Expression, function, and regulation of the embryonic transcription factor TBX1 in parathyroid tumors

Chiara Verdelli, Laura Avagliano, Vito Guarnieri, Filomena Cetani, Stefano Ferrero, Leonardo Vicentini, Edoardo Beretta, Alfredo Scillitani, Pasquale Creo, Gaetano Pietro Bulfamante, Valentina Vaira, Sabrina Corbetta

Research output: Contribution to journalArticle

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Abstract

Transcription factors active in embryonic parathyroid cells can be maintained in adult parathyroids and be involved in tumorigenesis. TBX1, the candidate gene of 22q11.2-DiGeorge syndrome, which includes congenital hypoparathyroidism, is involved in parathyroid embryogenesis. The study aimed to investigate expression, function, and regulation of the parathyroid embryonic transcription factor TBX1 in human parathyroid adult normal and tumor tissues. TBX1 transcripts were detected in normal parathyroids and were deregulated in parathyroid tumors. Using immunohistochemistry, TBX1 protein was detected, mainly at the nuclear level, in a consistent proportion of cells in normal adult parathyroids, whereas TBX1 immunoreactivity was absent in fetal parathyroids. TBX1-expressing cells were markedly reduced in about a half of adenomas (PAds) and two-thirds of carcinomas and the proportion of TBX1-expressing cells negatively correlated with the serum albumin-corrected calcium levels in the analyzed tumors. Moreover, a subset of TBX1-expressing tumor cells coexpressed PTH. TBX1 silencing in HEK293 cells, expressing endogenous TBX1, increased the proportion of cells in the G0/G1 phase of cell cycle; concomitantly, CDKN1A/p21 and CDKN2A/p16 transcripts increased and ID1 mRNA levels decreased. TBX1 silencing exerted similar effects in PAd-derived cells, suggesting cell cycle arrest. Moreover, in PAd-derived cells GCM2 and PTH mRNA levels were unaffected by TBX1 deficiency, whereas it was associated with reduction of WNT5A, an antagonist of canonical WNT/β-catenin pathway. WNT/β-catenin activation by lithium chloride inhibited TBX1 expression levels both in HEK293 and PAd-derived cells. In conclusion, TBX1 is expressed in adult parathyroid cells and deregulated in parathyroid tumors, where TBX1 deficiency may potentially contribute to the low proliferative nature of parathyroid tumors.

Original languageEnglish
Pages (from-to)1488-1499
Number of pages12
JournalLaboratory Investigation
Volume97
Issue number12
DOIs
Publication statusPublished - Dec 2017

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Transcription Factors
Neoplasms
Catenins
DiGeorge Syndrome
Lithium Chloride
Hypoparathyroidism
Cell Cycle Resting Phase
Messenger RNA
HEK293 Cells
G1 Phase
Cell Cycle Checkpoints
Serum Albumin
Adenoma
Embryonic Development
Cell Cycle
Carcinogenesis
Immunohistochemistry
Calcium
Carcinoma
Genes

Keywords

  • Cell Cycle
  • Female
  • Fetus
  • Gene Silencing
  • HEK293 Cells
  • Humans
  • Male
  • Middle Aged
  • Parathyroid Glands
  • Parathyroid Neoplasms
  • T-Box Domain Proteins
  • Journal Article

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Expression, function, and regulation of the embryonic transcription factor TBX1 in parathyroid tumors. / Verdelli, Chiara; Avagliano, Laura; Guarnieri, Vito; Cetani, Filomena; Ferrero, Stefano; Vicentini, Leonardo; Beretta, Edoardo; Scillitani, Alfredo; Creo, Pasquale; Bulfamante, Gaetano Pietro; Vaira, Valentina; Corbetta, Sabrina.

In: Laboratory Investigation, Vol. 97, No. 12, 12.2017, p. 1488-1499.

Research output: Contribution to journalArticle

Verdelli, Chiara ; Avagliano, Laura ; Guarnieri, Vito ; Cetani, Filomena ; Ferrero, Stefano ; Vicentini, Leonardo ; Beretta, Edoardo ; Scillitani, Alfredo ; Creo, Pasquale ; Bulfamante, Gaetano Pietro ; Vaira, Valentina ; Corbetta, Sabrina. / Expression, function, and regulation of the embryonic transcription factor TBX1 in parathyroid tumors. In: Laboratory Investigation. 2017 ; Vol. 97, No. 12. pp. 1488-1499.
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abstract = "Transcription factors active in embryonic parathyroid cells can be maintained in adult parathyroids and be involved in tumorigenesis. TBX1, the candidate gene of 22q11.2-DiGeorge syndrome, which includes congenital hypoparathyroidism, is involved in parathyroid embryogenesis. The study aimed to investigate expression, function, and regulation of the parathyroid embryonic transcription factor TBX1 in human parathyroid adult normal and tumor tissues. TBX1 transcripts were detected in normal parathyroids and were deregulated in parathyroid tumors. Using immunohistochemistry, TBX1 protein was detected, mainly at the nuclear level, in a consistent proportion of cells in normal adult parathyroids, whereas TBX1 immunoreactivity was absent in fetal parathyroids. TBX1-expressing cells were markedly reduced in about a half of adenomas (PAds) and two-thirds of carcinomas and the proportion of TBX1-expressing cells negatively correlated with the serum albumin-corrected calcium levels in the analyzed tumors. Moreover, a subset of TBX1-expressing tumor cells coexpressed PTH. TBX1 silencing in HEK293 cells, expressing endogenous TBX1, increased the proportion of cells in the G0/G1 phase of cell cycle; concomitantly, CDKN1A/p21 and CDKN2A/p16 transcripts increased and ID1 mRNA levels decreased. TBX1 silencing exerted similar effects in PAd-derived cells, suggesting cell cycle arrest. Moreover, in PAd-derived cells GCM2 and PTH mRNA levels were unaffected by TBX1 deficiency, whereas it was associated with reduction of WNT5A, an antagonist of canonical WNT/β-catenin pathway. WNT/β-catenin activation by lithium chloride inhibited TBX1 expression levels both in HEK293 and PAd-derived cells. In conclusion, TBX1 is expressed in adult parathyroid cells and deregulated in parathyroid tumors, where TBX1 deficiency may potentially contribute to the low proliferative nature of parathyroid tumors.",
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