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, Marianna; Capiluongo, Anna; D’Andrea, Barbara; Vuttariello, Emilia; Luciano, Antonio; Cerchia, Laura; Chiappetta, Gennaro; Arra, Claudio

doi:10.3390/cancers10040092

Cited by 10 publications

(9 citation statements)

References 33 publications

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“…These data, even though limited by the low number of tumors that we could analyze ex-vivo, support an inhibitory role of PATZ1 on tumor cell proliferation and are consistent with our previous results showing that PATZ1 expression inhibits in vitro cell proliferation of FRTL5-Ras cells [19]. Furthermore, as consistent with previous studies [16,17,18], PATZ1 expression tends to be lost in vivo. It is likely downregulated as a consequence of the tumor aptitude to select cells that have a higher proliferative potential.…”

Section: Discussionsupporting

confidence: 92%

“…Indeed, a tumor suppressor role has been demonstrated for PATZ1 in vitro and in vivo by using human thyroid cancer, normal cells, and nude mice transplanted with these cells, respectively, where it counteracts EMT and partially induce the reverse process MET [ 16 , 17 ]. Moreover, we recently showed that the loss of one or two alleles of the Patz1 gene enhances thyroid carcinogenesis in mice transgenic for the RET/PTC1 oncogene [ 18 ]. On the other hand, with the present work, we showed that PATZ1 enhances the stemness potential of rat thyroid cancer cells and tumor engraftment in nude mice, thus suggesting an oncogenic role.…”

Section: Discussionmentioning

confidence: 99%

“…In thyroid cancer, PATZ1 expression has been investigated in human thyroid cancer specimens and found to be downregulated with respect to normal thyroid tissue and increasingly downregulated going from well differentiated papillary carcinomas to poorly differentiated and anaplastic carcinomas, which suggests a tumor suppressor role involved in counteracting thyroid cancer progression toward a less differentiated phenotype [ 16 , 17 ]. This hypothesis has been recently sustained by in vivo studies in Patz1 -ko mice mated with mice transgenic for the thyroid specific oncogene RET/PTC1 , which showed that homozygous deletion of the Patz1 gene worsens the thyroid cancer outcome in RET/PTC1 mice, by inducing the development of anaplastic thyroid carcinomas (ATC) and solid variants of papillary thyroid carcinomas (PTC) [ 18 ]. Restoration of PATZ1 expression in human thyroid cancer cells partially reverts their malignant phenotype [ 16 , 17 ], whereas its silencing induces malignant transformation of normal thyroid cells [ 17 ], thus confirming a tumor suppressor role for PATZ1 in thyroid carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Dual Oncogenic/Anti-Oncogenic Role of PATZ1 in FRTL5 Rat Thyroid Cells Transformed by the Ha-RasV12 Oncogene

Vitiello

Palma

Monaco

et al. 2019

Genes

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PATZ1 is a transcriptional factor downregulated in thyroid cancer whose re-expression in thyroid cancer cells leads to a partial reversion of the malignant phenotype, including the capacity to proliferate, migrate, and undergo epithelial-to-mesenchymal transition. We have recently shown that PATZ1 is specifically downregulated downstream of the Ras oncogenic signaling through miR-29b, and that restoration of PATZ1 in Ha-Ras transformed FRTL5 rat thyroid cells is able to inhibit their capacities to proliferate and migrate in vitro. Here, we analyzed the impact of PATZ1 expression on the in vivo tumorigenesis of these cells. Surprisingly, FRTL5-Ras-PATZ1 cells showed enhanced tumor initiation when engrafted in nude mice, even if their tumor growth rate was reduced compared to that of FRTL5-Ras control cells. To further investigate the cause of the enhanced tumor engraftment of FRTL5-Ras-PATZ1 cells, we analyzed the stem-like potential of these cells through their capacity to grow as thyrospheres. The results showed that restoration of PATZ1 expression in these cells increases stem cell markers’ expression and self-renewal ability of the thyrospheres while limiting their growth capacity. Therefore, we suggest that PATZ1 may play a role in enhancing the stem cell potential of thyroid cancer cells, but, at the same time, it impairs the proliferation of non-stem cells.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dual Oncogenic/Anti-Oncogenic Role of PATZ1 in FRTL5 Rat Thyroid Cells Transformed by the Ha-RasV12 Oncogene

Vitiello

Palma

Monaco

et al. 2019

Genes

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“…A role for PATZ1 has been demonstrated in various malignancies such as thyroid and testicular cancer (Fedele et al, 2008(Fedele et al, , 2017Valentino, Palmieri, Vitiello, Pierantoni et al, 2013;Chiappetta et al, 2015;Vitiello et al, 2016;Monaco et al, 2018). The interaction between PATZ1 and the tumour suppressor p53 (Valentino, Palmieri, Vitiello, Pierantoni et al, 2013;Valentino, Palmieri, Vitiello, Simeone et al, 2013;Chiappetta et al, 2015;Keskin et al, 2015) mediated by a motif in the zinc-finger DNA-binding domain rather than the BTB domain also links this protein to cancer.…”

Section: Discussionmentioning

confidence: 99%

Structural analysis of the PATZ1 BTB domain homodimer

Piepoli

Alt

Atılgan

et al. 2020

Acta Cryst Sect D Struct Biol

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PATZ1 is a ubiquitously expressed transcriptional repressor belonging to the ZBTB family that is functionally expressed in T lymphocytes. PATZ1 targets the CD8 gene in lymphocyte development and interacts with the p53 protein to control genes that are important in proliferation and in the DNA-damage response. PATZ1 exerts its activity through an N-terminal BTB domain that mediates dimerization and co-repressor interactions and a C-terminal zincfinger motif-containing domain that mediates DNA binding. Here, the crystal structures of the murine and zebrafish PATZ1 BTB domains are reported at 2.3 and 1.8 Å resolution, respectively. The structures revealed that the PATZ1 BTB domain forms a stable homodimer with a lateral surface groove, as in other ZBTB structures. Analysis of the lateral groove revealed a large acidic patch in this region, which contrasts with the previously resolved basic co-repressor binding interface of BCL6. A large 30-amino-acid glycine-and alanine-rich central loop, which is unique to mammalian PATZ1 amongst all ZBTB proteins, could not be resolved, probably owing to its flexibility. Molecular-dynamics simulations suggest a contribution of this loop to modulation of the mammalian BTB dimerization interface. ISSN 2059-7983 research papers 582 Piepoli et al. PATZ1 BTB domain homodimer Acta Cryst. (2020). D76, 581-593Figure 1Sequence alignment of BTB domains of ZBTB transcription factors identifies a unique central region in PATZ1 that is conserved in mammals. (a) Sequence alignment of PATZ1 BTB domains from selected vertebrate species. The unique central sequence of the A2/B3 loop that is conserved in mammals and is missing in fish and amphibians is indicated in bold. (b) Sequence alignment of selected human ZBTB proteins and their predicted secondary structure. The sequences of the human PATZ1 and cKrox BTB domains with their unique extra region between the A2 helix and B3 strand are shown above. The PATZ1 amino acids that correspond to this region without electron-density assignments from the crystal structure are shown in bold. Arrows and rods identify predicted conserved -strand and -helical regions. The eight BTB domains with solved structures are annotated on the left with their common names in addition to the ZBTB nomenclature. Shading, asterisks, colons and periods identify conserved residues according to the Clustal format. A consensus sequence is shown at the bottom, with the three predicted degron residues involved in BTB domain stability indicated by arrows. research papers Acta Cryst. (2020). D76, 581-593 Piepoli et al. PATZ1 BTB domain homodimer 583 research papers Acta Cryst. (2020). D76, 581-593 Piepoli et al. PATZ1 BTB domain homodimer 591

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“…Although recent improvements in treating PTC, for example surgery, radioiodine and endocrine therapy. PTC cells still showed occasional metastasis, loss of differentiation, anaplastic thyroid and high aggressiveness [4,5]. Hence, the elucidation of mechanism and novel targets of signaling involved in PTC oncogenesis are still required.…”

Section: Introductionmentioning

confidence: 99%

KIFC1 accelerates the proliferation, migration and invasion of papillary thyroid cancer cells via MAPK signaling

Nie¹,

Han²,

Wen³

et al. 2020

Preprint

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Kinesin family member C1 (KIFC1) acts as a kind of minus end-directed motorized protein and is considered as an oncogene of some cancer types. However, no studies have fully elucidated its biological activity and molecular mechanisms in papillary thyroid cancer (PTC). The study focused on reporting the overexpression of KIFC1 in cell lines and tissues of PTC. Moreover, clinicopathological features analysis showed that KIFC overexpression is significantly correlated with extrathyroidal invasion and lymph node metastasis. Knockdown of KIFC1 significantly reduced cell growth, migration and invasion in PTC cells, and concomitant increased levels of differentiation markers, such as Tg and Nis. Knockdown of KIFC1 markedly increased the expression level of epithelial cell marker (E-cadherin), and decreased the expression levels of epithelial-mesenchymal transition (EMT) related transcriptional factor N-cadherin, Snail and ZEB1. Further study revealed that knockdown of KIFC1 downregulated stemness markers ALDH2 and SOX2, and inhibited the MAPK signaling cascades and downstream signaling, including p-ERK, ERK, p-JNK, JNK, MMP2, and MMP9, which can affect the expression of the EMT associated factors. Taken together, we reported that KIFC1 might promoted the proliferation, migration and invasion of PTC cells and offer a candidate molecular target for therapeutic intervention.

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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

Cited by 10 publications

References 33 publications

Dual Oncogenic/Anti-Oncogenic Role of PATZ1 in FRTL5 Rat Thyroid Cells Transformed by the Ha-RasV12 Oncogene

Dual Oncogenic/Anti-Oncogenic Role of PATZ1 in FRTL5 Rat Thyroid Cells Transformed by the Ha-RasV12 Oncogene

Structural analysis of the PATZ1 BTB domain homodimer

KIFC1 accelerates the proliferation, migration and invasion of papillary thyroid cancer cells via MAPK signaling

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