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Dysregulated mitogen‐activated protein kinase signalling as an oncogenic basis for clear cell sarcoma of the kidney
Author(s) -
Kenny Colin,
McDonagh Naomi,
Lazaro Antonio,
O'Meara Elaine,
Klinger Rut,
O'Connor Darran,
Roche Fiona,
Hokamp Karsten,
O'Sullivan Maureen J
Publication year - 2018
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5020
Subject(s) - biology , pi3k/akt/mtor pathway , cancer research , mapk/erk pathway , protein kinase b , protein kinase a , transfection , cell culture , kinase , microbiology and biotechnology , signal transduction , genetics
The oncogenic mechanisms and tumour biology underpinning clear cell sarcoma of the kidney (CCSK), the second commonest paediatric renal malignancy, are poorly understood and currently, therapy depends heavily on doxorubicin with cardiotoxic side‐effects. Previously, we characterized the balanced t(10;17)(q22;p13) chromosomal translocation, identified at that time as the only recurrent genetic aberration in CCSK. This translocation results in an in‐frame fusion of the genes YWHAE (encoding 14‐3‐3ϵ) and NUTM2 , with a somatic incidence of 12%. Clinico‐pathological features of that cohort suggested that this aberration might be associated with higher stage and grade disease. Since no primary CCSK cell line exists, we generated various stably transfected cell lines containing doxycycline‐inducible HA‐tagged YWHAE–NUTM2 , in order to study the effect of expressing this transcript. 14‐3‐3ϵ–NUTM2‐expressing cells exhibited significantly greater cell migration compared to isogenic controls. Gene and protein expression studies were indicative of dysregulated MAPK/PI3K–AKT signalling, and by blocking these pathways using neutralizing antibodies, the migratory advantage conferred by the transcript was abrogated. Importantly, CCSK tumour samples similarly show up‐regulation/activation of these pathways. These results support the oncogenic role of 14‐3‐3ϵ–NUTM2 in CCSK and provide avenues for the exploration of novel therapeutic approaches. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.