.