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

Abstract

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 (CPTAC) 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 pancreatic 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 promoted 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.