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Histopathology. 2014 Mar;64(4):477-83. doi: 10.1111/his.12250. Epub 2013 Nov 18.

Signalling pathways in succinate dehydrogenase B-associated renal carcinoma.

Author information

1
Division of Molecular Medicine, University of Dundee, Dundee, UK.

Abstract

AIMS:

Renal tumours have recently been described in association with mutations in the gene encoding the B subunit of succinate dehydrogenase, a mitochondrial Krebs 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 (Ser2448), p-S6 riboprotein (Ser235/236)] or hypoxia-inducible (carbonic anhydrase 9 and EGFR) pathways. However, there was immunohistochemical reactivity for phosphorylated AMP-dependent kinase (p-AMPK Thr172) and glycogen synthase kinase 3 (GSK3) phosphorylation (p-GSK3 Ser12), and nuclear expression of cyclin D1.

CONCLUSIONS:

We suggest that these tumours may arise through a mechanism involving ATP depletion, activation of AMPK, and induction of cyclin D1, and that this may be a unique pathway of tumour development that has the potential for therapeutic intervention in these rare tumours.

KEYWORDS:

AMPK; cell signalling; renal carcinoma; succinate dehydrogenase

PMID:
24236567
DOI:
10.1111/his.12250
[Indexed for MEDLINE]

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