Calreticulin promotes EMT in pancreatic cancer via mediating Ca2+ dependent acute and chronic endoplasmic reticulum stress.
J Exp Clin Cancer Res
; 39(1): 209, 2020 Oct 07.
Article
em En
| MEDLINE
| ID: mdl-33028359
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 IRE1α silencing (one of the key stressors in unfolded protein response). Meanwhile, CRT was co-immunoprecipitated and co-localized with IRE1α in vitro and its silencing led to the chronic ERS via upregulating IRE1α independent of IRE1-XBP1 axis. 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 vivo, CRT silencing decreased subcutaneous tumor size and distant liver metastasis following with the increase of IRE1α expression. A negative relationship between CRT and IRE1α 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 IRE1α-mediated chronic ERS via Slug and ERK/MAPK signaling.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Biomarcadores Tumorais
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Regulação Neoplásica da Expressão Gênica
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Cálcio
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Calreticulina
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Transição Epitelial-Mesenquimal
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Estresse do Retículo Endoplasmático
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Exp Clin Cancer Res
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China