Original contributionDown-regulation of polycystin in lymphatic malformations: possible role in the proliferation of lymphatic endothelial cells☆,☆☆
Introduction
Lymphatic malformations (LMs) are slow-flow vascular anomalies characterized by ectatic lymphatic vessels filled with proteinaceous fluid [1]. With a reported incidence of 1.2 to 2.8 per 1000 births [2], LMs are typically congenital and present at birth [3]. Most of these lesions appeared in the head and neck areas and lead to the deformity [3]. Under certain pathological conditions (eg, infection, trauma), LMs may rapidly enlarge, resulting in dysphasia and even life-threatening complications [2]. Although great progress has been made, curative effects of diffuse LMs remain far from satisfactory. Moreover, basic studies on the mechanisms of LMs are rarely performed.
Polycystins are transmembrane proteins composed of multiple members, among which polycystin-1 (PC-1) and polycystin-2 (PC-2) are of particular concern [4], [5]. PC-1 and PC-2, which are encoded by PKD1 and PKD2, respectively, are expressed in various cells (eg, epithelial and endothelial cells) and regulate cell function and proliferation [5], [6]. Numerous studies have demonstrated that mutations in these 2 genes could result in fluid-filled cysts of the kidney known as autosomal dominant polycystic kidney disease and severe cardiovascular complications affecting humans [5], [7]. More recent studies have demonstrated that PKD1 and PKD2 also play important roles in lymphatic development [5], [8]. Most importantly, distended lymphatic capillary and lymphatic vessel defects are detected in PKD-null embryos in mice [5], [8]. Nevertheless, the expression change and potential roles of PC-1 and PC-2 in LMs remain largely unknown.
Previous studies have demonstrated that abnormal proliferation of lymphatic endothelial cells (LECs) and lymphangiogenesis are involved in the rapid progress of LMs [1], [9]. In addition, PC-1 and PC-2 regulate the activation of ERK signaling, which affects LEC proliferation and lymphatic vessel growth [6], [10], [11]. Given that Ki67 is a representative biomarker for the evaluation of cell proliferation, we evaluated the protein and gene expression levels of PC-1, PC-2, ERK, and proliferation-related molecule Ki67 in LMs and normal human skin tissues by immunoreactivity and real-time polymerase chain reaction (PCR). In addition, the correlations among these molecules were analyzed to determine their roles in the progression of LMs.
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Clinical samples and immunohistochemistry
Twenty-one samples of primary LMs and 10 samples of healthy donor skin were collected at the Hospital of Stomatology, Wuhan University. Informed consent was obtained from all individual participants included in the study. According to guidelines of the National Institutes of Health, the specimens were fixed in buffered 4% paraformaldehyde, embedded in paraffin, and cut into 4-μm sections for immunostaining. The study was approved by the review board of the ethics committee of the Hospital of
PC-1 and PC-2 expression was significantly down-regulated in the LECs of LMs
Initially, LYVE-1 and Prox-1 were used to confirm the location of lymphatic vessels and LECs in 10 normal skin tissue samples and 21 clinical LM samples. The information from patients with LMs is presented in Supplementary Table 2. Immunohistochemical images of LYVE-1–positive and Prox-1–positive staining in the detected specimens are presented in Supplementary Fig. 1. Subsequently, PC-1 and PC-2 expression levels were investigated. As presented in Fig. 1A-D, both PC-1 and PC-2 were strongly
Discussion
LMs are composed of aberrant lymphatic vessels and regarded as benign growths of the lymphatic system [1]. Previous studies have reported that clinical features of LMs may result from dysregulated lymphatic overgrowth and remodeling [1]. Undoubtedly, LEC proliferation plays critical roles in the above processes. In the present study, the up-regulation of Ki67, a representative biomarker of cell proliferation, was noted in the LECs of LMs compared with normal skin tissues, indicating increased
Supplementary data
The following are the Supplementary data to this article.
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Competing interests: The authors have no conflict of interest related to this article.