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First published online 14 April 2009
doi: 10.1242/jcs.025957

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

Lihua Ying¹, Agatha Lau², Cristina M. Alvira¹, Robert West³, Gordon M. Cann¹, Bin Zhou^2,*, Caroline Kinnear², Eric Jan⁴, Peter Sarnow⁴, Matt Van de Rijn³ and Marlene Rabinovitch^1,

¹ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA
² Department of Pediatrics, Laboratory Medicine, Pathobiology and Medicine at the University of Toronto, Ontario, Canada M5G 1X8
³ Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA
⁴ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA

Author for correspondence (e-mail: marlener{at}stanford.edu)

Accepted 29 December 2008

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.

Key words: mRNA translation, Microtubule-associated protein, Tumor invasiveness, LC3, Fibronectin, Connective tissue growth factor

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