Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Hemant P. Joshi, Indira V. Subramanian, Erica K. Schnettler, Goutam Ghosh, Rajesha Rupaimoole, Colleen Evans, manju saluja, Yawu Jing, Ivan Cristina, Sabita Roy, Yan Zeng, Vijay H. Shah, Anil K. Sood, Sundaram Ramakrishnan

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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 dominantnegative 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.

Original languageEnglish (US)
Pages (from-to)5331-5336
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number14
DOIs
StatePublished - Jan 1 2014

Keywords

  • Iron regulation
  • MicroRNA

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    Joshi, H. P., Subramanian, I. V., Schnettler, E. K., Ghosh, G., Rupaimoole, R., Evans, C., saluja, M., Jing, Y., Cristina, I., Roy, S., Zeng, Y., Shah, V. H., Sood, A. K., & Ramakrishnan, S. (2014). Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis. Proceedings of the National Academy of Sciences of the United States of America, 111(14), 5331-5336. https://doi.org/10.1073/pnas.1317242111