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TCF21 hypermethylation regulates renal tumor cell clonogenic proliferation and migration.

TCF21 hypermethylation regulates renal tumor cell clonogenic proliferation and migration.
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Gooskens SL, Klasson TD, Gremmels H, Logister I, Pieters R, Perlman EJ, Giles RH, van den Heuvel-Eibrink MM,


Gooskens SL, Klasson TD, Gremmels H, Logister I, Pieters R, Perlman EJ, Giles RH, van den Heuvel-Eibrink MM, (click to view)

Gooskens SL, Klasson TD, Gremmels H, Logister I, Pieters R, Perlman EJ, Giles RH, van den Heuvel-Eibrink MM,

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Molecular oncology 2017 10 27() doi 10.1002/1878-0261.12149
Abstract

We recently identified hypermethylation at the gene promoter of transcription factor 21 (TCF21) in clear cell sarcoma of the kidney (CCSK), a rare pediatric renal tumor. TCF21 is a transcription factor involved in tubular epithelial development of the kidney and is a candidate tumor suppressor. As there are no in vitro models of CCSK, we employed a well-established clear cell renal cell carcinoma (ccRCC) cell line, 786-O, which also manifests high methylation at the TCF21 promoter, with consequent low TCF21 expression. The tumor suppressor function of TCF21 has not been functionally addressed in ccRCC cells; we aimed to explore the functional potential of TCF21 expression in ccRCC cells in vitro. 786-O clones stably transfected with either pBABE-TCF21-HA construct or pBABE vector alone were functionally analyzed. We found that ectopic expression of TCF21 in 786-O cells results in a trend towards decreased cell proliferation (not significant) and significantlyldecreased migration compared to mock-transfected 786-O cells. Although the number of colonies established in colony formation assays was not different between 786-O clones, colony size was significantly reduced in 786-O cells expressing TCF21. To investigate whether the changes in migration were due to epithelial-to-mesenchymal transition changes, we interrogated the expression of selected epithelial and mesenchymal markers. Although we observed upregulation of mRNA and protein levels of epithelial marker E-cadherin in clones overexpressing TCF21, this did not result in surface expression of E-cadherin as measured by FACS and immunofluorescence. Furthermore, mRNA expression of the mesenchymal markers VIM and SNAI1 was not significantly decreased in TCF21-expressing 786-O cells, while protein levels of vimentin were markedly decreased. We conclude that re-expression of TCF21 in renal cancer cells that have silenced their endogenous TCF21 locus through hypermethylation results in reduced clonogenic proliferation, reduced migration, and reduced mesenchymal-like characteristics, suggesting a tumor suppressor function for TCF21.

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