Calreticulin promotes EMT in pancreatic cancer via mediating Ca2+ dependent acute and chronic endoplasmic reticulum stress.
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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 signal pathway and molecular mechanism involving the oncogenic role of CRT in PC. METHODS:We investigated the potential role and mechanism of CRT in regulating intracellular free 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). TG-promoted cell invasion and migration was also rescued by CRT silencing but enhanced by IRE1? silencing (one of the key stressors in unfolded?protein?response). Meanwhile, CRT was co-immunoprecipitated and co-localized with IRE1? in vitro and its silencing led to the chronic ERS via upregulating IRE1? independent of IRE1-XBP1 axis. Moreover, CRT silencing inhibited IRE1? silencing-promoted EMT, including inhibiting the activation of EMT and ERK/MAPK signaling and the promotion of cell mobility. In vivo, CRT silencing decreased subcutaneous tumor size and distant liver metastasis following with the increase of IRE1? expression. A negative relationship between CRT and IRE1? was also observed in clinical PC samples, which coordinately promoted the advanced clinical stages and poor prognosis of PC patients. CONCLUSIONS:CRT promotes EMT in PC via mediating intracellular free Ca2+ dependent TG-induced acute ERS and IRE1?-mediated chronic ERS via Slug and ERK/MAPK signaling.
SUBMITTER: Sheng W
PROVIDER: S-EPMC7542892 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
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