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

Lihua Ying, Agatha Lau, Cristina M. Alvira, Robert West, Gordon M. Cann, Bin Zhou, Caroline Kinnear, Eric Jan, Peter Sarnow, Matt Van de Rijn, Marlene Rabinovitch

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1441-1451
Number of pages11
JournalJournal of cell science
Volume122
Issue number9
DOIs
StatePublished - May 1 2009

Keywords

  • Connective tissue growth factor
  • Fibronectin
  • LC3
  • Microtubule-associated protein
  • Tumor invasiveness
  • mRNA translation

ASJC Scopus subject areas

  • Cell Biology

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    Ying, L., Lau, A., Alvira, C. M., West, R., Cann, G. M., Zhou, B., Kinnear, C., Jan, E., Sarnow, P., Van de Rijn, M., & Rabinovitch, M. (2009). LC3-mediated fibronectin mRNA translation induces fibrosarcoma growth by increasing connective tissue growth factor. Journal of cell science, 122(9), 1441-1451. https://doi.org/10.1242/jcs.025957