Hilgers Katharina, Ibrahim Sherif Abdelaziz, Kiesel Ludwig, Greve Burkhard, Espinoza-Sánchez Nancy A, Götte Martin
Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany.
Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt.
Front Oncol. 2022 Jan 27;12:803899. doi: 10.3389/fonc.2022.803899. eCollection 2022.
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. , 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. 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.
宫颈癌是全球女性中最常被诊断出的恶性肿瘤之一，排名第四。先前发表的证据表明，膜结合型硫酸乙酰肝素蛋白聚糖Syndecan - 1（Sdc - 1）的表达与宫颈癌的发展之间可能存在联系。Sdc - 1作为受体酪氨酸激酶和其他信号通路的基质受体和共受体。它影响细胞增殖、黏附和迁移，并被视为肿瘤微环境的调节剂。在一个称为脱落的过程中，其细胞外结构域发生蛋白水解切割后，Sdc - 1可以作为旁分泌效应物。Sdc - 1表达的丧失与宫颈癌的低分化以及淋巴结转移率的增加有关。在这里，我们通过分析公共基因表达数据集来分析Sdc - 1表达的临床影响，并通过功能分析研究Sdc - 1及其膜结合形式和可溶性形式的过表达对人宫颈癌细胞系HeLa恶性特性的影响。为此，用对照质粒pcDNA3.1和三种不同的Sdc - 1 - DNA构建体稳定转染HeLa细胞，这三种构建体分别编码野生型、永久膜结合型和组成型可溶性Sdc - 1。在临床标本中，Sdc - 1 mRNA在局部肿瘤组织中的表达高于正常和转移性宫颈癌组织。此外，在Kaplan - Meier生存分析中，高Sdc - 1表达与不良预后相关，表明Sdc - 1在这类癌症的进展中起重要作用。我们发现，可溶性以及永久膜结合形式的Sdc - 1调节增殖和细胞周期，而膜结合型Sdc1调节HeLa细胞凋亡。Sdc - 1及其可溶性形式的过表达增加了侵袭性。划痕/伤口愈合试验显示，Sdc - 1依赖性细胞运动性降低，这与Rho - GTPase信号通路有关。总之，在宫颈癌中，Sdc - 1调节与发病机制相关的过程，这取决于Sdc - 1与膜的结合。
