Loss of One or Two PATZ1 Alleles Has a Critical Role in the Progression of Thyroid Carcinomas Induced by the RET/PTC1 Oncogene

Mario Monaco, Giuseppe Palma, Michela Vitiello, Anna Capiluongo, Barbara D'Andrea, Emilia Vuttariello, Antonio Luciano, Laura Cerchia, Gennaro Chiappetta, Claudio Arra, Alfredo Fusco, Monica Fedele

Research output: Contribution to journalArticle

Abstract

POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is an emerging cancer-related gene that is downregulated in different human malignancies, including thyroid cancer, where its levels gradually decrease going from papillary thyroid carcinomas (PTC) to poorly differentiated and undifferentiated highly aggressive anaplastic carcinomas (ATC). The restoration of PATZ1 expression in thyroid cancer cells reverted their malignant phenotype by inducing mesenchymal-to-epithelial transition, thus validating a tumor suppressor role for PATZ1 and suggesting its involvement in thyroid cancer progression. Here, we investigated the consequences of the homozygous and heterozygous loss of PATZ1 in the context of a mouse modeling of PTC, represented by mice carrying the RET/PTC1 oncogene under the thyroid specific control of the thyroglobulin promoter RET/PTC1 (RET/PTC1TG). The phenotypic analysis of RET/PTC1TG mice intercrossed with Patz1-knockout mice revealed that deficiency of both Patz1 alleles enhanced thyroid cancer incidence in RET/PTC1TG mice, but not the heterozygous knockout of the Patz1 gene. However, both RET/PTC1TG;Patz1+/- and RET/PTC1TG;Patz1-/- mice developed a more aggressive thyroid cancer phenotype-characterized by higher Ki-67 expression, presence of ATCs, and increased incidence of solid variants of PTC-than that shown by RET/PTC1TG; Patz1+/+ compound mice. These results confirm that PATZ1 downregulation has a critical role in thyroid carcinogenesis, showing that it cooperates with RET/PTC1 in thyroid cancer progression.

Original languageEnglish
JournalCancers
Volume10
Issue number4
DOIs
Publication statusPublished - Mar 27 2018

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Oncogenes
Thyroid Neoplasms
Alleles
AT-Hook Motifs
Thyroid Gland
Down-Regulation
Phenotype
Gene Knockout Techniques
Epithelial-Mesenchymal Transition
Thyroglobulin
Neoplasm Genes
Zinc Fingers
Incidence
Knockout Mice
Neoplasms
Carcinogenesis
Carcinoma
Papillary Thyroid cancer
Proteins

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Loss of One or Two PATZ1 Alleles Has a Critical Role in the Progression of Thyroid Carcinomas Induced by the RET/PTC1 Oncogene. / Monaco, Mario; Palma, Giuseppe; Vitiello, Michela; Capiluongo, Anna; D'Andrea, Barbara; Vuttariello, Emilia; Luciano, Antonio; Cerchia, Laura; Chiappetta, Gennaro; Arra, Claudio; Fusco, Alfredo; Fedele, Monica.

In: Cancers, Vol. 10, No. 4, 27.03.2018.

Research output: Contribution to journalArticle

Monaco, M, Palma, G, Vitiello, M, Capiluongo, A, D'Andrea, B, Vuttariello, E, Luciano, A, Cerchia, L, Chiappetta, G, Arra, C, Fusco, A & Fedele, M 2018, 'Loss of One or Two PATZ1 Alleles Has a Critical Role in the Progression of Thyroid Carcinomas Induced by the RET/PTC1 Oncogene', Cancers, vol. 10, no. 4. https://doi.org/10.3390/cancers10040092
Monaco, Mario ; Palma, Giuseppe ; Vitiello, Michela ; Capiluongo, Anna ; D'Andrea, Barbara ; Vuttariello, Emilia ; Luciano, Antonio ; Cerchia, Laura ; Chiappetta, Gennaro ; Arra, Claudio ; Fusco, Alfredo ; Fedele, Monica. / Loss of One or Two PATZ1 Alleles Has a Critical Role in the Progression of Thyroid Carcinomas Induced by the RET/PTC1 Oncogene. In: Cancers. 2018 ; Vol. 10, No. 4.
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AU - Palma, Giuseppe

AU - Vitiello, Michela

AU - Capiluongo, Anna

AU - D'Andrea, Barbara

AU - Vuttariello, Emilia

AU - Luciano, Antonio

AU - Cerchia, Laura

AU - Chiappetta, Gennaro

AU - Arra, Claudio

AU - Fusco, Alfredo

AU - Fedele, Monica

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AB - POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is an emerging cancer-related gene that is downregulated in different human malignancies, including thyroid cancer, where its levels gradually decrease going from papillary thyroid carcinomas (PTC) to poorly differentiated and undifferentiated highly aggressive anaplastic carcinomas (ATC). The restoration of PATZ1 expression in thyroid cancer cells reverted their malignant phenotype by inducing mesenchymal-to-epithelial transition, thus validating a tumor suppressor role for PATZ1 and suggesting its involvement in thyroid cancer progression. Here, we investigated the consequences of the homozygous and heterozygous loss of PATZ1 in the context of a mouse modeling of PTC, represented by mice carrying the RET/PTC1 oncogene under the thyroid specific control of the thyroglobulin promoter RET/PTC1 (RET/PTC1TG). The phenotypic analysis of RET/PTC1TG mice intercrossed with Patz1-knockout mice revealed that deficiency of both Patz1 alleles enhanced thyroid cancer incidence in RET/PTC1TG mice, but not the heterozygous knockout of the Patz1 gene. However, both RET/PTC1TG;Patz1+/- and RET/PTC1TG;Patz1-/- mice developed a more aggressive thyroid cancer phenotype-characterized by higher Ki-67 expression, presence of ATCs, and increased incidence of solid variants of PTC-than that shown by RET/PTC1TG; Patz1+/+ compound mice. These results confirm that PATZ1 downregulation has a critical role in thyroid carcinogenesis, showing that it cooperates with RET/PTC1 in thyroid cancer progression.

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