Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation

Holzer,Kerstin; Drucker,Elisabeth; Oliver,Scott; Winkler,Juliane; Eiteneuer,Eva; Herpel,Esther; Breuhahn,Kai; Singer,Stephan

doi:10.3892/ijo.2016.3388

Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation

Authors:
- Kerstin Holzer
- Elisabeth Drucker
- Scott Oliver
- Juliane Winkler
- Eva Eiteneuer
- Esther Herpel
- Kai Breuhahn
- Stephan Singer
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Affiliations: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
Published online on: February 9, 2016 https://doi.org/10.3892/ijo.2016.3388
Pages: 1679-1687

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Abstract

Thyroid carcinoma is among the most common malignant endocrine neoplasms with a rising incidence. Genetic alterations occurring in thyroid cancer frequently affect the RAS/RAF/MEK/ERK-pathway such as the oncogenic, kinase-activating BRAFV600E mutation. Nuclear transport receptors including importins and exportins represent an important part of the nuclear transport machinery providing nucleo-cytoplasmic exchange of macromolecules. The role of nuclear transport receptors in the development and progression of thyroid carcinomas is largely unknown. Here, we studied the expression and function of the exportin cellular apoptosis susceptibility (CAS) in thyroid carcinogenesis and its link to the BRAFV600E mutation. By using immunohistochemistry (IHC) we found significantly increased IHC scores of CAS in primary papillary (PTC) and medullary (MTC), but not in follicular (FTC) thyroid carcinoma compared to non-tumorous (NT) thyroid tissue. Interestingly, metastases of the aforementioned subtypes including FTC showed a strong CAS positivity. Among PTCs we observed that CAS immunoreactivity was significantly higher in the tumors harboring the BRAFV600E mutation. Furthermore, depletion of CAS by RNAi in the BRAFV600E-positive PTC cell line B-CPAP led to reduced tumor cell growth measured by crystal violet assays. This phenotype could be attributed to reduced proliferation and increased cell death as assayed by BrdU ELISAs and immunoblotting for PARP-cleavage, respectively. Finally, we found additive effects of CAS siRNA and vemurafenib treatment in B-CPAP cells. Collectively, these data suggest that CAS overexpression in thyroid carcinoma depends on the subtype and the disease stage. Our findings also indicate that CAS maintains PTC cell proliferation and survival. Targeting CAS could represent a potential therapeutic approach particularly in combination with BRAF inhibitors such as vemurafenib in BRAFV600E-positive tumors.

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