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      Calreticulin promotes EMT in pancreatic cancer via mediating Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ dependent TG-induced acute ERS and IRE1α-mediated chronic ERS via Slug and ERK/MAPK signaling.

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          Most cited references70

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          Calreticulin: one protein, one gene, many functions.

          The endoplasmic reticulum (ER) plays a critical role in the synthesis and chaperoning of membrane-associated and secreted proteins. The membrane is also an important site of Ca(2+) storage and release. Calreticulin is a unique ER luminal resident protein. The protein affects many cellular functions, both in the ER lumen and outside of the ER environment. In the ER lumen, calreticulin performs two major functions: chaperoning and regulation of Ca(2+) homoeostasis. Calreticulin is a highly versatile lectin-like chaperone, and it participates during the synthesis of a variety of molecules, including ion channels, surface receptors, integrins and transporters. The protein also affects intracellular Ca(2+) homoeostasis by modulation of ER Ca(2+) storage and transport. Studies on the cell biology of calreticulin revealed that the ER membrane is a very dynamic intracellular compartment affecting many aspects of cell physiology.
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            Molecular and evolutionary basis of the cellular stress response.

            The cellular stress response is a universal mechanism of extraordinary physiological/pathophysiological significance. It represents a defense reaction of cells to damage that environmental forces inflict on macromolecules. Many aspects of the cellular stress response are not stressor specific because cells monitor stress based on macromolecular damage without regard to the type of stress that causes such damage. Cellular mechanisms activated by DNA damage and protein damage are interconnected and share common elements. Other cellular responses directed at re-establishing homeostasis are stressor specific and often activated in parallel to the cellular stress response. All organisms have stress proteins, and universally conserved stress proteins can be regarded as the minimal stress proteome. Functional analysis of the minimal stress proteome yields information about key aspects of the cellular stress response, including physiological mechanisms of sensing membrane lipid, protein, and DNA damage; redox sensing and regulation; cell cycle control; macromolecular stabilization/repair; and control of energy metabolism. In addition, cells can quantify stress and activate a death program (apoptosis) when tolerance limits are exceeded.
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              Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response

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                Author and article information

                Contributors
                dongming@cmu.edu.cn
                Journal
                J Exp Clin Cancer Res
                J Exp Clin Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                7 October 2020
                7 October 2020
                2020
                : 39
                : 209
                Affiliations
                [1 ]GRID grid.412449.e, ISNI 0000 0000 9678 1884, Department of Gastrointestinal Surgery, The First Hospital, , China Medical University, ; Shenyang, 110001 Liaoning China
                [2 ]GRID grid.260463.5, ISNI 0000 0001 2182 8825, Department of General Surgery, The First Affliated Hospital, , Nanchang University, ; Nanchang, 330006 Jiangxi China
                [3 ]GRID grid.452816.c, ISNI 0000 0004 1757 9522, Department of General Surgery, , The People’s Hospital of Liaoning province, ; Shenyang, 110034 Liaoning China
                [4 ]Department of Clinical Laboratory, The Sixth Peoples’ hospital of Shenyang, Shenyang, 110003 Liaoning China
                Author information
                http://orcid.org/0000-0003-2685-1420
                Article
                1702
                10.1186/s13046-020-01702-y
                7542892
                33028359
                46033dc8-15b5-48a7-aef4-a50fff14b02a
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 21 June 2020
                : 7 September 2020
                Funding
                Funded by: Chinese National Science Foundation for youth scholar
                Award ID: 81401941
                Award Recipient :
                Funded by: Chinese National Science Foundation
                Award ID: 81672835
                Award Recipient :
                Funded by: Scientific innovation plan from Young and middle-aged talents of Shenyang City
                Award ID: RC200357
                Award Recipient :
                Funded by: Scientific research project of Education Department of Liaoning Province
                Award ID: L2020
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                calreticulin,intracellular free ca2 +,endoplasmic reticulum stress,ire1α,epithelial mesenchymal transition,pancreatic cancer

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