LC3-mediated fibronectin mRNA translation induces fibrosarcoma growth by increasing connective tissue growth factor.

Abstract

Previously, we related fibronectin (Fn1) mRNA translation to an interaction between an AU-rich element in the Fn1 3' UTR and light chain 3 (LC3) of microtubule-associated proteins 1A and 1B. Since human fibrosarcoma (HT1080) cells produce little fibronectin and LC3, we used these cells to investigate how LC3-mediated Fn1 mRNA translation might alter tumor growth. Transfection of HT1080 cells with LC3 enhanced fibronectin mRNA translation. Using polysome analysis and RNA-binding assays, we show that elevated levels of translation depend on an interaction between a triple arginine motif in LC3 and the AU-rich element in Fn1 mRNA. Wild-type but not mutant LC3 accelerated HT1080 cell growth in culture and when implanted in SCID mice. Comparison of WT LC3 with vector-transfected HT1080 cells revealed increased fibronectin-dependent proliferation, adhesion and invasion. Microarray analysis of genes differentially expressed in WT and vector-transfected control cells indicated enhanced expression of connective tissue growth factor (CTGF). Using siRNA, we show that enhanced expression of CTGF is fibronectin dependent and that LC3-mediated adhesion, invasion and proliferation are CTGF dependent. Expression profiling of soft tissue tumors revealed increased expression of both LC3 and CTGF in some locally invasive tumor types.

DOI: 10.1242/jcs.025957

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Cite this paper

@article{Ying2009LC3mediatedFM, title={LC3-mediated fibronectin mRNA translation induces fibrosarcoma growth by increasing connective tissue growth factor.}, author={Lihua Ying and Agatha Lau and Cristina M Alvira and Robert B. West and Gordon M. Cann and Bin Zhou and Caroline Kinnear and E. E. Jan and Peter Sarnow and Matt van de Rijn and Marlene Rabinovitch}, journal={Journal of cell science}, year={2009}, volume={122 Pt 9}, pages={1441-51} }