Syndecan‐1, a key regulator of cell viability in endometrial cancer

Abstract

Syndecan-1 is one of the major proteoglycans on cell surfaces involved in major biological processes. Although loss of syndecan-1 correlates well with the gain of cancerous characteristics in a wide range of cancers, increased expression of syndecan-1 also coincides with adverse outcomes in some cancers, including breast, ovarian and pancreatic cancers. For this Janus-faced attitude of syndecan-1, we sought to examine expression patterns of syndecan-1 in endometrial carcinoma (EC) and gain insight into the roles of syndecan-1. Immunohistochemical examinations of 109 endometrial tissue samples from myoma, hyperplasia and EC uteri revealed that syndecan-1 expression was significantly upregulated in EC compared with hyperplasia (p < 0.001). To evaluate pathophysiological functions of syndecan-1, its expression level was altered, and subsequent outcomes were examined using human endometrial cancer cell lines such as HEC-1A, AN3CA and KLE cells. Overexpression of syndecan-1 increased the growth of HEC-1A cells regardless of anchorage dependence while silencing syndecan-1 by antisense RNAs caused apoptotic cell death. Consistent with decreased viability, the loss of syndecan-1 was also accompanied by a decrease in the activation of Erk and Akt and a concomitant decrease in the phosphorylation of PTEN and PDK1, which are known as negative and positive regulators of Akt activation, respectively. These down-regulatory effects were reversed upon overexpression of syndecan-1. Collectively together, the aforementioned findings lend support to the notion that upregulation of syndecan-1 may be a critical element for endometrial cancers in maintaining their viability and thus can serve as a cancer specific therapeutic and diagnostic marker. ' 2007 Wiley-Liss, Inc.Key words: endometrial cancers; syndecan-1; apoptotic cell death; Erk/Akt pathway Endometrial carcinoma (EC) is the world's 7th most frequent malignancy with a much higher rate of incidence in well-developed countries.1 In the United States alone, a little over 41,200 women develop EC, and about 7,350 women die from this malignancy each year.2 Though there are multitudes of possible oncogenic abnormalities throughout cancer development, EC can be characterized with a certain number of frequent genetic alterations or regulation of gene expression. Mutations and overexpression of k-ras, steroid hormone receptors, PTEN, Her2/neu and p53 are common abnormalities in EC.3-6 Moreover, recent findings showed that atypical expression of cell surface proteins participating in the cell-cell or the cell-matrix interaction can help progression of endometrial cancer. 5,7,8 Consequently, these abnormalities contribute to the altered expression of proteins involved in cell cycle regulation and survival. 9,10 Syndecan is a four-membered cell membrane proteoglycan that shows a heavy modification on its ectodomain with heparan sulfate (HS) glucosaminoglycan chains. As a cell surface receptor, it shows a deep involvement in both normal and pathological events by regulating the cell-cell ...

The expression of syndecan-1 is related to the risk of endometrial hyperplasia progressing to endometrial carcinoma

“…18 In endometrial cancer, there have been recent histological studies on endometrial tissues suggesting that the expression of syndecan-1 is closely correlated with the gain of carcinogenesis in the human endometrium. 7 Syndecan belongs to the heparan sulfate proteoglycan family found as components of cell surface and take part in cell-cell interaction, cell-matrix adhesion, and growth factor signaling. 19 Thereby, syndecan is known to regulate cell differentiation, proliferation, migration, and homeostasis.…”

“…7 Microscopic analyses were evaluated independently by one pathologist (HJH) with no prior knowledge of the clinical data.…”

“…6 Previous studies have suggested a correlation between the expression of syndecan-1 and the development of cancer characteristics in the human endometrium. 7 However, it is not yet clear whether syndecan-1 is closely correlated with the onset of tumorigenesis or if it plays a role as a positive predictive …”

Syndecan-1 Overexpression Promotes Tumor Growth and Angiogenesis in an Endometrial Cancer Xenograft Model

“…10 Cellular expression level of syndecan-1 was verified by immunocytochemistry and by immunoblotting before use.…”

“…8,9 In the case of endometrial cancer, overexpression of syndecan-1 has been implicated in occurrence and progression of cancer by promoting cell proliferation via viability signals that are seemingly mediated by the PI3K-Akt signaling pathway. 10 The progression and metastasis of malignant tumors are characterized by their ability to produce matrix-degrading enzymes to disseminate them from the primary tumor and invade surrounding tissues as well. Matrix metalloproteinases (MMPs) play a key role in these processes owing to their proteolytic activities in degradation of extracellular matrix (ECM) and basement membranes.…”