Dataset Information

DEAR1 is a chromosome 1p35 tumor suppressor and master regulator of TGF-?-driven epithelial-mesenchymal transition.

ABSTRACT: UNLABELLED:Deletion of chromosome 1p35 is a common event in epithelial malignancies. We report that DEAR1 (annotated as TRIM62) is a chromosome 1p35 tumor suppressor that undergoes mutation, copy number variation, and loss of expression in human tumors. Targeted disruption in the mouse recapitulates this human tumor spectrum, with both Dear1(-/-) and Dear1(+/-) mice developing primarily epithelial adenocarcinomas and lymphoma with evidence of metastasis in a subset of mice. DEAR1 loss of function in the presence of TGF-? results in failure of acinar morphogenesis, upregulation of epithelial-mesenchymal transition (EMT) markers, anoikis resistance, migration, and invasion. Furthermore, DEAR1 blocks TGF-?-SMAD3 signaling, resulting in decreased nuclear phosphorylated SMAD3 by binding to and promoting the ubiquitination of SMAD3, the major effector of TGF-?-induced EMT. Moreover, DEAR1 loss increases levels of SMAD3 downstream effectors SNAIL1 and SNAIL2, with genetic alteration of DEAR1/SNAIL2 serving as prognostic markers of overall poor survival in a cohort of 889 cases of invasive breast cancer. SIGNIFICANCE:Cumulative results provide compelling evidence that DEAR1 is a critical tumor suppressor involved in multiple human cancers and provide a novel paradigm for regulation of TGF-?-induced EMT through DEAR1's regulation of SMAD3 protein levels. DEAR1 loss of function has important therapeutic implications for targeted therapies aimed at the TGF-?-SMAD3 pathway.

SUBMITTER: Chen N

PROVIDER: S-EPMC4107927 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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DEAR1 is a chromosome 1p35 tumor suppressor and master regulator of TGF-β-driven epithelial-mesenchymal transition.

Chen Nanyue N Balasenthil Seetharaman S Reuther Jacquelyn J Frayna Aileen A Wang Ying Y Chandler Dawn S DS Abruzzo Lynne V LV Rashid Asif A Rodriguez Jaime J Lozano Guillermina G Cao Yu Y Lokken Erica E Chen Jinyun J Frazier Marsha L ML Sahin Aysegul A AA Wistuba Ignacio I II Sen Subrata S Lott Steven T ST Killary Ann McNeill AM

Cancer discovery 20130709 10

<h4>Unlabelled</h4>Deletion of chromosome 1p35 is a common event in epithelial malignancies. We report that DEAR1 (annotated as TRIM62) is a chromosome 1p35 tumor suppressor that undergoes mutation, copy number variation, and loss of expression in human tumors. Targeted disruption in the mouse recapitulates this human tumor spectrum, with both Dear1(-/-) and Dear1(+/-) mice developing primarily epithelial adenocarcinomas and lymphoma with evidence of metastasis in a subset of mice. DEAR1 loss of ...[more]

PMID: 23838884

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Project description:STUDY QUESTION:Does the upregulation of the zinc finger E-box binding homeobox 2 (ZEB2) transcription factor in human trophoblast cells lead to alterations in gene expression consistent with an epithelial-mesenchymal transition (EMT) and a consequent increase in invasiveness? SUMMARY ANSWER:Overexpression of ZEB2 results in an epithelial-mesenchymal shift in gene expression accompanied by a substantial increase in the invasive capacity of human trophoblast cells. WHAT IS KNOWN ALREADY:In-vivo results have shown that cytotrophoblast differentiation into extravillous trophoblast involves an epithelial-mesenchymal transition. The only EMT master regulatory factor which shows changes consistent with extravillous trophoblast EMT status and invasive capacity is the ZEB2 transcription factor. STUDY DESIGN, SIZE, DURATION:This study is a mechanistic investigation of the role of ZEB2 in trophoblast differentiation. We generated stable ZEB2 overexpression clones using the epithelial BeWo and JEG3 choriocarcinoma lines. Using these clones, we investigated the effects of ZEB2 overexpression on the expression of EMT-associated genes and proteins, cell morphology and invasive capability. PARTICIPANTS/MATERIALS, SETTING, METHODS:We used lentiviral transduction to overexpress ZEB2 in BeWo and JEG3 cells. Stable clones were selected based on ZEB2 expression and morphology. A PCR array of EMT-associated genes was used to probe gene expression. Protein measurements were performed by western blotting. Gain-of-function was assessed by quantitatively measuring cell invasion rates using a Transwell assay, a 3D bioprinted placenta model and the xCelligenceTM platform. MAIN RESULTS AND THE ROLE OF CHANCE:The four selected clones (2 × BeWo, 2 × JEG3, based on ZEB2 expression and morphology) all showed gene expression changes indicative of an EMT. The two clones (1 × BeWo, 1 × JEG3) showing >40-fold increase in ZEB2 expression also displayed increased ZEB2 protein; the others, with increases in ZEB2 expression <14-fold did not. The two high ZEB2-expressing clones demonstrated robust increases in invasive capacity, as assessed by three types of invasion assay. These data identify ZEB2-mediated transcription as a key mechanism transforming the epithelial-like trophoblast into cells with a mesenchymal, invasive phenotype. LARGE SCALE DATA:PCR array data have been deposited in the GEO database under accession number GSE116532. LIMITATIONS, REASONS FOR CAUTION:These are in-vitro studies using choriocarcinoma cells and so the results should be interpreted in view of these limitations. Nevertheless, the data are consistent with in-vivo findings and are replicated in two different cell lines. WIDER IMPLICATIONS OF THE FINDINGS:The combination of these data with the in-vivo findings clearly identify ZEB2-mediated EMT as the mechanism for cytotrophoblast differentiation into extravillous trophoblast. Having characterized these cellular mechanisms, it will now be possible to identify the intracellular and extracellular regulatory components which control ZEB2 and trophoblast differentiation. It will also be possible to identify the aberrant factors which alter differentiation in invasive pathologies such as preeclampsia and abnormally invasive placenta (AKA accreta, increta, percreta). STUDY FUNDING AND COMPETING INTEREST(s):Funding was provided by the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and Surgery at Hackensack Meridian Health, Hackensack, NJ. The 3D bioprinted placental model work done in Drs Kim and Fisher's labs was supported by the Children's National Medical Center. The xCELLigence work done in Dr Birge's lab was supported by NIH CA165077. The authors declare no competing interests.

Dataset Information

DEAR1 is a chromosome 1p35 tumor suppressor and master regulator of TGF-?-driven epithelial-mesenchymal transition.

Publications

DEAR1 is a chromosome 1p35 tumor suppressor and master regulator of TGF-β-driven epithelial-mesenchymal transition.

Similar Datasets

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