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HRG/HER2/HER3 signaling promotes AhR-mediated Memo-1 expression and migration in colorectal cancer

2016-12-12 16:19:36

Oncogene; 12 December 2016: /DOI:10.1038/onc.2016.390

V Bogoevska, G Wolters-Eisfeld, B T Hofmann, A T El Gammal, B Mercanoglu, F Gebauer, Y K Vashist, D Bogoevski, D Perez, N Gagliani, J R Izbicki, M Bockhorn and C Güngör



Abstract


Colorectal cancer (CRC) is a complex disease with still unsatisfactory prognosis even in western societies, although substantial progress has been made in pre-screening programs, surgical techniques and targeted therapy options. Mediator of motility-1 (Memo-1) was previously recognized as an important effector of cell migration downstream of receptor tyrosine kinase signaling in breast cancer. This study identified Memo-1 as frequently overexpressed in CRC and established a close link between extracellular HER2 activation, AhR/ARNT transcriptional activity and Memo-1 expression. Dissection of the hMemo-1 gene promoter using reporter assays and chromatin IP techniques revealed recruitment of Aryl hydrocarbon receptor (AhR)/Aryl hydrocarbon receptor nuclear-translocator (ARNT) complex, which positively influenced Memo-1 expression in cancer cells. We found that Memo-1 depletion negatively influenced the cellular actin network and that its expression is required for HER2-mediated cell migration and invasion. Moreover, analyses of Memo-1 expression in primary CRC revealed correlation with clinical parameters that point to Memo-1 as a new prognostic factor of aggressive disease in CRC patients. Altogether, these observations demonstrate that Memo-1 is an important downstream regulator of HER2-driven CRC cell migration and invasion through connecting extracellular signals from membrane to the cytoskeletal actin network.



Empire's RP11-749C19 BAC Clone was used to subclone Memo-1 promoter sequence
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