Abstract
Background: Our previous study showed that calreticulin (CRT) promoted EGF-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) via Integrin/EGFR-ERK/MAPK signaling. We next investigated the novel signaling pathway and molecular mechanism involving the oncogenic role of CRT in PC development. Methods: We investigated the potential role and mechanism of CRT in regulating Ca2+ dependent acute and chronic endoplasmic reticulum stress (ERS)-induced EMT in PC in vitro and vivo.Results: Thapsigargin (TG) induced acute ERS via increasing intracellular free Ca2+ in PC cells, which was reversed by CRT silencing. Additionally, CRT silencing inhibited TG-induced EMT in vitro by reversing TG-induced changes of the key proteins in EMT signaling (ZO-1, E-cadherin and Slug) and ERK/MAPK signaling (pERK), and inhibiting TG-promoted cell invasion and migration. Meanwhile, CRT was coimmunoprecipitated with inositol-requiring enzyme 1α (IRE1α, one of the key stressors in unfolded protein response) in vitro and its silencing led to the chronic ERS via upregulating IRE1α but independent of X-box-binding protein 1 (XBP1). Moreover, CRT silencing inhibited IRE1α silencing-promoted EMT, including inhibiting the activation of EMT and ERK/MAPK signaling and the promotion of cell mobility. In addition, CRT silencing decreased subcutaneous tumor size and distant liver metastasis in vivo. Furthermore, a negative relationship between CRT and IRE1α was observed in vivo and in clinical PC samples, which coordinately promoted the advanced clinical stages and poor prognosis of PC patients. Conclusions: CRT promoted EMT in PC via mediating Ca2+ dependent TG-induced acute ERS and IRE1α-mediated chronic ERS via Slug and ERK/MAPK signaling.
GINS2 promotes EMT in pancreatic cancer via specifically stimulating ERK/MAPK signaling