SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis.
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.
Tseng
Ruo-Chia
RC
Institute of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, Republic of China.
Lee
Shih-Hua
SH
Hsu
Han-Shui
HS
Chen
Ben-Han
BH
Tsai
Wan-Ching
WC
Tzao
Ching
C
Wang
Yi-Ching
YC
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D019175:DNA Methylation; D000077209:Decitabine; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
D001374:Azacitidine; D015820:Cadherins; D000077209:Decitabine; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D051058:Oncogene Protein v-akt; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C471644:BTRC protein, human; C000605506:GSK3B protein, human