TROP2 is epigenetically inactivated and modulates

Authors: 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

Publish Date: 2012/06/04

Volume: 4, Issue: 6, Pages: 472-485

PDF Link

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 growthNSCLC remains a major cause of cancer mortality worldwide The etiology of NSCLC especially in non‐smokers is still unknown and effective therapy is not available Trop‐2 is a cell‐surface glycoprotein that contains extracellular epidermal growth factor‐like and thyroglobulin type‐1 repeat domains Its cytoplasmic tail contains a conserved PIP2‐binding domain with one phosphorylation site S303 The TROP2 expression has been found to associate with tumour formation and progression of various cancers but positive and negative effects were both reported However the role of TROP2 in lung cancer remains unclear Improving our understanding of the molecular role played by Trop‐2 in lung carcinogenesis may help us to develop new strategies for more effective treatment and prevention of lung cancerWe explored the potential role of TROP2 gene in lung cancer with several different aspects including cancer genomics epigenetics in vitro in vivo and clinical studies These results suggested that TROP2 gene was downregulated in lung cancer patients via DNA hypermethylation on its promoter region Re‐expression of Trop‐2 in lung CL attenuates cell proliferation and colony formation while conversely TROP2 silencing promotes tumour growth We also showed that Trop‐2 may act on IGF‐1R signalling pathway to suppress the activation of AKT and ERK through disrupting the interaction between IGF‐1 and IGF‐1R The crosstalk between Trop‐2 and IGF‐1R signalling may play an important role on the tumour progression in lung adenocarcinomaWe showed that TROP2 expression is downregulated in lung adenocarcinoma through DNA hypermethylation on its promoter region Both IGFBP3 and Trop‐2 have conserved thyroglobulin type‐1 domains which may allow Trop‐2 to interfere with IGF‐1R signalling by interacting with IGF‐1 In addition downregulation of Trop‐2 induces the expression of slug which is one of the key players in lung cancer progression invasion/metastasis and EGFR‐TKI resistance The findings indicate the existence of important crosstalk between Trop‐2 signalling and EGFR‐TKI sensitivity suggesting that downregulation of Trop‐2 in lung adenocarcinoma may associate with the activation of IGF‐1R signalling and EGFR‐TKI resistance Trop‐2 may be a potential biomarker and therapeutic target in NSCLCAberrant expression and/or mutation of membrane proteins may lead to persistent activation of cell‐survival signalling cellular transformation and invasion as seen in various lung tumours The EGFR Grandis Sok 2004 and IGF‐1R Ludovini et al 2009 signalling pathways are typical examples of pathways whose dysregulation may drive lung cancer growth and malignancy Recently researchers successfully developed an effective strategy for treating non‐small cell lung cancer NSCLC by targeting the protein tyrosine kinases responsible for activating EGFR and IGF‐1R signalling Lee et al 2007 Shepherd et al 2005 This development further illustrates the importance of membrane proteins in lung cancer carcinogenesis

Keywords: