KSRP suppresses cell invasion and metastasis through miR-23a-mediated EGR3 mRNA degradation in non-small cell lung cancer
Journal
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
Journal Volume
1860
Journal Issue
10
Pages
1013-1024
Date Issued
2017
Author(s)
Chien M.-H.
Lee W.-J.
Yang Y.-C.
Li Y.-L.
Chen B.-R.
Yang P.-W.
Wang M.-Y.
Jan Y.-H.
Lin Y.-K.
Hsiao M.
Abstract
KH-type splicing regulatory protein (KSRP) is a single-strand RNA binding protein which regulates mRNA stability either by binding to AU-rich elements (AREs) of mRNA 3′UTR or by facilitating miRNA biogenesis to target mRNA. Unlike its well-characterized function at the molecular level in maintaining RNA homeostasis, the role of KSRP in cancer progression remains largely unknown. Here we investigate the role of KSRP in non-small cell lung cancer (NSCLC). We first examined KSRP expression by immunohistochemistry in a cohort containing 196 NSCLC patients and observed a strong positive correlation between KSRP expression and survival of NSCLC patients. Multivariate analysis further identified KSRP as an independent prognostic factor. Manipulating KSRP expression significantly affected in vitro cell mobility and in vivo metastatic ability of NSCLC cells. Microarray analysis identified an ARE-containing gene, EGR3, as a downstream effector of KSRP in NSCLC. Interestingly, we found that KSRP decreased EGR3 mRNA stability in an ARE-independent manner. By screening KSRP-regulated miRNAs in NSCLC cells, we further found that miR-23a directly binds to EGR3 3′UTR, reducing EGR3 expression and thereby inhibiting NSCLC cell mobility. Our findings implicate a targetable KSRP/miR-23a/EGR3 signaling axis in advanced tumor phenotypes. ? 2017 Elsevier B.V.
SDGs
Other Subjects
biological marker; early growth response factor 3; KH type splicing regulatory protein; messenger RNA; microRNA; microRNA 23a; RNA binding protein; unclassified drug; early growth response factor 3; EGR3 protein, human; KHSRP protein, human; microRNA; MIRN23 microRNA, human; RNA; RNA binding protein; transactivator protein; tumor protein; 3' untranslated region; animal experiment; animal model; animal tissue; Article; AU rich element; cancer prognosis; cancer survival; cell invasion; cell motility; cohort analysis; controlled study; correlation analysis; disease free survival; female; human; human cell; human tissue; immunohistochemistry; in vitro study; in vivo study; lung adenocarcinoma; major clinical study; male; metastasis; microarray analysis; molecular biology; mouse; multivariate analysis; non small cell lung cancer; nonhuman; overall survival; phenotype; priority journal; protein expression; protein function; regulatory mechanism; retrospective study; RNA degradation; signal transduction; animal; genetics; lung tumor; metabolism; metastasis; non small cell lung cancer; nonobese diabetic mouse; pathology; RNA stability; SCID mouse; tumor invasion; Animals; Carcinoma, Non-Small-Cell Lung; Early Growth Response Protein 3; Female; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; RNA Stability; RNA, Neoplasm; RNA-Binding Proteins; Trans-Activators
Publisher
Elsevier B.V.
Type
journal article