MicroRNA-1911-3p targets mEAK-7 to suppress mTOR signaling in human lung cancer cells
Daniela Baccelli Mendonça,
Joe Truong Nguyen,
Fatima Haidar,
Alexandra Lucienne Fox,
Connor Ray,
Halimah Amatullah,
Fei Liu,
Jin Koo Kim,
Paul H. Krebsbach
Affiliations
Daniela Baccelli Mendonça
Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
Joe Truong Nguyen
Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
Fatima Haidar
Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
Alexandra Lucienne Fox
Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
Connor Ray
Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
Halimah Amatullah
Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48105, USA
Fei Liu
Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, 48105, USA
Jin Koo Kim
Section of Periodontics, University of California, Los Angeles, School of Dentistry, Los Angeles, CA, 90095, USA
Paul H. Krebsbach
Section of Periodontics, University of California, Los Angeles, School of Dentistry, Los Angeles, CA, 90095, USA; Corresponding author.
Regulation of mTOR signaling depends on an intricate interplay of post-translational protein modification. Recently, mEAK-7 (mTOR associated protein, eak-7 homolog) was identified as a positive activator of mTOR signaling via an alternative mTOR complex. However, the upstream regulation of mEAK-7 in human cells is not known. Because microRNAs are capable of modulating protein translation of RNA in eukaryotes, we conducted a bioinformatic search for relevant mEAK-7 targeting microRNAs using the Exiqon miRSearch V3.0 algorithm. Based on the score obtained through miRSearch V3.0, the top predicted miRNA (miR-1911-3p) was studied. miR-1911-3p mimics decreased protein levels of both mEAK-7 and mTORC1 downstream effectors p-S6 and p-4E-BP1 in non-small cell lung carcinoma (NSCLC) cell lines H1975 and H1299. miR-1911-3p levels and MEAK7 mRNA/mEAK-7/mTOR signaling levels were negatively correlated between normal lung and NSCLC cells. miR-1911-3p directly interacted with MEAK7 mRNA at the 3′-UTR to negatively regulate mEAK-7 and significantly decreased mTOR localization to the lysosome. Furthermore, miR-1911-3p significantly decreased cell proliferation and migration in both H1975 and H1299 cells. Thus, miR-1911-3p functions as a suppressor of mTOR signaling through the regulation of MEAK7 mRNA translation in human cancer cells.
