Epigenetic silencing of RASSF1A deregulates cytoskeleton and promotes malignant behavior of adrenocortical carcinoma

Molecular Cancer

Research

Manju L Prasad¹  Amir H Ameri²  Tobias Carling³  Annabelle L Fonseca³  James M Healy³  Reju Korah³  John W Kunstman³ 

[1] Department of Pathology, Yale University School of Medicine, New Haven, CT, USA;Department of Surgery, Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, Box 208062, 333 Cedar Street, TMP202, 06520, New Haven, CT, USA;Department of Surgery, Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, Box 208062, 333 Cedar Street, TMP202, 06520, New Haven, CT, USA;Departments of Surgery, Yale University School of Medicine, New Haven, CT, USA;

关键词: Adrenal cortex;    Carcinoma;    Adenoma;    RASSF1A;    Hypermethylation;    Epigenetic silencing;    Cytoskeleton;   

DOI  :  10.1186/1476-4598-12-87

 received in 2013-05-08, accepted in 2013-08-03,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundAdrenocortical carcinoma (ACC) is a rare endocrine malignancy with high mutational heterogeneity and a generally poor clinical outcome. Despite implicated roles of deregulated TP53, IGF-2 and Wnt signaling pathways, a clear genetic association or unique mutational link to the disease is still missing. Recent studies suggest a crucial role for epigenetic modifications in the genesis and/or progression of ACC. This study specifically evaluates the potential role of epigenetic silencing of RASSF1A, the most commonly silenced tumor suppressor gene, in adrenocortical malignancy.ResultsUsing adrenocortical tumor and normal tissue specimens, we show a significant reduction in expression of RASSF1A mRNA and protein in ACC. Methylation-sensitive and -dependent restriction enzyme based PCR assays revealed significant DNA hypermethylation of the RASSF1A promoter, suggesting an epigenetic mechanism for RASSF1A silencing in ACC. Conversely, the RASSF1A promoter methylation profile in benign adrenocortical adenomas (ACAs) was found to be very similar to that found in normal adrenal cortex. Enforced expression of ectopic RASSF1A in the SW-13 ACC cell line reduced the overall malignant behavior of the cells, which included impairment of invasion through the basement membrane, cell motility, and solitary cell survival and growth. On the other hand, expression of RASSF1A/A133S, a loss-of-function mutant form of RASSF1A, failed to elicit similar malignancy-suppressing responses in ACC cells. Moreover, association of RASSF1A with the cytoskeleton in RASSF1A-expressing ACC cells and normal adrenal cortex suggests a role for RASSF1A in modulating microtubule dynamics in the adrenal cortex, and thereby potentially blocking malignant progression.ConclusionsDownregulation of RASSF1A via promoter hypermethylation may play a role in the malignant progression of adrenocortical carcinoma possibly by abrogating differentiation-promoting RASSF1A- microtubule interactions.

【 授权许可】

Unknown   
© Korah et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.