The ERK MAP kinase-PEA3/ETV4-MMP-1 axis is operative in oesophageal adenocarcinoma

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.

ETS-related Transcription Factors ETV4 and ETV5 Are Involved in Proliferation and Induction of Differentiation-associated Genes in Embryonic Stem (ES) Cells

“…Ectopic forced expression of ETV4 in breast cancer cells promotes proliferation of MDA 231 breast cancer cells with induction of cyclin D3 expression (62), and functional inhibition of ETV4 or ETV5 by RNAi in mouse mammary tumor cells reduces cell proliferation with decreased expression of cyclin D1 and D2 (63). Proliferation of esophageal adenocarcinoma cells is also regulated by ETV4 (64). Our present data show reduced proliferation of Etv4/5 dKO ES cells.…”

Barrett’s to Oesophageal Cancer Sequence: A Model of Inflammatory-Driven Upper Gastrointestinal Cancer

“…They are involved in the processes of inflammation and carcinogenesis, as many are produced by inflammatory and stromal cells, and so may have a role in inflammatory-driven cancers. In the oesophagus, MMP-1 has been found to be increased in BO and Barrett's-derived cancers and in OAC cell lines; it also correlates with lymph-node metastasis and poor prognosis [49][50][51]. Another study found that MMP-1, -3, -7 and -10 along with TIMP-1 were increased along the sequence from BO to OAC [19].…”

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

“…ETV genes (i.e., members of the PEA3 subfamily of ETS genes) have previously been implicated as transcriptional regulators of cancer invasion and metastasis in various cancer types, and several of their targets include genes associated with metastatic dissemination (51,52,62,63). Furthermore, it has previously been proposed that ETV4 may be particularly relevant for prostate cancer progression, because it is robustly up-regulated in PC3 human prostate cancer cells, and its depletion in these cells impairs their anchorageindependent growth in cell culture (50).…”

“…7 A and B; SI Appendix and Datasets S4 and S5). Notably, these ETS transcription factors have been previously implicated in mediating Ras signaling in prostate (49,50) and other cancers (51,52), as well as in regulation of EMT markers, including Snail (53,54).…”