title: Inhibition of lactate dehydrogenase A by microRNA-34a resensitizes colon cancer cells to 5-fluorouracil.
abstract: 5-Fluorouracil (5-FU) chemotherapy is widely used in the treatment of advanced colon cancer. However, the development of resistance to 5-FU is a significant obstacle to successful treatment. MicroRNA-34a (miR-34a) has been reported to be downregulated in a number of tumor types and has also been shown to act as a tumor suppressor. However, the mechanisms underlying the biological effects of miR-34a in chemoresistance remain unclear. The present study showed that the expression of miR-34a is downregulated in 5-FU-resistant colon cancer cells. In addition, 5-FU-resistant colon cancer cells exhibited upregulation of lactate dehydrogenase A (LDHA) expression and activity compared with parental cells. Furthermore, LDHA was shown to be a direct target of miR-34a. Overexpression of miR-34a reduced the expression of LDHA, probably through binding to the 3' untranslated region, leading to the re-sensitization of 5-FU-resistant cancer cells to 5-FU. Additionally, overexpression of LDHA rendered colon cancer cells resistant to 5-FU, suggesting that the miR-34a-induced sensitization to 5-FU is mediated through the inhibition of LDHA. In conclusion, the current study showed that miR-34a is involved in sensitivity to 5-FU in part through its effects on LDHA expression. This indicates that miR-34a‑mediated inhibition of glucose metabolism may be a therapeutic target in patients with chemoresistant colon cancer.
authors.affiliation: Department of Hematology and Oncology, The 101st Hospital of the People's Liberation Army, Wuxi, Jiangsu 214044, P.R. China.
authors.forename: Xiangyong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, The 101st Hospital of the People's Liberation Army, Wuxi, Jiangsu 214044, P.R. China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Hematology and Oncology, The 101st Hospital of the People's Liberation Army, Wuxi, Jiangsu 214044, P.R. China.
authors.forename: Xijian
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Hematology and Oncology, The 101st Hospital of the People's Liberation Army, Wuxi, Jiangsu 214044, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Song
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D034622:RNA Interference
chemical_list: D020413:3' Untranslated Regions; D007527:Isoenzymes; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D005472:Fluorouracil