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.
Highlights
Cervical cancer represents a major public health problem worldwide
Sdc-1 plays an important role in the progression of different types of cancers by regulating the hallmarks of cancer such as proliferation, angiogenesis, apoptosis, invasion, and metastasis [7, 9, 25, 30, 31]
Low Sdc-1 expression was observed in the progression of cervical intraepithelial neoplasia (CIN) grade I to grade III, while in poorly differentiated squamous cell carcinomas, Sdc-1 was almost absent [13]
Summary
Cervical cancer represents a major public health problem worldwide. More than 500,000 new cases and approximately 250,000 deaths are reported each year, making cervical cancer the fourth most common type of cancer in women [1]. The ECM receptor Syndecan-1 (Sdc-1) is differentially expressed in cervical intraepithelial neoplasias and carcinoma in situ [6] This cell surface heparan sulfate proteoglycan is one of four members of the Sdc family expressed in mouse and human tissues [7]. Sdc-1 has well-documented roles in regulating inflammation by modulating the expression and activity of cytokines, chemokines, growth factors, and adhesion molecules through its heparin-related heparan sulfate chains, functioning as a signaling co-receptor for different signaling pathways including Rho, Wnt, Hedgehog, Notch, and STAT3 [8, 9]. Several preclinical and clinical studies have demonstrated that therapies targeting Sdc-1 can inhibit the aggressive behavior of tumor cells [7, 12] This protein has emerged as a novel target for the development of selective and more potent therapies. Understanding the mechanisms by which different forms of Sdc-1 promote these processes could help to better understand the behavior of cervical cancer cells and to find specific therapeutic targets
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