TROP2 is epigenetically inactivated and modulates IGF-1R signalling in lung adenocarcinoma

Jau-Chen Lin, Yi-Ying Wu, Jing-Yi Wu, Tzu-Chieh Lin, Chen-Tu Wu, Yih-Leong Chang, Yuh-Shan Jou, Tse-Ming Hong, Pan-Chyr Yang
2012 EMBO Molecular Medicine  
Trop-2, a cell surface glycoprotein, contains both extracellular epidermal growth factor-like and thyroglobulin type-1 repeat domains. Low TROP2 expression was observed in lung adenocarcinoma tissues as compared with their normal counterparts. The lack of expression could be due to either the loss of heterozygosity (LOH) or hypermethylation of the CpG island DNA of TROP2 upstream promoter region as confirmed by bisulphite sequencing and methylation-specific (MS) polymerase chain reaction (PCR).
more » ... 5-Aza-2 0 -deoxycytidine treatment on lung cancer cell (CL) lines, CL1-5 and A549, reversed the hypermethylation status and elevated both TROP2 mRNA and protein expression levels. Enforced expression of TROP2 in the lung CL line H1299 reduced AKT as well as ERK activation and suppressed cell proliferation and colony formation. Conversely, silencing TROP2 with shRNA transfection in the less efficiently tumour-forming cell line H322M enhanced AKT activation and increased tumour growth. Trop-2 could attenuate IGF-1R signalling-mediated AKT/b-catenin and ERK activation through a direct binding of IGF1. In conclusion, inactivation of TROP2 due to LOH or by DNA methylation may play an important role in lung cancer tumourigenicity through losing its suppressive effect on IGF-1R signalling and tumour growth. Research Article Epigenetic inactivation of TROP2 promotes lung tumours These authors contributed equally to this work. 472 ß 2012 EMBO Molecular Medicine EMBO Mol Med 4, 472-485 www.embomolmed.org Research Article Jau-Chen Lin et al. www.embomolmed.org EMBO Mol Med 4, 472-485 ß 2012 EMBO Molecular Medicine ß 2012 EMBO Molecular Medicine EMBO Mol Med 4, 472-485 www.embomolmed.org Research Article Jau-Chen Lin et al. www.embomolmed.org EMBO Mol Med 4, 472-485 ß 2012 EMBO Molecular Medicine ß 2012 EMBO Molecular Medicine EMBO Mol Med 4, 472-485 www.embomolmed.org Human DNA sequence clone RP4-592A1 http://www.ncbi.nlm.nih.gov/nuccore/AL035411.28 Conserved domain database in the NCBI website http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi TROP2 (Human) http://www.ncbi.nlm.nih.gov/nuccore/BC009409 Web Promoter Scan Service
doi:10.1002/emmm.201200222 pmid:22419550 pmcid:PMC3443948 fatcat:pigcdu24ajh2jb6e7mvk3ljsg4