Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis.
Hypoxia-driven changes in the tumor microenvironment facilitate cancer metastasis. In the present study, we investigated the regulatory cross talk between endocytic pathway, hypoxia, and tumor metastasis. Dynamin 2 (DNM2), a GTPase, is a critical mediator of endocytosis. Hypoxia decreased the levels of DNM2. DNM2 promoter has multiple hypoxia-inducible factor (HIF)-binding sites and genetic deletion of them relieved hypoxia-induced transcriptional suppression. Interestingly, DNM2 reciprocally regulated HIF. Inhibition of DNM2 GTPase activity and dominant-negative mutant of DNM2 showed a functional role for DNM2 in regulating HIF. Furthermore, the opposite strand of DNM2 gene encodes miR-199a, which is similarly reduced in cancer cells under hypoxia. miR-199a targets the 3'-UTR of HIF-1α and HIF-2α. Decreased miR-199a expression in hypoxia increased HIF levels. Exogenous expression of miR-199a decreased HIF, cell migration, and metastasis of ovarian cancer cells. miR-199a-mediated changes in HIF levels affected expression of the matrix-remodeling enzyme, lysyloxidase (LOX). LOX levels negatively correlated with progression-free survival in ovarian cancer patients. These results demonstrate a regulatory relationship between DNM2, miR-199a, and HIF, with implications in cancer metastasis.
Departments of Pharmacology, Obstetrics and Gynecology, and Surgery, and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455.
Hemant P
HP
Joshi
Indira V
IV
Subramanian
Erica K
EK
Schnettler
Goutam
G
Ghosh
Rajesha
R
Rupaimoole
Colleen
C
Evans
Manju
M
Saluja
Yawu
Y
Jing
Ivan
I
Cristina
Sabita
S
Roy
Yan
Y
Zeng
Vijay H
VH
Shah
Anil K
AK
Sood
Sundaram
S
Ramakrishnan
D015536:Down-Regulation; D034285:Dynamin II / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008084:Lipoxygenase / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000556:secondary
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; C531408:mirn199 microRNA, human; D008084:Lipoxygenase; D034285:Dynamin II
iron regulation; microRNA