Differential Impact of Membrane-Bound and Soluble Forms of the Prognostic Marker Syndecan-1 on the Invasiveness, Migration, Apoptosis, and Proliferation of Cervical Cancer Cells

Abstract

Cervical cancer ranks fourth among the most commonly diagnosed malignant tumors in women worldwide. Previously published evidence suggested a possible connection between the expression of the membrane-bound heparan sulfate proteoglycan syndecan-1 (Sdc-1) and the development of cervical carcinoma. Sdc-1 serves as a matrix receptor and coreceptor for receptor tyrosine kinases and additional signaling pathways. It influences cell proliferation, adhesion, and migration and is seen as a modulator of the tumor microenvironment. Following proteolytic cleavage of its extracellular domain in a process called shedding, Sdc-1 can act as a paracrine effector. The loss of Sdc-1 expression is associated with low differentiation of cervical carcinoma and with an increased rate of lymph node metastases. Here, we analyzed the clinical impact of Sdc-1 expression by analysis of public gene expression datasets and studied the effect of an overexpression of Sdc-1 and its membrane-bound and soluble forms on the malignant properties of the human cervical carcinoma cell line HeLa through functional analysis. For this purpose, the HeLa cells were stably transfected with the control plasmid pcDNA3.1 and three different Sdc-1-DNA constructs,encoding wild-type, permanently membrane-bound, and constitutively soluble Sdc-1. In clinical specimens, Sdc-1 mRNA was more highly expressed in local tumor tissues than in normal and metastatic cervical cancer tissues. Moreover, high Sdc-1 expression correlated with a poor prognosis in Kaplan-Meier survival analysis, suggesting the important role of Sdc-1 in the progression of this type of cancer. In vitro, we found that the soluble, as well as the permanently membrane-bound forms of Sdc-1 modulated the proliferation and the cell cycle, while membrane-bound Sdc1 regulated HeLa cell apoptosis. The overexpression of Sdc-1 and its soluble form increased invasiveness. In vitro scratch/wound healing assay, showed reduced Sdc-1-dependent cell motility which was linked to the Rho-GTPase signaling pathway. In conclusion, in cervical cancer Sdc-1 modulates pathogenetically relevant processes, which depend on the membrane-association of Sdc-1.

The Heparan Sulfate Proteoglycan Syndecan-1 Triggers Breast Cancer Cell-Induced Coagulability by Induced Expression of Tissue Factor

“…Since previous studies using the overexpression of murine Sdc-1 in human breast cancer cells provided insights into its role in cell-cycle progression [ 24 ], we performed cell cycle analysis for Sdc-1-overexpressing cells with respect to TFPI treatment. Athough there was no impact of either Sdc-1 overexpression or TFPI treatment on the cell cycle in MCF-7 cells ( Figure 4 D, left), the overexpression of soluble 392-Sdc-1 in MDA-MB-231 cells led to a strong accumulation in the G2/M phase, causing cell cycle arrest in this phase.…”

Effect of miR-21 in mesenchymal stem cells-derived extracellular vesicles behavior

“…Surprisingly, although they were detected 1848 proteins only SDC1 was statistically significant, this may be due to the fact that the MSCs from the human umbilical cord stroma have a lot of variability because of different ages from the donors [4]. Syndecans are integral membrane proteoglycans, they are characterized by the similarity of transmembrane and cytoplasmic domains of the central proteins and they may regulate cell behavior by participating in growth factor binding and matrix recognition [10]. SDC1 level is associated with salivary gland function and inflammation in patients with Sjögren's syndrome and it is increased in saliva [12].…”

Identification of Key Regulators in Pancreatic Ductal Adenocarcinoma using Network theoretical Approach

“…SDC1 has been shown to play a tumor-suppressor role in CRCs (60). In cervical cancer, SDC1 expression is associated with low differentiation and increased lymph node metastases (61). High SDC1 expression in cervical cancer is also correlated with a poor prognosis (62).…”