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Signalling pathways in succinate dehydrogenase B ‐associated renal carcinoma
Author(s) -
Fleming Stewart,
Mayer Nick J,
Vlatkovic Ljiljana J,
McLean Joanne,
McConachie Michelle,
Baty David
Publication year - 2014
Publication title -
histopathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.626
H-Index - 124
eISSN - 1365-2559
pISSN - 0309-0167
DOI - 10.1111/his.12250
Subject(s) - ampk , biology , gsk 3 , cancer research , sdhb , pi3k/akt/mtor pathway , signal transduction , succinate dehydrogenase , immunohistochemistry , kinase , phosphorylation , protein kinase a , mitochondrion , microbiology and biotechnology , biochemistry , gene , mutation , immunology , germline mutation
Aims Renal tumours have recently been described in association with mutations in the gene encoding the B subunit of succinate dehydrogenase, a mitochondrial K rebs cycle and electron transport chain enzyme ( SDHB ‐associated renal cell carcinomas). The aim of this study was to investigate the roles of different signalling pathways in the pathogenesis of these tumours. Methods and results We used immunohistochemistry and antibodies against phospho‐specific epitopes to examine the activity of three potential signalling pathways in tumour cells of three genetically confirmed cases of SDHB ‐associated renal cell carcinomas. We found no evidence supporting a role for either the mTOR [p‐ mTOR ( S er2448), p‐ S 6 riboprotein ( S er235/236)] or hypoxia‐inducible (carbonic anhydrase 9 and EGFR ) pathways. However, there was immunohistochemical reactivity for phosphorylated AMP ‐dependent kinase (p‐ AMPK T hr172) and glycogen synthase kinase 3 ( GSK 3) phosphorylation (p‐ GSK 3 S er12), and nuclear expression of cyclin D 1. Conclusions We suggest that these tumours may arise through a mechanism involving ATP depletion, activation of AMPK , and induction of cyclin D 1, and that this may be a unique pathway of tumour development that has the potential for therapeutic intervention in these rare tumours.