Interleukin‑32 regulates downstream molecules and promotes the invasion of pancreatic cancer cells

Takagi, Kohji; Shimomura, Akiko; Imura, Johji; Mori, Hisashi; Noguchi, Akira; Tanaka, Shinichi; Mizutani, Takashi; Nishida, Takeshi; Hatta, Hideki; Nakajima, Takahiko

doi:10.3892/ol.2021.13132

Cited by 4 publications

(4 citation statements)

References 30 publications

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“…Interestingly, this population also expressed CALB1 which is associated with the kidney duct [ 28 ]. Lastly, cluster #8 (i.e., PP-4) was enriched in inflammatory and EMT-inducing markers, often associated with pancreatitis and pancreatic ductal adenocarcinoma, such as LTB [ 29 ], IL32 [ 30 ], and AREG [ 31 ]. Cluster #9 was assigned to endocrine cells for their high expression levels of CHGA , INS , NEUROG3 , and NKX2.2 [ 32 ] (~8.7%, cluster #9.…”

Section: Resultsmentioning

confidence: 99%

Photo-click hydrogels for 3D in situ differentiation of pancreatic progenitors from induced pluripotent stem cells

Arkenberg,

Ueda,

Hashino

et al. 2023

Stem Cell Res Ther

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Background Induced pluripotent stem cells (iPSC) can be differentiated to cells in all three germ layers, as well as cells in the extraembryonic tissues. Efforts in iPSC differentiation into pancreatic progenitors in vitro have largely been focused on optimizing soluble growth cues in conventional two-dimensional (2D) culture, whereas the impact of three-dimensional (3D) matrix properties on the morphogenesis of iPSC remains elusive. Methods In this work, we employ gelatin-based thiol-norbornene photo-click hydrogels for in situ 3D differentiation of human iPSCs into pancreatic progenitors (PP). Molecular analysis and single-cell RNA-sequencing were utilized to elucidate on the distinct identities of subpopulations within the 2D and 3D differentiated cells. Results We found that, while established soluble cues led to predominately PP cells in 2D culture, differentiation of iPSCs using the same soluble factors led to prominent branching morphogenesis, ductal network formation, and generation of diverse endoderm populations. Through single-cell RNA-sequencing, we found that 3D differentiation resulted in enrichments of pan-endodermal cells and ductal cells. We further noted the emergence of a group of extraembryonic cells in 3D, which was absent in 2D differentiation. The unexpected emergence of extraembryonic cells in 3D was found to be associated with enrichment of Wnt and BMP signaling pathways, which may have contributed to the emergence of diverse cell populations. The expressions of PP signature genes PDX1 and NKX6.1 were restored through inhibition of Wnt signaling at the beginning of the posterior foregut stage. Conclusions To our knowledge, this work established the first 3D hydrogel system for in situ differentiation of human iPSCs into PPs.

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Section: Resultsmentioning

confidence: 99%

Photo-click hydrogels for 3D in situ differentiation of pancreatic progenitors from induced pluripotent stem cells

Arkenberg,

Ueda,

Hashino

et al. 2023

Stem Cell Res Ther

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“…Based on the report, IL-32 is highly expressed in patients with pancreatic cancer or gastric cancer and IL-32 has pro-cancer effects that inhibit apoptosis, stimulate DNA synthesis in the proliferation of cancer cells, and increase invasion associated with tumor progression and metastasis [ 33 , 34 , 35 , 36 ]. Likewise, ENO1 is expressed in pancreatic cancer and liver cancer cells and ENO1 promotes cell proliferation, migration, invasion, and tumorigenesis in non-small cell lung cancer [ 37 , 38 , 39 , 40 , 41 ]. Therefore, we expect that IL-32 regulation by ENO1 could be applied to treat cancers with inflammatory responses as well as inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

The Role of α-Enolase on the Production of Interleukin (IL)-32 in Con A-Mediated Inflammation and Rheumatoid Arthritis (RA)

Jo,

Shin,

Agura

et al. 2024

Pharmaceuticals

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Interleukin (IL)-32 is produced by T lymphocytes, natural killer cells, monocytes, and epithelial cells. IL-32 induces the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-8, and IL-32 expression is highly increased in rheumatoid arthritis (RA) patients. Enolase-1 (ENO1) is a glycolytic enzyme and the stimulation of ENO1 induces high levels of pro-inflammatory cytokines in concanavalin A (Con A)-activated peripheral blood mononuclear cells (PBMCs) and macrophages in RA patients. In addition, there are many reports that anti-ENO1 antibody is correlated with the disease progression of RA. It implies that ENO1 could regulate IL-32 production during inflammation related to the pathogenesis of RA. Therefore, we investigated the role of ENO1 in IL-32 production using Con A-activated PBMCs and RA PBMCs. IL-32 expression is increased by ENO1 stimulation using real-time PCR and ELISA. In addition, we confirmed that IL-32 production was decreased in Con A-activated PBMCs and RA PBMCs pre-treated with NF-κB or p38 MAPK pathway inhibitors. Taken together, these results suggest that ENO1 plays an important role in inflammation through the induction of IL-32 production by the activation of the NF-κB and p38 MAPK pathways.

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“…Among the top five downregulated genes in 4 days pH e 6.6 cells, we find PXDN, coding for Peroxidasin, a heme peroxidase which has been associated with proliferation in endothelial cells [65] and with cancer cells in-vasive phenotype [66,67], Guanylate Cyclase 1 Soluble Subunit Alpha 2 coding gene (GUCY1A2), which mediates cell growth and survival in different cancer cell types [68][69][70][71][72], and PRICKLE1, prickle planar cell polarity protein 1, a member of the planar cell polarity (PCP) pathway which is involved in cancer cell metastasis [73,74]. Stronger gene deregulations are observed for pH e -selected + 7.4 cells, where the top 10 upregulated genes include Interferon Alpha Inducible Protein 27 (IFI27), a prognostic marker for pancreatic cancer [75] that promotes PDAC cell proliferation, migration, and invasion [76]; bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-β (TGF-β) family reported to be involved in tumor metastasis, including pancreatic cancer where it promotes EMT and invasiveness in PANC-1 cells via matrix metalloproteinase (MMP)-2 upregulation [77]; Interleukin-32 (IL32), involved in PDAC cells invasiveness [78]; tripartite motif-containing 2 (TRIM2), which increases PDAC tumorigenesis both in vitro and in vivo [79]. Among top downregulated genes, amphiregulin (AREG) is involved in EMT and growth in different types of cancer, including PDAC [80], while Adhesion G Protein-Coupled Receptor F1 (ADGRF1) has an important role in inducing quiescence and chemoresistance in breast cancer [81].…”

Section: Differential Transcriptomic Profiles In Panc-1 Cells In Resp...mentioning

confidence: 99%

Acidic Growth Conditions Promote Epithelial-to-Mesenchymal Transition to Select More Aggressive PDAC Cell Phenotypes In Vitro

Audero

Carvalho

Loeck

et al. 2023

Cancers

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Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by an acidic microenvironment, which contributes to therapeutic failure. So far there is a lack of knowledge with respect to the role of the acidic microenvironment in the invasive process. This work aimed to study the phenotypic and genetic response of PDAC cells to acidic stress along the different stages of selection. To this end, we subjected the cells to short- and long-term acidic pressure and recovery to pHe 7.4. This treatment aimed at mimicking PDAC edges and consequent cancer cell escape from the tumor. The impact of acidosis was assessed for cell morphology, proliferation, adhesion, migration, invasion, and epithelial–mesenchymal transition (EMT) via functional in vitro assays and RNA sequencing. Our results indicate that short acidic treatment limits growth, adhesion, invasion, and viability of PDAC cells. As the acid treatment progresses, it selects cancer cells with enhanced migration and invasion abilities induced by EMT, potentiating their metastatic potential when re-exposed to pHe 7.4. The RNA-seq analysis of PANC-1 cells exposed to short-term acidosis and pHe-selected recovered to pHe 7.4 revealed distinct transcriptome rewiring. We describe an enrichment of genes relevant to proliferation, migration, EMT, and invasion in acid-selected cells. Our work clearly demonstrates that upon acidosis stress, PDAC cells acquire more invasive cell phenotypes by promoting EMT and thus paving the way for more aggressive cell phenotypes.

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Interleukin‑32 regulates downstream molecules and promotes the invasion of pancreatic cancer cells

Cited by 4 publications

References 30 publications

Photo-click hydrogels for 3D in situ differentiation of pancreatic progenitors from induced pluripotent stem cells

Photo-click hydrogels for 3D in situ differentiation of pancreatic progenitors from induced pluripotent stem cells

The Role of α-Enolase on the Production of Interleukin (IL)-32 in Con A-Mediated Inflammation and Rheumatoid Arthritis (RA)

Acidic Growth Conditions Promote Epithelial-to-Mesenchymal Transition to Select More Aggressive PDAC Cell Phenotypes In Vitro

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