Increasing 14‐3‐3 sigma expression with declining estrogen receptor α and estrogen‐responsive finger protein expression defines malignant progression of endometrial carcinoma

Abstract

14-3-3 sigma (sigma) is a negative regulator of the cell cycle and contributes to G2 arrest. Lack of its expression due to hypermethylation of CpG islands has been reported in some carcinomas. A recent study showed that 14-3-3 sigma was down-regulated through proteolysis by estrogen-responsive finger protein (Efp). Here, we investigated the expression of 14-3-3 sigma, hormone receptors, Efp and p53 in 86 cases of endometrial adenocarcinoma and 46 cases of normal or non-neoplastic endometria by means of immunohistochemistry and methylation-specific polymerase chain reaction. In normal endometrium, 14-3-3 sigma was overexpressed in the mid- to late-secretory phase due to hypomethylation. In endometrial adenocarcinoma, 14-3-3 sigma expression was low in low grade endometrioid adenocarcinoma due to hypermethylation, and increased significantly with increasing histological grade due to hypomethylation. 14-3-3 sigma expression inversely correlated with estrogen receptor alpha, progesterone receptor and Efp, and positively correlated with myometrial invasion and lymph node metastasis. These results suggest that 14-3-3 sigma was one of the menstrual cycle-related proteins regulated by epigenetic methylation, and its expression was influenced by epigenetic methylation or hormone receptors in progression of endometrial adenocarcinoma, and therefore was more than just a cell-cycle regulator.

Viral defense, carcinogenesis and ISG15: Novel roles for an old ISG

“…Immunohistochemical analysis of endometrial adenocarcinomas and normal endometrial tissue demonstrated increased Efp and estrogen receptor (ER) expression in endometrial adenocarcinomas (80). Increased Efp in cancer cells was inversely proportional with 14-3-3α levels in these samples.…”

Regulation of 14-3-3σ expression in human thyroid carcinoma is epigenetically regulated by aberrant cytosine methylation

“…Previous studies in other tumors suggest that 14-3-3σ may be a prognostic marker, and high grade, advanced stage endometrial carcinomas over expressed 14-3-3σ when compared to low-grade lesions [13]. In these tumors, increased 14-3-3σ expression was correlated with hypomethylation of the CpG island.…”

“…Loss of 14-3-3σ expression in association with hypermethylation has also been reported in several other cancers, including ovarian [8], hepatocellular [9], prostate [10], some lung [11], gastric [12] and endometrial carcinomas [13]. It is important to point out that this is not the only mechanism for 14-3-3σ down-regulation.…”

“…For calculation of the total or overall promoter methylation frequency, the total of all the CpG sites that were methylated from all the clones was counted and divided by the total number of CpG sites. Bisulfite-treated DNA was also used for methylation-specific PCR using previously published primer sets [13] to distinguish between methylated and unmethylated DNA in both tumor cell lines and primary thyroid tissues and tumors.…”

Three-Gene Molecular Diagnostic Model for Thyroid Cancer

“…The functionality of MRC2 has also been implicated in prostate cancer progression (40). Higher SFN/14-3-3r expression has been reported in lung cancer (41), squamous cell carcinoma (42), pancreatic cancer (43) endometrial carcinoma (44), cervical cancer (45), and colorectal carcinoma (46) and appears to be associated with an overall worse prognosis. Specifically, higher SFN/14-3-3r expression significantly correlates with large tumor size and depth of invasion of vulva squamous cell carcinoma (42).…”