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Oncotarget. 2015 Aug 28;6(25):21655-74.

Noncanonical roles of membranous lysyl-tRNA synthetase in transducing cell-substrate signaling for invasive dissemination of colon cancer spheroids in 3D collagen I gels.

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Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea.
Department of Pharmacy, Medicinal Bioconvergence Research Center, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.
Department of Medicine, University of Ulsan, College of Medicine, Seoul, Republic of Korea.
Cancer Science Institute, National University of Singapore, Singapore.
Institute of Molecular and Cell Biology, A*STAR, Singapore.
Department of Biochemistry, School of Medicine, National University of Singapore, Singapore.


The adhesion properties of cells are involved in tumor metastasis. Although KRS at the plasma membrane is shown important for cancer metastasis, additionally to canonical roles of cytosolic KRS in protein translation, how KRS and its downstream effectors promote the metastatic migration remains unexplored. Disseminative behaviors (an earlier metastatic process) of colon cancer cell spheroids embedded in 3D collagen gels were studied with regards to cell adhesion properties, and relevance in KRS(-/+) knocked-down animal and clinical colon cancer tissues. Time-lapse imaging revealed KRS-dependent cell dissemination from the spheroids, whereas KRS-suppressed spheroids remained static due to the absence of outbound movements supported by cell-extracellular matrix (ECM) adhesion. While keeping E-cadherin at the outward disseminative cells, KRS caused integrin-involved intracellular signaling for ERK/c-Jun, paxillin, and cell-ECM adhesion-mediated signaling to modulate traction force for crawling movement. KRS-suppressed spheroids became disseminative following ERK or paxillin re-expression. The KRS-dependent intracellular signaling activities correlated with the invasiveness in clinical colon tumor tissues and in KRS(-/+) knocked-down mice tissues. Collectively, these observations indicate that KRS at the plasma membrane plays new roles in metastatic migration as a signaling inducer, and causes intracellular signaling for cancer dissemination, involving cell-cell and cell-ECM adhesion, during KRS-mediated metastasis.


3D culture; cancer metastasis; cell-ECM adhesion; lysyl-tRNA synthetase; signal transduction

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