title: MicroRNA-497 regulates cisplatin chemosensitivity of cervical cancer by targeting transketolase.
abstract: Cervical cancer is one of the most lethal malignancies amongst women, partially because it is unresponsive to many chemotherapeutic drugs. The mechanism underlying cisplatin (DDP) resistance in cervical cancer remains largely elusive. In this study, by detecting the 12 most reported down-regulated miRNAs in chemotherapy-sensitive and -resistant cervical cancer cells, we found that miR-497 was significantly reduced in chemotherapy-resistant HeLa/DDP cells and contributed to DDP chemosensitivity. Transketolase (TKT), a thiamine-dependent enzyme that plays a role in the channeling of excess glucose phosphates to glycolysis in the pentose phosphate pathway, was identified as a direct target of miR-497. TKT expression in clinical specimens was characterized by immunohistochemistry and the result showed that TKT was highly expressed in 81.1% (60/74) of samples examined. Data from Oncomine databases revealed that TKT was significantly up-regulated in cervical cancer tissues compared to normal controls. Gain-of-function and loss-of-function studies showed that the miR-497/TKT axis was a critical modulator in DDP chemosensitivity as demonstrated by cell viability and apoptosis assays. Mechanistically, DDP chemosensitivity induced by the miR-497/TKT axis was associated with glutathione (GSH) depletion and reactive oxygen species (ROS) generation, and GSH treatment effectively abrogated miR-497/TKT-mediated chemosensitivity. In conclusion, these findings suggest that a deregulated miR-497/TKT axis has important implications in the cervical cancer cellular response to DDP, and thus targeting this axis may be a promising way to improve chemosensitivity in cervical cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Huaian Maternal and Child Health Care Hospital Huaian 223002, Jiangsu, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Women Health Care, Nanjing Maternal and Child Health Care Hospital, Affiliated to Nanjing Medical University Nanjing 210004, Jiangsu, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University Nanjing 210003, Jiangsu, China.
authors.forename: Kai-Hua
authors.initials: KH
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University Nanjing 210003, Jiangsu, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University Nanjing 210003, Jiangsu, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Ju
authors.affiliation: Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University Nanjing 210003, Jiangsu, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University Nanjing 210003, Jiangsu, China.
authors.forename: Yan-Wei
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University Nanjing 210003, Jiangsu, China.
authors.forename: Song-Lin
authors.initials: SL
authors.lastname: Xue
authors.affiliation: College of Life Sciences, Nanjing Normal University Nanjing 210023, Jiangsu, China.
authors.forename: Ye-Xin
authors.initials: YX
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University Nanjing 210003, Jiangsu, China.
authors.forename: Yong-Feng
authors.initials: YF
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University Nanjing 210003, Jiangsu, China.
authors.forename: Min-Min
authors.initials: MM
authors.lastname: Yu
keywords: MicroRNA-497; cervical cancer; chemosensitivity; pentose phosphate pathway; reactive oxygen species; transketolase