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Article

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
  • View Affiliations / Copyright

    Affiliations: Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
  • Pages: 1679-1687
    |
    Published online on: February 9, 2016
       https://doi.org/10.3892/ijo.2016.3388
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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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1 

Xing M: Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 13:184–199. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Roberts PJ and Der CJ: Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 26:3291–3310. 2007. View Article : Google Scholar : PubMed/NCBI

3 

Cantwell-Dorris ER, O'Leary JJ and Sheils OM: BRAFV600E: Implications for carcinogenesis and molecular therapy. Mol Cancer Ther. 10:385–394. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 159:676–690. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Luke JJ and Hodi FS: Vemurafenib and BRAF inhibition: A new class of treatment for metastatic melanoma. Clin Cancer Res. 18:9–14. 2012. View Article : Google Scholar

6 

Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, et al: BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 90:6373–6379. 2005. View Article : Google Scholar : PubMed/NCBI

7 

Kim TH, Park YJ, Lim JA, Ahn HY, Lee EK, Lee YJ, Kim KW, Hahn SK, Youn YK, Kim KH, et al: The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: A meta-analysis. Cancer. 118:1764–1773. 2012. View Article : Google Scholar

8 

Xing M, Alzahrani AS, Carson KA, Shong YK, Kim TY, Viola D, Elisei R, Bendlová B, Yip L, Mian C, et al: Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol. 33:42–50. 2015. View Article : Google Scholar :

9 

Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, et al: Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 363:809–819. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Kim KB, Cabanillas ME, Lazar AJ, Williams MD, Sanders DL, Ilagan JL, Nolop K, Lee RJ and Sherman SI: Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAF(V600E) mutation. Thyroid. 23:1277–1283. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Chook YM and Süel KE: Nuclear import by karyopherin-βs: Recognition and inhibition. Biochim Biophys Acta. 1813:1593–1606. 2011. View Article : Google Scholar :

12 

Stewart M: Molecular mechanism of the nuclear protein import cycle. Nat Rev Mol Cell Biol. 8:195–208. 2007. View Article : Google Scholar : PubMed/NCBI

13 

D'Angelo MA and Hetzer MW: Structure, dynamics and function of nuclear pore complexes. Trends Cell Biol. 18:456–466. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Kutay U, Bischoff FR, Kostka S, Kraft R and Görlich D: Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor. Cell. 90:1061–1071. 1997. View Article : Google Scholar : PubMed/NCBI

15 

Brinkmann U, Brinkmann E, Gallo M and Pastan I: Cloning and characterization of a cellular apoptosis susceptibility gene, the human homologue to the yeast chromosome segregation gene CSE1. Proc Natl Acad Sci USA. 92:10427–10431. 1995. View Article : Google Scholar : PubMed/NCBI

16 

Brinkmann U, Brinkmann E, Gallo M, Scherf U and Pastan I: Role of CAS, a human homologue to the yeast chromosome segregation gene CSE1, in toxin and tumor necrosis factor mediated apoptosis. Biochemistry. 35:6891–6899. 1996. View Article : Google Scholar : PubMed/NCBI

17 

Behrens P, Brinkmann U, Fogt F, Wernert N and Wellmann A: Implication of the proliferation and apoptosis associated CSE1L/CAS gene for breast cancer development. Anticancer Res. 21:2413–2417. 2001.PubMed/NCBI

18 

Wellmann A, Flemming P, Behrens P, Wuppermann K, Lang H, Oldhafer K, Pastan I and Brinkmann U: High expression of the proliferation and apoptosis associated CSE1L/CAS gene in hepatitis and liver neoplasms: Correlation with tumor progression. Int J Mol Med. 7:489–494. 2001.PubMed/NCBI

19 

Winkler J, Ori A, Holzer K, Sticht C, Dauch D, Eiteneuer EM, Pinna F, Geffers R, Ehemann V, Andres-Pons A, et al: Prosurvival function of the cellular apoptosis susceptibility/importin-α1 transport cycle is repressed by p53 in liver cancer. Hepatology. 60:884–895. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Brustmann H: Expression of cellular apoptosis susceptibility protein in serous ovarian carcinoma: A clinicopathologic and immunohistochemical study. Gynecol Oncol. 92:268–276. 2004. View Article : Google Scholar : PubMed/NCBI

21 

Peiró G, Diebold J, Baretton GB, Kimmig R and Löhrs U: Cellular apoptosis susceptibility gene expression in endometrial carcinoma: Correlation with Bcl-2, Bax, and caspase-3 expression and outcome. Int J Gynecol Pathol. 20:359–367. 2001. View Article : Google Scholar : PubMed/NCBI

22 

Bar-Shira A, Pinthus JH, Rozovsky U, Goldstein M, Sellers WR, Yaron Y, Eshhar Z and Orr-Urtreger A: Multiple genes in human 20q13 chromosomal region are involved in an advanced prostate cancer xenograft. Cancer Res. 62:6803–6807. 2002.PubMed/NCBI

23 

Wellmann A, Krenacs L, Fest T, Scherf U, Pastan I, Raffeld M and Brinkmann U: Localization of the cell proliferation and apoptosis-associated CAS protein in lymphoid neoplasms. Am J Pathol. 150:25–30. 1997.PubMed/NCBI

24 

Böni R, Wellmann A, Man YG, Hofbauer G and Brinkmann U: Expression of the proliferation and apoptosis-associated CAS protein in benign and malignant cutaneous melanocytic lesions. Am J Dermatopathol. 21:125–128. 1999. View Article : Google Scholar : PubMed/NCBI

25 

Tai CJ, Hsu CH, Shen SC, Lee WR and Jiang MC: Cellular apoptosis susceptibility (CSE1L/CAS) protein in cancer metastasis and chemotherapeutic drug-induced apoptosis. J Exp Clin Cancer Res. 29:1102010. View Article : Google Scholar : PubMed/NCBI

26 

Liao CF, Luo SF, Li LT, Lin CY, Chen YC and Jiang MC: CSE1L/CAS, the cellular apoptosis susceptibility protein, enhances invasion and metastasis but not proliferation of cancer cells. J Exp Clin Cancer Res. 27:152008. View Article : Google Scholar : PubMed/NCBI

27 

Jiang MC and Liao CF: CSE1/CAS overexpression inhibits the tumorigenicity of HT-29 colon cancer cells. J Exp Clin Cancer Res. 23:325–332. 2004.PubMed/NCBI

28 

Yoshiura K, Nishishita T, Nakaoka T and Yamashita N and Yamashita N: Inhibition of B16 melanoma growth and metastasis in C57BL mice by vaccination with a syngeneic endothelial cell line. J Exp Clin Cancer Res. 28:132009. View Article : Google Scholar : PubMed/NCBI

29 

Tai CJ, Shen SC, Lee WR, Liao CF, Deng WP, Chiou HY, Hsieh CI, Tung JN, Chen CS, Chiou JF, et al: Increased cellular apoptosis susceptibility (CSE1L/CAS) protein expression promotes protrusion extension and enhances migration of MCF-7 breast cancer cells. Exp Cell Res. 316:2969–2981. 2010. View Article : Google Scholar : PubMed/NCBI

30 

Tanaka T, Ohkubo S, Tatsuno I and Prives C: hCAS/CSE1L associates with chromatin and regulates expression of select p53 target genes. Cell. 130:638–650. 2007. View Article : Google Scholar : PubMed/NCBI

31 

Wang J, Lu Z, Wientjes MG and Au JL: Delivery of siRNA therapeutics: Barriers and carriers. AAPS J. 12:492–503. 2010. View Article : Google Scholar : PubMed/NCBI

32 

Senapedis WT, Baloglu E and Landesman Y: Clinical translation of nuclear export inhibitors in cancer. Semin Cancer Biol. 27:74–86. 2014. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Holzer K, Drucker E, Oliver S, Winkler J, Eiteneuer E, Herpel E, Breuhahn K and Singer S: Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation. Int J Oncol 48: 1679-1687, 2016.
APA
Holzer, K., Drucker, E., Oliver, S., Winkler, J., Eiteneuer, E., Herpel, E. ... Singer, S. (2016). Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation. International Journal of Oncology, 48, 1679-1687. https://doi.org/10.3892/ijo.2016.3388
MLA
Holzer, K., Drucker, E., Oliver, S., Winkler, J., Eiteneuer, E., Herpel, E., Breuhahn, K., Singer, S."Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation". International Journal of Oncology 48.4 (2016): 1679-1687.
Chicago
Holzer, K., Drucker, E., Oliver, S., Winkler, J., Eiteneuer, E., Herpel, E., Breuhahn, K., Singer, S."Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation". International Journal of Oncology 48, no. 4 (2016): 1679-1687. https://doi.org/10.3892/ijo.2016.3388
Copy and paste a formatted citation
x
Spandidos Publications style
Holzer K, Drucker E, Oliver S, Winkler J, Eiteneuer E, Herpel E, Breuhahn K and Singer S: Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation. Int J Oncol 48: 1679-1687, 2016.
APA
Holzer, K., Drucker, E., Oliver, S., Winkler, J., Eiteneuer, E., Herpel, E. ... Singer, S. (2016). Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation. International Journal of Oncology, 48, 1679-1687. https://doi.org/10.3892/ijo.2016.3388
MLA
Holzer, K., Drucker, E., Oliver, S., Winkler, J., Eiteneuer, E., Herpel, E., Breuhahn, K., Singer, S."Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation". International Journal of Oncology 48.4 (2016): 1679-1687.
Chicago
Holzer, K., Drucker, E., Oliver, S., Winkler, J., Eiteneuer, E., Herpel, E., Breuhahn, K., Singer, S."Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation". International Journal of Oncology 48, no. 4 (2016): 1679-1687. https://doi.org/10.3892/ijo.2016.3388
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