TROP2 is epigenetically inactivated and modulates IGF-1R signalling in lung adenocarcinoma
Journal
EMBO Molecular Medicine
Journal Volume
4
Journal Issue
6
Pages
472-485
Date Issued
2012
Author(s)
Abstract
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). 5-Aza-2′-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/β-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. ? 2012 EMBO Molecular Medicine.
SDGs
Other Subjects
5 aza 2' deoxycytidine; antineoplastic agent; beta catenin; bisulfite; cell surface protein; DNA; messenger RNA; mitogen activated protein kinase; protein kinase B; short hairpin RNA; somatomedin C; somatomedin C receptor; Trop 2 protein; unclassified drug; adult; apoptosis; article; attenuation; cancer cell; cancer cell culture; cancer chemotherapy; cancer radiotherapy; cancer tissue; cell proliferation; colony formation; controlled study; CpG island; diagnostic test accuracy study; DNA methylation; epigenetics; female; gene activation; gene expression; gene inactivation; gene sequence; gene silencing; genetic transfection; heterozygosity loss; histopathology; human; human cell; human tissue; immunohistochemistry; low drug dose; lung adenocarcinoma; lung carcinogenesis; lung resection; major clinical study; male; methylation specific polymerase chain reaction; polymerase chain reaction; priority journal; promoter region; protein binding; protein expression; receptor down regulation; signal transduction; tumor cell; tumor growth; Western blotting; Adenocarcinoma; Aged; Animals; Antigens, Neoplasm; Azacitidine; Base Sequence; Cell Adhesion Molecules; Cell Line, Tumor; Disease Models, Animal; Epigenesis, Genetic; Female; Gene Expression; Gene Expression Regulation; Gene Silencing; Histocytochemistry; Humans; Immunohistochemistry; Lung Neoplasms; Male; Mice; Middle Aged; Models, Biological; Molecular Sequence Data; Receptor, IGF Type 1; Signal Transduction
Type
journal article