Deregulation of the <i>HOXA10</i> Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition

Yoshida, Hiroyuki; Broaddus, Russell R.; Cheng, Wenjun; Xie, Shuai; Naora, Honami

doi:10.1158/0008-5472.can-05-2828

Cited by 123 publications

(112 citation statements)

References 42 publications

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“…41 Recently, several transcription factors that are molecular mediators of epithelial-to-mesenchymal transition, such as Twist, ZEB1, and HOXA10, have been shown to be expressed in endometrial carcinoma. 8,42,43 Of particular interest is that ZEB1 has an expression pattern in endometrial carcinoma quite similar to that for S100A4. None of these transcription factors has been shown previously to directly regulate S100A4 expression.…”

Section: Discussionmentioning

confidence: 99%

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

et al. 2007

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Expression of various S100 genes has been associated with clinically aggressive subtypes in a variety of different cancers. We hypothesized that S100A4 would be overexpressed in endometrial carcinoma compared to benign endometrium. Quantitative real-time RT-PCR (qRT-PCR) was used to quantify the mRNA level of S100A4 in benign endometrium (n ¼ 19), endometrioid adenocarcinoma (n ¼ 87), and non-endometrioid tumors (n ¼ 21). Immunohistochemistry was used to verify the results of qRT-PCR and to assess protein localization. Possible mechanisms of S100A4 gene regulation were also examined. S100A4 was overexpressed in the grade 3 endometrioid tumors, uterine papillary serous carcinoma, and uterine malignant mixed mü llerian tumor. Expression in grade 1 and grade 2 endometrioid tumors was comparable to that of normal endometrium, which was quite low. Expression was significantly higher in stage III and IV tumors compared with stage I. By immunohistochemistry, S100A4 was expressed in the tumor cell cytoplasm of poorly differentiated tumors, but was not detected in normal endometrial glandular epithelium. In benign endometrium, S100A4 expression was confined to stromal cells. S100A4 was not regulated by estrogen or progesterone, and its expression in tumors was not significantly correlated to estrogen receptor or progesterone receptor content. However, methylation of the S100A4 gene was detected in benign endometrium and grade 1 tumors with low S100A4 expression. In contrast, grade 3 endometrioid tumors with high S100A4 mRNA and protein expression showed no methylation of the gene. These methylation results were verified in endometrial cancer cell lines with differential baseline levels of S100A4 protein. These results suggest that hypomethylation is an important mechanism of regulating the expression of the S100A4 gene. These results support the emerging concept that hypomethylation may play a role in the upregulation of genes during later stages of tumorigenesis. Keywords: endometrial cancer; S100A gene family; S100A4; methylation Endometrial carcinoma is the most common malignant neoplasm of the female genital tract and the fourth most frequently diagnosed cancer in women, following cancers of the breast, lung, and colon. 1 On the basis of histological and clinical features, endometrial carcinoma has been classified into two types. 2-4 Type I tumors (approximately 80% of all endometrial carcinomas) are typically low-grade (grade 1 or grade 2) endometrioid adenocarcinoma, most of which are confined to the uterus and have a favorable prognosis. Type II tumors (approximately 20%) are comprised of uterine papillary serous carcinoma, malignant mixed mü llerian tumors, and clear cell carcinoma. The nature of high-grade (grade 3) endometrioid adenocarcinoma is more controversial, as a subset may behave more like the Type II tumors. Type II cancers are associated with extrauterine spread and carry a high mortality rate. Previous studies have documented interesting molecular differences between endometrioid and nonendometrioid ...

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Section: Discussionmentioning

confidence: 99%

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

et al. 2007

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“…Common genetic abnormalities in EC include mutations in PTEN, K-RAS, PI3CA and CTNNB1; TP53 mutations are very rare (Prat et al, 2007). Epigenetic studies have linked hypermethylation to the loss of expression of DNA repair enzymes, MLH1 and O6-methylguanine DNA methyltransferase (MGMT), the tumor suppressors, PTEN, p53 and TIG1, the progesterone receptor, the b-catenin/Wnt signaling regulator, APC (adenomatous polyposis coli), the transcription factor, C/EBPa, and the differentiation gene, HoxA10 (Furlan et al, 2006;Shang, 2006;Yoshida et al, 2006;Zhou et al, 2007). Alternatively, hypomethylation has been described as a contributing factor for oncogene overexpression in EC.…”

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DNA methylation inhibits p53-mediated survivin repression

2009

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The molecular progression of endometrial cancer is poorly understood, and both genetic and epigenetic factors play a role. Survivin is a member of the inhibitor of apoptosis (IAP) gene family and contains a canonical CpG island that has been described as epigenetically regulated. As survivin is overexpressed in endometrial tumors, we hypothesized that hypomethylation could explain this expression pattern. Surprisingly, methylation-specific PCR and pyrosequencing showed that survivin was hypermethylated in endometrial tumors and correlated with increased survivin expression. We speculated that methylation could inhibit the binding of p53, a repressor of survivin expression. Our data indicates that demethylation of the survivin promoter by decitabine results in p53-dependent survivin repression and that p53 binding can be inhibited by DNA methylation. We are the first to report survivin de-repression by DNA methylation. We also present microarray data, which suggest that de-repression by methylation is a general mechanism of p53 regulation. Demethylation induced by decitabine is traditionally thought to be active in tumors by allowing the reexpression of tumor suppressor genes. However, our results indicate that an additional important mechanism is to decrease the expression of oncogenes.

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“…The role of HOXA10 in human endometrial epithelial cells is unclear. Studies have demonstrated that the expression of HOXA10 in endometrial adenocarcinoma, which arises from the glandular epithelium, is either increased (Lane et al, 2004) or decreased (Yoshida et al, 2006) compared with normal endometrium. Thus, it remains uncertain as to the role of HOXA10 in endometrial adenocarcinoma or in normal epithelial cell differentation.…”

Section: Discussionmentioning

confidence: 99%

Global Analysis of Genes Regulated by HOXA10 in Decidualization Reveals a Role in Cell Proliferation.

Kim

Hardt

2008

Biology of Reproduction

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Homeobox (HOX) A10 is essential for fertility as demonstrated in transgenic mice, specifically affecting implantation and decidualization. Its role in human decidualization, however, remains unknown. In this study, we used gene silencing followed by microarray analysis to decipher the role of HOXA10 during decidualization of human endometrial stromal cells (HESCs). HOXA10 was knocked down using siRNA oligonucleotide transfection and cells were treated with estradiol, medroxyprogesterone acetate and dibutyryl cAMP (H + cAMP) to induce decidualization. Genes significantly regulated were identified using the Affymetrix microarray chip. With this method, 2361 transcripts were significantly altered by 1.5-fold or higher (P < 0.05) with H + cAMP treatment only. Of these genes, 258 were significantly up-regulated by HOXA10 knockdown and 236 transcripts were significantly down-regulated by more than 1.5-fold, totaling 494 genes that were regulated by HOXA10 during decidualization. Data analysis using the Ingenuity System revealed that many of the genes regulated by HOXA10 knockdown during H + cAMP treatment were associated with cell cycle. Real-time PCR was used to confirm that HOXA10 knockdown decreased expression of the cell cycle genes CDC2 and CCNB2. In addition, a higher percentage of cells were arrested in the G2/M phase. Next, we observed that cell proliferation as measured by BrdU incorporation was decreased upon HOXA10 knockdown and H + cAMP treatment. Apoptosis, on the other hand, as measured by Annexin V staining was not influenced by siHOXA10 in decidualizing cells. Together, these data demonstrate that during decidualization of HESC, HOXA10 is actively involved in promoting cell proliferation through the regulation of hundreds of genes.

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Deregulation of the HOXA10 Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition

Cited by 123 publications

References 42 publications

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

DNA methylation inhibits p53-mediated survivin repression

Global Analysis of Genes Regulated by HOXA10 in Decidualization Reveals a Role in Cell Proliferation.

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