Abstract
BackgroundMany members of the ETS-domain transcription factor family are important drivers of tumourigenesis. In this context, their activation by Ras-ERK pathway signaling is particularly relevant to the tumourigenic properties of many ETS-domain transcription factors. The PEA3 subfamily of ETS-domain transcription factors have been implicated in tumour metastasis in several different cancers.ResultsHere, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in oesophageal adenocarcinomas and determined their role in oesophageal adenocarcinoma cell function. PEA3 plays an important role in controlling both the proliferation and invasive properties of OE33 oesophageal adenocarcinoma cells. A key target gene is MMP-1. The ERK MAP kinase pathway activates PEA3 subfamily members and also plays a role in these PEA3 controlled events, establishing the ERK-PEA3-MMP-1 axis as important in OE33 cells. PEA3 subfamily members are upregulated in human adenocarcinomas and expression correlates with MMP-1 expression and late stage metastatic disease. Enhanced ERK signaling is also more prevalent in late stage oesophageal adenocarcinomas.ConclusionsThis study shows that the ERK-PEA3-MMP-1 axis is upregulated in oesophageal adenocarcinoma cells and is a potentially important driver of the metastatic progression of oesophageal adenocarcinomas.
Highlights
Oesophageal adenocarcinoma is a devastating disease that has been rising year on year over the past three decades and is the 6th highest cause of cancer mortality in the UK, accounting for around 5% of all cancers [1,2]
Active ERK signaling correlates with enhanced stage suggesting an important role in promoting metastasis via PEA3 and ER81. These results indicate that the ERK-PEA3-MMP1 axis identified in oesophageal cancer cells is likely to be operative in oesophageal adenocarcinoma tissue
The expression of PEA3 family members in oesophageal tissues To establish whether members of the PEA3 subfamily ETS-domain transcription factors might play a role in oesophageal adenocarcinomas, we first determined the expression of PEA3 protein in normal oesophageal tissue and oesophageal adenocarcinomas by constructing a TMA from 27 samples from normal patients and 58 samples from oesophageal adenocarcinomas, along with samples from adjacent normal tissue
Summary
Oesophageal adenocarcinoma is a devastating disease that has been rising year on year over the past three decades and is the 6th highest cause of cancer mortality in the UK, accounting for around 5% of all cancers [1,2]. There are few clear prognostic indicators of susceptibility to developing oesophageal adenocarcinoma patients with Barrett’s oesophagus are thought to be more at risk to developing oesophageal adenocarcinoma. The progression from Barrett’s oesophagus to dysplasia and subsequent adenocarcinoma is unpredictable and poorly understood [7]. Many members of the ETS-domain transcription factor family are important drivers of tumourigenesis. In this context, their activation by Ras-ERK pathway signaling is relevant to the tumourigenic properties of many ETS-domain transcription factors. The PEA3 subfamily of ETS-domain transcription factors have been implicated in tumour metastasis in several different cancers
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