title: HPV E6/p53 mediated down-regulation of miR-34a inhibits Warburg effect through targeting LDHA in cervical cancer.
abstract: MicroRNAs (miRNA) play crucial roles in regulating cell proliferation, differentiation and developmental timing. Aberrantly expressed miRNAs have recently emerged as key regulators of metabolism. However, little is known about its role in tumor metabolism of cervical cancer. In this study, we determined the oncogenic effects of miRNAs on Warburg effect, a metabolic phenotype that allows cancer cells to utilize glucose even under aerobic conditions. A gain-of-function study was performed in 12 down-regulated miRNAs that frequently reported in cervical cancer. We found that miR-34a plays a suppressive role in Warburg effect as evidenced by decreased lactate production and glucose consumption. Knockdown of oncoprotein E6 expression of human papillomavirus in SiHa and HeLa cells by siRNAs lead to an increased protein level of p53, decreased level of miR-34a, as well as reduced Warburg effect. Subsequently, lactate dehydrogenase A (LDHA), which catalyzes the last key step in glycolysis, was identified as a direct target of miR-34a. Silencing of LDHA or introduction of miR-34a significantly attenuated colony formation ability and invasive capacity of SiHa and HeLa cells, and these effects were fully compromised by reintroduction of LDHA. In conclusion, our findings demonstrated that deregulated miR-34a/LDHA axis induced by HPV E6/p53 signaling facilitates tumor growth and invasion through regulating Warburg effect in cervical cancer, and provided new insights into the mechanism by which miR-34a contributes to the development and progression of cervical cancer.
authors.affiliation: Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University Nanjing 210003, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Huaian Maternal and Child Health Care Hospital Huaian 223002, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Medical School of Southeast University Nanjing 210009, China.
authors.forename: Song-Lin
authors.initials: SL
authors.lastname: Xue
authors.affiliation: Department of Obstetrics and Gynecology, Huaian Maternal and Child Health Care Hospital Huaian 223002, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University Nanjing 210003, 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, 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, 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, China.
authors.forename: Yan-Wei
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Nanjing Normal University Nanjing 210023, China.
authors.forename: Ye-Xin
authors.initials: YX
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Huaian Maternal and Child Health Care Hospital Huaian 223002, China.
authors.forename: Jian-Fang
authors.initials: JF
authors.lastname: Hu
authors.affiliation: Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University Nanjing 210003, China.
authors.forename: Min-Min
authors.initials: MM
authors.lastname: Yu
keywords: Human papillomavirus; LDHA; Warburg effect; cervical cancer; miR-34a