Calreticulin promotes EMT in pancreatic cancer via mediating Ca2+ dependent acute and chronic endoplasmic reticulum stress

Sheng, Weiwei; Wang, Guosen; Tang, Jingtong; Shi, Xiasheng; Cao, Rongxian; Sun, Jian; Lin, Yuxi; Chen, Jia; Chen, Chuanping; Zhou, Jianping; Dong, Ming

doi:10.1186/s13046-020-01702-y

Cited by 27 publications

(27 citation statements)

References 78 publications

(89 reference statements)

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“…4 B and C). Given recent studies showing that CALR promotes epithelial-mesenchymal transition in PDAC [ 28 , 29 ], our results indicate that CALR and ITGA3 could be one of the pathways through which CAFs send the epithelial-mesenchymal transition signal to ETCs. In summary, these results suggest that poor-prognostic CCIs activated along with tumor grades can be potential therapeutic targets for PDAC.…”

Section: Resultssupporting

confidence: 58%

Cell-to-cell interaction analysis of prognostic ligand-receptor pairs in human pancreatic ductal adenocarcinoma

Suzuki

Kuno

Ozaki

2021

Biochemistry and Biophysics Reports

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Cell-to-cell interactions (CCIs) through ligand-receptor (LR) pairs in the tumor microenvironment underlie the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). However, there is scant knowledge of the association of CCIs with PDAC prognosis, which is critical to the identification of potential therapeutic candidates. Here, we sought to identify the LR pairs associated with PDAC patient prognosis by integrating survival analysis and single-cell CCI prediction. Via survival analysis using gene expression from cancer cohorts, we found 199 prognostic LR pairs. CCI prediction based on single-cell RNA-seq data revealed the enriched LR pairs associated with poor prognosis. Notably, the CCIs involved epithelial tumor cells, cancer-associated fibroblasts, and tumor-associated macrophages through integrin-related and ANXA1 – FPR pairs. Finally, we determined that CCIs involving 33 poor-prognostic LR pairs were associated with tumor grade. Although the clinical implication of the set of LR pairs must be determined, our results may provide potential therapeutic targets in PDAC.

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Section: Resultssupporting

confidence: 58%

Cell-to-cell interaction analysis of prognostic ligand-receptor pairs in human pancreatic ductal adenocarcinoma

Suzuki

Kuno

Ozaki

2021

Biochemistry and Biophysics Reports

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“…The TG used as an inducer of ERS has been reported in previous studies [23,42] Our results indicated that the putative IRES can effectively initiate the expression of GFP in vitro (Fig. 6).…”

Section: Discussionsupporting

confidence: 77%

Identification of Cryptic Putative IRESs Initiating the Translation of Nonstructural Proteins Encoded by the HRV16 Genome

Shi

Song

Luo

et al. 2021

Preprint

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Cap-dependent initiation of translation is a canonical mechanism adopted by eukaryotic cells. Internal ribosome entry site (IRES)-dependent translation is a mechanism distinct from 5′ cap-dependent translation. IRES elements are located mainly in the 5′-untranslated regions (UTRs) of viral and eukaryotic mRNAs. In addition, IRESs are found in the coding regions of some viral and eukaryotic genomes and initiate the translation of some functional truncated isoforms. Here, via IRES-initiated expression of proteins, bicistronic vectors and ribosome profiling of the human rhinovirus 16 (HRV16), we found that the coding region of the nonstructural proteins P2 and P3 contained 5 putative IRES elements. These 5 putative IRESs were located within nucleotides 4286-4585, 5002-5126, 6245-6394, 6619-6718 and 6629-6778 and initiated green fluorescent protein (GFP) expression in vitro. This alternative mechanism might be effective and economical for eliminating the time and raw material required to synthesize the full-length polyprotein.

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“…PERK is also responsible for the constitutive activation of Nrf2 in EMT dedifferentiated breast epithelial cells, leading to the activation of a multidrug-resistant (MDR) mechanism and insensitivity to chemotherapy [ 180 ]. In pancreatic cancer cells, induction of acute ERS with thapsigargin activated PERK phosphorylation, accompanied by a decrease of EMT epithelial markers E-cadherin and ZO-1 and an increase of mesenchymal regulators Snail1, Slug, and ZEB1 [ 181 ].…”

Section: Relationship Between Ers and Emtmentioning

confidence: 99%

Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

Kumari

Reabroi

North

2021

Mediators of Inflammation

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G protein-coupled receptors (GPCRs) represent a large family of transmembrane proteins that transduce an external stimulus into a variety of cellular responses. They play a critical role in various pathological conditions in humans, including cancer, by regulating a number of key processes involved in tumor formation and progression. The epithelial-mesenchymal transition (EMT) is a fundamental process in promoting cancer cell invasion and tumor dissemination leading to metastasis, an often intractable state of the disease. Uncontrolled proliferation and persistent metabolism of cancer cells also induce oxidative stress, hypoxia, and depletion of growth factors and nutrients. These disturbances lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and induce a cellular condition called ER stress (ERS) which is counteracted by activation of the unfolded protein response (UPR). Many GPCRs modulate ERS and UPR signaling via ERS sensors, IRE1α, PERK, and ATF6, to support cancer cell survival and inhibit cell death. By regulating downstream signaling pathways such as NF-κB, MAPK/ERK, PI3K/AKT, TGF-β, and Wnt/β-catenin, GPCRs also upregulate mesenchymal transcription factors including Snail, ZEB, and Twist superfamilies which regulate cell polarity, cytoskeleton remodeling, migration, and invasion. Likewise, ERS-induced UPR upregulates gene transcription and expression of proteins related to EMT enhancing tumor aggressiveness. Though GPCRs are attractive therapeutic targets in cancer biology, much less is known about their roles in regulating ERS and EMT. Here, we will discuss the interplay in GPCR-ERS linked to the EMT process of cancer cells, with a particular focus on oncogenes and molecular signaling pathways.

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Calreticulin promotes EMT in pancreatic cancer via mediating Ca2+ dependent acute and chronic endoplasmic reticulum stress

Cited by 27 publications

References 78 publications

Cell-to-cell interaction analysis of prognostic ligand-receptor pairs in human pancreatic ductal adenocarcinoma

Cell-to-cell interaction analysis of prognostic ligand-receptor pairs in human pancreatic ductal adenocarcinoma

Identification of Cryptic Putative IRESs Initiating the Translation of Nonstructural Proteins Encoded by the HRV16 Genome

Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

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