SMAD4 gene promoter mutations in patients with thyroid tumors
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2015
Authors
Nikolić, AleksandraRistanović, Momcilo
Zivaljević, Vladan
Divac Rankov, Aleksandra
Radojković, Dragica
Paunović, Ivan
Article (Published version)
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As a key component of the transforming growth factor beta (TGFB) pathway, which regulates the expression of thyroid-specific genes, tumor suppressor SMAD4 is crucial for thyroid development and function. Aberrant expression of SMAD4 in thyroid tumor tissue was reported and mutations affecting the coding region have been detected, but a potential role of mutations in SMAD4 gene regulatory regions remains unexplored. The aim of this study was to analyze SMAD4 gene promoters in thyroid tumors. A total of 76 thyroidectomy specimens were studied, including 42 malignant and 34 benign tumors. The presence of mutations in four SMAD4 gene promoters was analyzed in thyroid tumor tissue and peripheral blood by PCR and DNA sequencing. The expression and intracellular localization of endogenous SMAD4 protein in selected tumor samples was studied by immunostaining and confocal microscopy. Of three novel variants detected, two were within promoter A (-204T/C and -5C/T) and one in promoter D (-180delA...). Unlike somatic mutations previously detected in the nearby region, germline mutation -180delA in promoter D doesn't appear to affect SMAD4 expression in the thyroid tumor tissue. However, all newly detected SMAD4 promoter variants affect predicted binding sites of transcription factors involved in cell cycle regulation and should be further characterized functionally. Although not directly involved in carcinogenesis, detected variants may alter SMAD4 transcriptional regulation to some extent. Considering that dosage dependence is of great importance for the role of SMAD4 protein as a tumor suppressor, potential clinical significance of SMAD4 gene promoter mutations is worth further investigation.
Keywords:
Thyroid tumor / SMAD4 / Promoter / MutationSource:
Experimental and Molecular Pathology, 2015, 99, 1, 100-103Publisher:
- Academic Press Inc Elsevier Science, San Diego
Funding / projects:
- Complex diseases as a model system for phenotype modulation- structural and functional analysis of molecular biomarkers (RS-MESTD-Basic Research (BR or ON)-173008)
DOI: 10.1016/j.yexmp.2015.06.005
ISSN: 0014-4800
PubMed: 26079547
WoS: 000358814200016
Scopus: 2-s2.0-84934887095
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Nikolić, Aleksandra AU - Ristanović, Momcilo AU - Zivaljević, Vladan AU - Divac Rankov, Aleksandra AU - Radojković, Dragica AU - Paunović, Ivan PY - 2015 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/797 AB - As a key component of the transforming growth factor beta (TGFB) pathway, which regulates the expression of thyroid-specific genes, tumor suppressor SMAD4 is crucial for thyroid development and function. Aberrant expression of SMAD4 in thyroid tumor tissue was reported and mutations affecting the coding region have been detected, but a potential role of mutations in SMAD4 gene regulatory regions remains unexplored. The aim of this study was to analyze SMAD4 gene promoters in thyroid tumors. A total of 76 thyroidectomy specimens were studied, including 42 malignant and 34 benign tumors. The presence of mutations in four SMAD4 gene promoters was analyzed in thyroid tumor tissue and peripheral blood by PCR and DNA sequencing. The expression and intracellular localization of endogenous SMAD4 protein in selected tumor samples was studied by immunostaining and confocal microscopy. Of three novel variants detected, two were within promoter A (-204T/C and -5C/T) and one in promoter D (-180delA). Unlike somatic mutations previously detected in the nearby region, germline mutation -180delA in promoter D doesn't appear to affect SMAD4 expression in the thyroid tumor tissue. However, all newly detected SMAD4 promoter variants affect predicted binding sites of transcription factors involved in cell cycle regulation and should be further characterized functionally. Although not directly involved in carcinogenesis, detected variants may alter SMAD4 transcriptional regulation to some extent. Considering that dosage dependence is of great importance for the role of SMAD4 protein as a tumor suppressor, potential clinical significance of SMAD4 gene promoter mutations is worth further investigation. PB - Academic Press Inc Elsevier Science, San Diego T2 - Experimental and Molecular Pathology T1 - SMAD4 gene promoter mutations in patients with thyroid tumors EP - 103 IS - 1 SP - 100 VL - 99 DO - 10.1016/j.yexmp.2015.06.005 ER -
@article{ author = "Nikolić, Aleksandra and Ristanović, Momcilo and Zivaljević, Vladan and Divac Rankov, Aleksandra and Radojković, Dragica and Paunović, Ivan", year = "2015", abstract = "As a key component of the transforming growth factor beta (TGFB) pathway, which regulates the expression of thyroid-specific genes, tumor suppressor SMAD4 is crucial for thyroid development and function. Aberrant expression of SMAD4 in thyroid tumor tissue was reported and mutations affecting the coding region have been detected, but a potential role of mutations in SMAD4 gene regulatory regions remains unexplored. The aim of this study was to analyze SMAD4 gene promoters in thyroid tumors. A total of 76 thyroidectomy specimens were studied, including 42 malignant and 34 benign tumors. The presence of mutations in four SMAD4 gene promoters was analyzed in thyroid tumor tissue and peripheral blood by PCR and DNA sequencing. The expression and intracellular localization of endogenous SMAD4 protein in selected tumor samples was studied by immunostaining and confocal microscopy. Of three novel variants detected, two were within promoter A (-204T/C and -5C/T) and one in promoter D (-180delA). Unlike somatic mutations previously detected in the nearby region, germline mutation -180delA in promoter D doesn't appear to affect SMAD4 expression in the thyroid tumor tissue. However, all newly detected SMAD4 promoter variants affect predicted binding sites of transcription factors involved in cell cycle regulation and should be further characterized functionally. Although not directly involved in carcinogenesis, detected variants may alter SMAD4 transcriptional regulation to some extent. Considering that dosage dependence is of great importance for the role of SMAD4 protein as a tumor suppressor, potential clinical significance of SMAD4 gene promoter mutations is worth further investigation.", publisher = "Academic Press Inc Elsevier Science, San Diego", journal = "Experimental and Molecular Pathology", title = "SMAD4 gene promoter mutations in patients with thyroid tumors", pages = "103-100", number = "1", volume = "99", doi = "10.1016/j.yexmp.2015.06.005" }
Nikolić, A., Ristanović, M., Zivaljević, V., Divac Rankov, A., Radojković, D.,& Paunović, I.. (2015). SMAD4 gene promoter mutations in patients with thyroid tumors. in Experimental and Molecular Pathology Academic Press Inc Elsevier Science, San Diego., 99(1), 100-103. https://doi.org/10.1016/j.yexmp.2015.06.005
Nikolić A, Ristanović M, Zivaljević V, Divac Rankov A, Radojković D, Paunović I. SMAD4 gene promoter mutations in patients with thyroid tumors. in Experimental and Molecular Pathology. 2015;99(1):100-103. doi:10.1016/j.yexmp.2015.06.005 .
Nikolić, Aleksandra, Ristanović, Momcilo, Zivaljević, Vladan, Divac Rankov, Aleksandra, Radojković, Dragica, Paunović, Ivan, "SMAD4 gene promoter mutations in patients with thyroid tumors" in Experimental and Molecular Pathology, 99, no. 1 (2015):100-103, https://doi.org/10.1016/j.yexmp.2015.06.005 . .