Down-Regulation of Cystatin C Promotes Pancreatic Cancer Cells Metastasis via SQSTM1/RELA Signaling Pathway

Purpose: Cystatin C (Cyst C) is involved in various human cancers. However, Cyst C has not yet been studied in pancreatic cancer (PC). This study aimed to examine Cyst C expression and its prognostic and biological role in PC.Methods: Cyst C expression in PC patients was assessed searching on the Clinical Proteomic Tumor Analysis Consortium (CP-TAC) database. It was further validated in microarray tissue by immunohistochemistry (IHC) analysis. The biological role of Cyst C and its mechanism were explored by several molecular biology methods.Results: Cyst C was downregulated in PC tissues compared to the pericarcinoma tissue. Cyst C low expression was associated with high tumor grade, high N stage and poor prognosis of PC patients. Furthermore, Cyst C overexpression inhibited PANC-1 (human pancreatic epithelioid carcinoma cell line) and MIA PaCa2 cells migration, while Cyst C expression inhibition promoted the cellular migration. In addition, Cyst C knockdown leaded to autophagic deficiency and SQSTM1 accumulation in pancre-atic cancer cells, followed by increased CDH2 and ZEB1 expression and decreased CDH1 expression. However, the expression patterns of these genes were reversed after SQSTM1 or RELA (V-Rel Reticuloendotheliosis Viral Oncogene Homolog A) down-regulation.Conclusions: This study revealed that Cyst C downregulation induces epithelial-to-mesenchymal transition (EMT) and pro-moted pancreatic cancer metastasis, at least partially due to SQSTM1/RELA signaling pathway activation. Cyst C might act as a promising biomarker for PC and provide a novel treatment strategy.