MicroRNA‐135a Regulates NHE9 To Inhibit Proliferation and Migration of Glioblastoma Cells

Abstract

Glioblastoma multiformae (GBM) is the most aggressive type of malignant brain tumor with complex molecular profile. Overexpression of Na+/H+ Exchanger isoform 9 (NHE9) promotes tumor progression and correlates positively with insensitivity to radiochemotherapy and poor prognosis. However, molecular mechanisms responsible for increase in NHE9 levels beyond a critical threshold have not been identified.We show that microRNA 135a (miR‐135a) targets NHE9 to downregulate its expression in U87 cells. MiR‐135a levels are significantly lower in glioblastoma cells compared to normal brain tissue. Downregulation of NHE9 expression by miR‐135a reduced proliferative and migratory capacity of U87 cells. Selectively increasing NHE9 expression in these cells restored their ability to proliferate and migrate. We demonstrate that miR‐135a takes a two‐pronged approach affecting epidermal growth factor receptors (EGFRs) to suppress tumor cell growth and migration. EGFR activity is a potent stimulator of oncogenic signaling. While miR‐135a targets EGFR transcripts to decrease the total number of receptors made, by targeting NHE9 it routes the few EGFRs made away from the plasma membrane to dampen oncogenic signaling. NHE9 is localized to sorting endosomes in glioblastoma cells where it alkalinizes the endosome lumen by leaking protons. Downregulation of NHE9 expression by miR‐135a acidifies sorting endosomes limiting EGFR trafficking to the glioblastoma cell membrane. We propose downregulation of miR‐135a as a potential mechanism underlying the high NHE9 expression observed in subset of glioblastomas. Future studies should explore miR‐135a as a potential therapeutic for glioblastomas with NHE9 overexpression.Support or Funding InformationFunds from the Department of Natural Sciences and the Office of Research and Sponsored Programs at the University of Michigan DearbornThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.