Abstract
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.
Highlights
Mammalian EAK-7, or MTOR associated protein, eak-7 homolog, is a positive regulator of mTOR signaling that functions through the S6K2/4E-BP1 axis in human cells [1]. mEAK-7 is expressed predominantly in metastatic human cancer and forms a novel mTOR complex involving DNA-PK to promote S6K2 signaling and suppress 4E-BP1 [2]
MiR-99b acts as a tumor suppressor in non-small cell lung carcinoma (NSCLC) by directly targeting fibroblast growth factor receptor 3 [27]
Another study reported that miR-320a-3p regulates cell metastasis and invasion as a tumor suppressor through PI3K/Akt inactivation in NSCLC [28], and bioinformatics and functional analyses have been used to identify potential miRNAs and their regulatory mechanism in NSCLC [29] showing that some target genes of downregulated miRNAs are associated with PI3K-Akt signaling pathway, among other pathways
Summary
Mammalian EAK-7, or MTOR associated protein, eak-7 homolog (mEAK-7), is a positive regulator of mTOR signaling that functions through the S6K2/4E-BP1 axis in human cells [1]. mEAK-7 is expressed predominantly in metastatic human cancer and forms a novel mTOR complex involving DNA-PK to promote S6K2 signaling and suppress 4E-BP1 [2]. Mammalian EAK-7, or MTOR associated protein, eak-7 homolog (mEAK-7), is a positive regulator of mTOR signaling that functions through the S6K2/4E-BP1 axis in human cells [1]. MEAK-7 is expressed predominantly in metastatic human cancer and forms a novel mTOR complex involving DNA-PK to promote S6K2 signaling and suppress 4E-BP1 [2]. Other research groups have identified an astrocyte-specific mTOR complex [8] and a rapamycin insensitive mTOR complex in human cancer cells [9]. It was later discovered that this class of mRNA regulation was essential for eukaryotic development and was discovered in many different animal phyla [12] Across eukaryotes, these conserved RNA molecules are known as miRNAs [13]. We investigated the extent to which miR-1911-3p regulates mTOR signaling through mEAK-7
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