title: Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation.
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 BRAF(V600E) 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 BRAF(V600E) 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 BRAF(V600E) mutation. Furthermore, depletion of CAS by RNAi in the BRAF(V600E)-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 BRAF(V600E)-positive tumors.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Holzer
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Drucker
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Scott
authors.initials: S
authors.lastname: Oliver
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Eiteneuer
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Singer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D029563:Cellular Apoptosis Susceptibility Protein / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D029563:Cellular Apoptosis Susceptibility Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf