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

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

doi:10.18632/oncotarget.3557

Abstract

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.

Highlights

Leucine-rich α2-glycoprotein (LRG) was first identified from human serum in 1977 [1]
We investigated the physiological functions of LRG in the TGFβ1-sensitive murine Lewis lung carcinoma (LLC) cell line, which expresses low levels of LRG, by comparing the proliferation of LLC cells in vitro and in vivo
In a series of in vitro and allograft model experiments, the growth of LLC cells was significantly inhibited in the presence of LRG in a TGFβ1-dependent manner (Fig. 5a)

Summary

Introduction

Leucine-rich α2-glycoprotein (LRG) was first identified from human serum in 1977 [1]. LRG is an approximately 50-kDa glycoprotein that contains repetitive sequences with a leucine-rich motif [2]. This family of proteins, characterised by the presence of leuicine-rich repeats in their amino acid sequences, has been shown to be involved in protein–protein interactions, signal transduction, and cell development [3]. It has been shown that LRG is highly expressed in the sera of patients with bacterial infections [8]. Our group has shown that elevated expression of LRG can be detected in sera and in the tumor tissues of pancreatic cancer [13]. LRG has been analyzed as a biomarker in these disorders, the physiological role of LRG in cancer has not been fully elucidated

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