Abstract
The Protocadherin 10 (PCDH10) is inactivated often by promoter hypermethylation in various human tumors, but its possible functional role as a tumor suppressor gene is not established. In this study, we identify PCDH10 as a novel Wnt pathway regulatory element in endometrioid endometrial carcinoma (EEC). PCDH10 was downregulated in EEC tumor cells by aberrant methylation of its promoter. Restoring PCDH10 levels suppressed cell growth and triggered apoptosis in EEC cells and tumor xenografts. Gene expression profiling revealed as part of the transcriptomic changes induced by PCDH10 a reduction in levels of MALAT1, a long noncoding RNA, that mediated tumor suppression functions of PCDH10 in EEC cells. We found that MALAT1 transcription was regulated by Wnt/β-catenin signaling via TCF promoter binding and PCDH10 decreased MALAT1 by modulating this pathway. Clinically, MALAT1 expression was associated with multiple parameters in patients with EEC. Taken together, our findings establish a novel PCDH10-Wnt/β-catenin-MALAT1 regulatory axis that contributes to EEC development. Cancer Res; 74(18); 5103-17. ©2014 AACR.
Highlights
Endometrial cancer is the most common gynecologic malignancy and ranks fourth in whole malignancies among women [1]
We identified Protocadherin 10 (PCDH10) as a tumor suppressor downregulated in endometrial carcinoma (EEC)
The downregulation of PCDH10 has been reported in a wide range of cancers [6, 9,10,11,12,13,14,15,16], as far as we know, this is the first study to demonstrate its association with EEC
Summary
Endometrial cancer is the most common gynecologic malignancy and ranks fourth in whole malignancies among women [1]. Endometrioid endometrial carcinoma (EEC), accounting for $80% to 90% of the whole cases, originates from epithelial cells lining the endometrium and is often associated with estrogen stimulation, hormone receptor positivity, obesity, and favorable prognosis [2]. Key mutational events have been characterized in EEC, but the underlying molecular mechanisms involving oncogenic or tumor suppressive factors remain poorly elucidated [3, 4]. We have discovered a novel miR193–YY1–adenomatous polyposis coli (APC) regulatory axis that exerts functional roles in EEC development [5]. The transcription factor YY1 plays an oncogenic function through. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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