Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies. Pancreatic ductal adenocarcinoma (PDAC) is characterised by the aberrant expression of mucins. However, the role of mucin (MUC) 20 in PDAC remains unclear. PDAC is usually surrounded by a dense fibrotic stroma consisting of an extracellular matrix and pancreatic stellate cells (PSCs). The stroma creates a nutrient-deprived, hypoxic, and acidic microenvironment, and promotes the malignant behaviours of PDAC cells. In this study, immunohistochemical staining demonstrated that high MUC20 expression correlated with poor progression-free survival and high local recurrence rate of PDAC patients (n = 61). The expression of MUC20 was induced by serum deprivation, hypoxia, and acidic pH in PDAC cells. MUC20 knockdown with siRNA decreased cell viability, as well as migration and invasion induced by PSCs in HPAC and HPAF-II cells. In intraperitoneal, subcutaneous, and orthotopic injection models, MUC20 knockdown decreased tumour growth in immunodeficient mice. Phospho-RTK array and western blot analysis indicated that MUC20 knockdown decreased HGF-mediated phosphorylation of MET in PDAC cells. Moreover, HGF-induced malignant phenotypes could be suppressed by MUC20 knockdown. Co-immunoprecipitation revealed the physical association of MUC20 and MET. These findings suggest that MUC20 knockdown suppresses the malignant phenotypes of PDAC cells at least partially through the inhibition of the HGF/MET pathway and that MUC20 could act as a potential therapeutic target.

中文翻译：

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沉默MUC20可通过抑制HGF / MET通路来抑制胰腺导管腺癌细胞的恶性特征。

粘蛋白是高度糖基化的蛋白质，在肿瘤恶性肿瘤的发病机理中起关键作用。胰腺导管腺癌（PDAC）的特征在于粘蛋白的异常表达。但是，尚不清楚粘蛋白（MUC）20在PDAC中的作用。PDAC通常被致密的纤维化基质包围，该基质由细胞外基质和胰腺星状细胞（PSC）组成。基质产生营养缺乏，缺氧和酸性的微环境，并促进PDAC细胞的恶性行为。在这项研究中，免疫组化染色表明，高MUC20表达与PDAC患者的无进展生存期差和局部复发率高相关（n = 61）。MUC20的表达是由PDAC细胞中的血清缺乏，缺氧和酸性pH诱导的。用siRNA进行MUC20敲低会降低细胞活力，以及HPSC和HPAF-II细胞中PSC诱导的迁移和侵袭。在腹膜内，皮下和原位注射模型中，MUC20敲低可降低免疫缺陷小鼠的肿瘤生长。磷酸RTK阵列和western印迹分析表明，MUC20敲低降低了HGF介导的PDAC细胞中MET的磷酸化。此外，MUC20敲低可以抑制HGF诱导的恶性表型。免疫共沉淀揭示了MUC20和MET的物理联系。这些发现表明，MUC20敲低至少部分通过抑制HGF / MET途径抑制PDAC细胞的恶性表型，并且MUC20可以作为潜在的治疗靶标。在腹膜内，皮下和原位注射模型中，MUC20敲低可降低免疫缺陷小鼠的肿瘤生长。磷酸RTK阵列和western印迹分析表明，MUC20敲低降低了HGF介导的PDAC细胞中MET的磷酸化。此外，MUC20敲低可以抑制HGF诱导的恶性表型。免疫共沉淀揭示了MUC20和MET的物理联系。这些发现表明，MUC20敲低至少部分通过抑制HGF / MET途径抑制PDAC细胞的恶性表型，并且MUC20可以作为潜在的治疗靶标。在腹膜内，皮下和原位注射模型中，MUC20敲低可降低免疫缺陷小鼠的肿瘤生长。磷酸RTK阵列和western印迹分析表明，MUC20敲低降低了HGF介导的PDAC细胞中MET的磷酸化。此外，MUC20敲低可以抑制HGF诱导的恶性表型。免疫共沉淀揭示了MUC20和MET的物理联系。这些发现表明，MUC20敲低至少部分通过抑制HGF / MET途径抑制PDAC细胞的恶性表型，并且MUC20可以作为潜在的治疗靶标。磷酸RTK阵列和western印迹分析表明，MUC20敲低降低了HGF介导的PDAC细胞中MET的磷酸化。此外，MUC20敲低可以抑制HGF诱导的恶性表型。免疫共沉淀揭示了MUC20和MET的物理联系。这些发现表明，MUC20敲低至少部分通过抑制HGF / MET途径抑制PDAC细胞的恶性表型，并且MUC20可以作为潜在的治疗靶标。磷酸RTK阵列和western印迹分析表明，MUC20敲低降低了HGF介导的PDAC细胞中MET的磷酸化。此外，MUC20敲低可以抑制HGF诱导的恶性表型。免疫共沉淀揭示了MUC20和MET的物理联系。这些发现表明，MUC20敲低至少部分通过抑制HGF / MET途径抑制PDAC细胞的恶性表型，并且MUC20可以作为潜在的治疗靶标。