title: HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells.
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.
authors.affiliation: Department of Urinary Surgery of Third Affiliated Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xin-Gang
authors.initials: XG
authors.lastname: Cui
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.|Department of Spine Surgery, Ruikang Hospital, Guangxi University Of Chinese Medicine, Guangxi, China.
authors.forename: Zhi-Tao
authors.initials: ZT
authors.lastname: Han
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Shao-Hui
authors.initials: SH
authors.lastname: He
authors.affiliation: Department of Pancreatic Surgery, the First Hospital of China Medical University, Shenyang, China.
authors.forename: Xing-da
authors.initials: XD
authors.lastname: Wu
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Tian-Rui
authors.initials: TR
authors.lastname: Chen
authors.affiliation: Department of Pancreatic Surgery, Changzheng Hospital, the Second Military Medical University, Shanghai, China.
authors.forename: Cheng-Hao
authors.initials: CH
authors.lastname: Shao
authors.affiliation: Department of Pancreatic Surgery, Changzheng Hospital, the Second Military Medical University, Shanghai, China.
authors.forename: Dan-Lei
authors.initials: DL
authors.lastname: Chen
authors.affiliation: Department of Colorectal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Su
authors.affiliation: Department of Spine Surgery, Ruikang Hospital, Guangxi University Of Chinese Medicine, Guangxi, China.
authors.forename: Yuan-Ming
authors.initials: YM
authors.lastname: Chen
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Dian-Wen
authors.initials: DW
authors.lastname: Song
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Wang-Jun
authors.initials: WJ
authors.lastname: Yan
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xing-Hai
authors.initials: XH
authors.lastname: Yang
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Tielong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Wei
authors.affiliation: Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5
keywords: HIF-1; HIF-2; LDHA; hypoxia; pancreatic cancer