Research Papers:

Leucine-rich α-2-glycoprotein promotes TGFβ1-mediated growth suppression in the Lewis lung carcinoma cell lines

Norihiko Takemoto, Satoshi Serada, Minoru Fujimoto, Honda Hiromi, Tomoharu Ohkawara, Tsuyoshi Takahashi, Shintaro Nomura, Hidenori Inohara and Tetsuji Naka _

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Oncotarget. 2015; 6:11009-11022. https://doi.org/10.18632/oncotarget.3557

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Norihiko Takemoto1,2, Satoshi Serada2, Minoru Fujimoto2, Hiromi Honda2, Tomoharu Ohkawara2, Tsuyoshi Takahashi2,4, Shintaro Nomura3, Hidenori Inohara1 and Tetsuji Naka2

1 Department of Otorhinolaryngology-Head and Neck surgery, Osaka University Graduate School of Medicine, Ibaraki, Osaka, Japan

2 Laboratory of Immune Signal, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan

3 Department of Animal Bioscience, Nagahama Institute of Bio-Science and Technology, Ibaraki, Osaka, Japan

4 Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

Correspondence to:

Tetsuji Naka, email:

Keywords: Leucine-rich α-2-glycoprotein, Lewis lung carcinoma, TGFβ, apoptosis, smad signal transduction

Received: December 18, 2014 Accepted: February 12, 2015 Published: March 12, 2015


Leucine-rich α2-glycoprotein (LRG) is an approximately 50-kDa glycoprotein that has been found to be elevated in the sera of patients with several types of cancer. LRG directly binds to transforming growth factor beta 1 (TGFβ1) and modulates TGFβ1 signaling in endothelial cells; however, the precise function of LRG in cancer remains unclear. This study aimed to investigate the role of LRG in cancer. Lewis lung carcinoma (LLC) cells hardly expressed LRG. The growth of LLC tumors allografted in the LRG knockout (KO) mice was significantly increased compared with wild-type (WT) mice. Conversely, overexpression of LRG significantly inhibited the growth of LLC tumors in WT mice. In the presence of LRG, TGFβ1 significantly inhibited the proliferation of LLC cells and human hepatocellular carcinoma Hep3B cells in vitro by inducing apoptosis via the potent activation of smad2 and its downstream signaling pathway. Furthermore, administration of a TGFβR1 inhibitor (SB431542) significantly enhanced the growth of LLC tumors in WT mice compared with LRG KO mice via inhibition of apoptosis. We propose that LRG potentiates the effect of TGFβ1 in cancer cells whose growth is suppressed in the presence of TGFβ1.

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