Journal
JOURNAL OF CELL SCIENCE
Volume 122, Issue 9, Pages 1441-1451Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.025957
Keywords
mRNA translation; Microtubule-associated protein; Tumor invasiveness; LC3; Fibronectin; Connective tissue growth factor
Categories
Funding
- NHLBI NIH HHS [R01 HL074186, R01 HL074186-03, R01 HL074186-02, R01 HL074186-05, R01 HL074186-04] Funding Source: Medline
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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.
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