SLIT2 Attenuation during Lung Cancer Progression Deregulates β-Catenin and E-Cadherin and Associates with Poor Prognosis

Ruo-Chia Tseng,Yi-Ching Wang,Han-Shui Hsu,Wan-Ching Tsai,Ben-Han Chen,Shih-Hua Lee,Ching Tzao

doi:10.1158/0008-5472.can-09-2084

Abstract

Chromosome 4p15.3 is frequently deleted in late-stage lung cancer. We investigated the significance of the SLIT2 gene located in this region to lung cancer progression. SLIT2 encodes an extracellular glycoprotein that can suppress breast cancer by regulating beta-catenin. In this study, we examined alterations in the structure or expression of SLIT2, its receptor ROBO1, and beta-catenin, along with the AKT/glycogen synthase kinase 3beta (GSK3beta)/beta-transducin repeat-containing protein (betaTrCP) pathway in lung cancer cell lines and patients. Low SLIT2 expression correlated with an upward trend of pathological stage and poorer survival in lung cancer patients. Importantly, SLIT2, betaTrCP, and beta-catenin expression levels predicted postoperative recurrence of lung cancer in patients. Stimulating SLIT2 expression by various methods increased the level of E-cadherin caused by attenuation of its transcriptional repressor SNAI1. Conversely, knocking down SLIT2 expression increased cell migration and reduced cell adhesion through coordinated deregulation of beta-catenin and E-cadherin/SNAI1 in the AKT/GSK3beta/betaTrCP pathway. Our findings indicate that SLIT2 suppresses lung cancer progression, defining it as a novel "theranostic" factor with potential as a therapeutic target and prognostic predictor in lung cancer. Cancer Res; 70(2); 543-51.

Highlights

Metastasis is a significant cause of death in lung cancer [1]
To examine the role of the SLIT2/roundabouts 1 (ROBO1) and β-transducin repeat-containing protein (βTrCP)/β-catenin pathways in cancer progression of non–small cell lung cancer (NSCLC), immunohistochemical analysis of SLIT2 and ROBO1 was performed on samples from 92 NSCLC patients
We provide the first compelling evidence that SLIT2 is a suppressor of NSCLC progression

Summary

Introduction

Metastasis is a significant cause of death in lung cancer [1]. Identification of genes and molecular pathways involved in lung cancer metastasis may lead to advances in therapeutics. Our previous data showed a high frequency of loss of heterozygosity at 4p15.3 and 3p12.3, the chromosomal sites of SLIT2 and roundabouts 1 (ROBO1) genes, in non–small cell lung cancer The chromosomal region 4p15.3 was frequently deleted in late-stage, but not early-stage, NSCLC patients, indicating its association with cancer progression [2, 3]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). SLIT2 is a ligand of the receptor ROBO1 that transducts intercellular signaling, for example, that of GTPase-activating proteins [5, 6]

Methods

Results

Conclusion