Research Papers:

This article has been corrected. Correction in: Oncotarget. 2016; 7(6):7367.

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

Seo Hee Nam, Doyeun Kim, Mi-Sook Lee, Doohyung Lee, Tae Kyoung Kwak, Minkyung Kang, Jihye Ryu, Hye-Jin Kim, Haeng Eun Song, Jungeun Choi, Gyu-Ho Lee, Sang-Yeob Kim, Song Hwa Park, Dae Gyu Kim, Nam Hoon Kwon, Tai Young Kim, Jean Paul Thiery, Sunghoon Kim and Jung Weon Lee _

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Oncotarget. 2015; 6:21655-21674. https://doi.org/10.18632/oncotarget.4130

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Seo Hee Nam1, Doyeun Kim2, Mi-Sook Lee2, Doohyung Lee2, Tae Kyoung Kwak2, Minkyung Kang2,3, Jihye Ryu2, Hye-Jin Kim2, Haeng Eun Song2, Jungeun Choi1, Gyu-Ho Lee2, Sang-Yeob Kim4, Song Hwa Park2, Dae Gyu Kim2, Nam Hoon Kwon2, Tai Young Kim2, Jean Paul Thiery5,6,7, Sunghoon Kim1,2 and Jung Weon Lee1,2

1 Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea

2 Department of Pharmacy, Medicinal Bioconvergence Research Center, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea

3 Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea

4 Department of Medicine, University of Ulsan, College of Medicine, Seoul, Republic of Korea

5 Cancer Science Institute, National University of Singapore, Singapore

6 Institute of Molecular and Cell Biology, A*STAR, Singapore

7 Department of Biochemistry, School of Medicine, National University of Singapore, Singapore

Correspondence to:

Jung Weon Lee, email:

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

Received: January 15, 2015 Accepted: April 30, 2015 Published: May 12, 2015


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.

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