Pituitary homeobox 2 (PITX2) promotes thyroid carcinogenesis by activation of cyclin D2

Huang, Yue; Guigon, Céline J.; Fan, Jin‐Hu; Cheng, Sheue-yann; Zhu, Guo‐Zhang

doi:10.4161/cc.9.7.11126

Cited by 40 publications

(44 citation statements)

References 32 publications

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“…In addition to its regulation by Wnt, PITX2 itself could directly activate Wnt ligand genes, activating the respective canonical Wnt/b-catenin signaling pathway, thus contributing to cancer progression (8). Overexpression of PITX2 has been frequently studied in human cancers, including thyroid, colorectal, and ovarian cancers (9)(10)(11). We recently found that PITX2 was frequently upregulated in ESCC tissues, as compared with the normal epithelial tissue.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Zhang

Chen

et al. 2017

Clinical Cancer Research

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Purpose: We previously reported the oncogenic role of pairedlike homeodomain 2 (PITX2) in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to identify the miRNA regulators of PITX2 and the mechanism underlying the pathogenesis of ESCC.Experimental Design: Using miRNA profiling and bioinformatics analyses, we identified miR-644a as a negative mediator of PITX2 in ESCC. A series of in vivo and in vitro assays were performed to confirm the effect of miR-644a on PITX2-mediated ESCC malignancy.Results: ESCC cells and tissues expressed less miR-644a than normal epithelial controls. In patient samples, lower expression of miR-644a in ESCC tissues was significantly correlated with tumor recurrence and/or metastasis, such that miR-644a, PITX2, and the combination of the two were independent prognostic indicators for ESCC patient's survival (P < 0.05). Gain-and lossof-function studies demonstrated that miR-644a inhibited ESCC cell growth, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. In addition, miR-644a dramatically suppressed self-renewal and stem cell-like traits in ESCC cells. Furthermore, the effect of upregulation of miR-644a was similar to that of PITX2 knockdown in ESCC cells. Mechanistic studies revealed that miR-644a attenuates ESCC cells' malignancy and stem cell-associated phenotype, at least partially, by inactivation of the Akt/GSK-3b/b-catenin signaling pathway through PITX2. Furthermore, promoter hypermethylation caused downregulation of miR-644a in ESCC.Conclusions: Downregulation of miR-644a plays an important role in promoting both aggressiveness and stem-like traits of ESCC cells, suggesting that miR-644a may be useful as a novel prognostic biomarker or therapeutic target for the disease. Clin Cancer Res; 23(1); 298-310. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 99%

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Zhang

Chen

et al. 2017

Clinical Cancer Research

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“…[24][25][26][27] Interestingly, Cyclins A1 and D2 are transcriptional targets of Pitx2 that are also over-expressed in human tumors. 26,28 Thus, the regulation of Pitx2 by p27 suggests its participation in the mentioned biological functions and in tumor development through this novel mechanism. Because decreased levels of p27 in human tumors are associated with a worse prognosis, 29 our data suggest these tumors have to show increased levels of Pitx2 and this could participate in their major malignancy.…”

Section: Discussionmentioning

confidence: 97%

p27Kip1 represses the Pitx2-mediated expression of p21Cip1 and regulates DNA replication during cell cycle progression

et al. 2016

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The tumor suppressor p21 regulates cell cycle progression and peaks at mid/late G. However, the mechanisms regulating its expression during cell cycle are poorly understood. We found that embryonic fibroblasts from p27 null mice at early passages progress slowly through the cell cycle. These cells present an elevated basal expression of p21 suggesting that p27 participates to its repression. Mechanistically, we found that p27 represses the expression of Pitx2 (an activator of p21 expression) by associating with the ASE-regulatory region of this gene together with an E2F4 repressive complex. Furthermore, we found that Pitx2 binds to the p21 promoter and induces its transcription. Finally, silencing Pitx2 or p21 in proliferating cells accelerates DNA replication and cell cycle progression. Collectively, these results demonstrate an unprecedented connection between p27, Pitx2 and p21 relevant for the regulation of cell cycle progression and cancer and for understanding human pathologies associated with p27 germline mutations.

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“…Indeed, the best-known Pitx2 targets would appear to increase cell division and, as such, loss of Pitx2c would be expected to reduce the number of mitoses (Kioussi et al, 2002;Baek et al, 2003); Pitx2 is overexpressed in many cancers and is generally thought to promote cell proliferation. Recent proteomic and transcriptomic approaches have produced datasets of potential interactors and novel targets of Pitx2 from a variety of different cell types, including those affected in individuals with Axenfeld-Rieger syndrome, but the pertinence of these with respect to asymmetric development in the epithalamus remains to be determined (Huang et al, 2010;Paylakhi et al, 2011). The apparent antagonistic activities of Nodal and Pitx2c on parapineal cell numbers could perhaps provide clues.…”

Section: Discussionmentioning

confidence: 99%

Pitx2c ensures habenular asymmetry by restricting parapineal cell number

et al. 2014

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Left-right (L/R) asymmetries in the brain are thought to underlie lateralised cognitive functions. Understanding how neuroanatomical asymmetries are established has been achieved through the study of the zebrafish epithalamus. Morphological symmetry in the epithalamus is broken by leftward migration of the parapineal, which is required for the subsequent elaboration of left habenular identity; the habenular nuclei flank the midline and show L/R asymmetries in marker expression and connectivity. The Nodal target pitx2c is expressed in the left epithalamus, but nothing is known about its role during the establishment of asymmetry in the brain. We show that abrogating Pitx2c function leads to the right habenula adopting aspects of left character, and to an increase in parapineal cell numbers. Parapineal ablation in Pitx2c loss of function results in right habenular isomerism, indicating that the parapineal is required for the left character detected in the right habenula in this context. Partial parapineal ablation in the absence of Pitx2c, however, reduces the number of parapineal cells to wild-type levels and restores habenular asymmetry. We provide evidence suggesting that antagonism between Nodal and Pitx2c activities sets an upper limit on parapineal cell numbers. We conclude that restricting parapineal cell number is crucial for the correct elaboration of epithalamic asymmetry.

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Pituitary homeobox 2 (PITX2) promotes thyroid carcinogenesis by activation of cyclin D2

Cited by 40 publications

References 32 publications

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

p27Kip1 represses the Pitx2-mediated expression of p21Cip1 and regulates DNA replication during cell cycle progression

Pitx2c ensures habenular asymmetry by restricting parapineal cell number

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