• Breast cancer stem cells
• IL-33
• Immunotherapy
• ST2 knockdown
• Wnt pathway

• Interleukin-33/metabolism
• Interleukin-33/genetics
• Breast Neoplasms/pathology
• Breast Neoplasms/metabolism
• Breast Neoplasms/genetics
• Animals
• Female
• Humans
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Mice
• Wnt Signaling Pathway
• Interleukin-1 Receptor-Like 1 Protein/genetics
• Interleukin-1 Receptor-Like 1 Protein/metabolism
• Cell Line, Tumor
• Neoplasm Metastasis
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Cell Movement
• Tumor Microenvironment

• 2023CX120 Graduate Innovative Research Program 2023 of Jilin University
• 2020SCZT027 Finance Program of Jilin Provincial
• 2024YX0259 Horizontal Research Program of Jilin University
• 20230204043YY Scientific Development Program of Jilin Province
• 2023YFC2413100 the National Key R&D Program of China

• Cytokines
• IL-33
• Immunocytes
• Inflammation
• Tumor microenvironment

• R37 CA269754 NCI NIH HHS
• T32 GM133391 NIGMS NIH HHS

• Cancer stem cells
• Cancer stem-like cells
• Cellular factors
• Non-cellular factors
• Tumor microenvironment

• Breast cancer
• Drug sensitivity
• Immune microenvironment
• Prognostic signature
• Triple-negative breast cancer
• Tumor-associated neutrophil

• Humans
• Neutrophils
• Prognosis
• Genes, Neoplasm
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/therapy
• Area Under Curve
• Tumor Microenvironment/genetics

• IkBα
• Interleukin-33
• MAPK.
• NF-κB
• dexamethasone
• glioblastoma

• Humans
• NF-kappa B/metabolism
• MAP Kinase Signaling System
• Glioblastoma/drug therapy
• Interleukin-33/genetics
• Interleukin-33/metabolism
• Signal Transduction
• Tumor Necrosis Factor-alpha
• Dexamethasone/pharmacology
• p38 Mitogen-Activated Protein Kinases
• Phenotype

• 81860474,81860474 National Natural Science Foundation of China
• 2018GXNSFBA281036 Natural Science Foundation of Guangxi Zhuang Autonomous Region

• Interleukin-33
• breast cancer
• immunotherapy
• metastasis
• tumor microenvironment

• JP11/18 and JP15/19 Faculty of Medical Sciences, University of Kragujevac, Serbia

• gastric cancer
• interleukin-33
• therapeutic target

• R37 CA269649 NCI NIH HHS
• This work was supported by NCI R37CA269649 (MDS) and by Brazilian National Council for Scientific and Technological Development - CNPq 154866/2019-9 and 200995/2022-6 (JMAM)

• Breast cancer
• CDK4/6
• ESR1
• Endocrine resistance
• TME

• Humans
• Female
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Estrogen Receptor alpha/genetics
• Estrogen Receptor alpha/metabolism
• Drug Resistance, Neoplasm/genetics
• Receptors, Estrogen
• Point Mutation
• Mutation
• Tumor Microenvironment

• R15 CA271221 NCI NIH HHS

• adaptation
• cancer
• cell-matrix integration
• developmental processes
• supracellular control of proliferation

• CDK4/6 inhibitors
• RNAi
• SERD
• SERM
• anti-estrogen therapy
• aromatase inhibitors
• estrogen receptor-positive breast cancer
• resistance
• targeted therapies

• breast cancer
• endocrine therapy resistance
• obesity

Recent epidemiological and genetic studies have revealed an interconnection between schizophrenia and breast cancer. The mutual underlying pathophysiological mechanisms may be immunologically driven. A new cluster of molecules called alarmins may be involved in sterile brain inflammation, and we have already reported the potential impact of interleukin-33 (IL-33) on positive symptoms onset and the role of its soluble trans-membranes full length receptor (sST2) on amelioration of negative symptoms in schizophrenia genesis. Furthermore, these molecules have already been shown to be involved in breast cancer etiopathogenesis. In this review article, we aim to describe the IL-33/suppressor of tumorigenicity 2 (ST2) axis as a crossroad in schizophrenia-breast cancer comorbidity. Considering that raloxifene could be tissue-specific and improve cognition and that tamoxifen resistance in breast carcinoma could be improved by strategies targeting IL-33, these selective estrogen receptor modulators could be useful in complementary treatment. These observations could guide further somatic, as well as psychiatric therapeutical protocols by incorporating what is known about immunity in schizophrenia.

• Interleukin-33
• Schizophrenia
• Breast cancer
• Neurodegeneration

Interleukin-33 (IL-33) is often released from damaged cells, acting as a danger signal. IL-33 exerts its function by interacting with its receptor suppression of tumorigenicity 2 (ST2) that is constitutively expressed on most immune cells. Therefore, IL-33/ST2 signaling can modulate immune responses to participate actively in a variety of pathological conditions, such as cancer. Like a two-faced Janus, which faces opposite directions, IL-33/ST2 signaling may play contradictory roles on its impact on cancer progression through both immune and nonimmune cellular components. Accumulating evidence demonstrates both pro- and anti-tumorigenic properties of IL-33, depending on the complex nature of different tumor immune microenvironments. We summarize and discuss the most recent studies on the contradictory effects of IL-33 on cancer progression and treatment, with a goal to better understanding the various ways for IL-33 as a therapeutic target.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, plays a critical role in maintaining tissue homeostasis as well as pathological conditions, such as allergy, infectious disease, and cancer, by promoting type 1 and 2 immune responses. Through its specific receptor ST2, IL-33 exerts multifaceted functions through the activation of diverse intracellular signaling pathways. ST2 is expressed in different types of immune cells, including Th2 cells, Th1 cells, CD8⁺ T cells, regulatory T cells (T_reg), cytotoxic NK cells, group 2 innate lymphoid cells (ILC2s), and myeloid cells. During cancer initiation and progression, the aberrant regulation of the IL-33/ST2 axis in the tumor microenvironment (TME) extrinsically and intrinsically mediates immune editing via modulation of both innate and adaptive immune cell components. The summarized results in this review suggest that IL-33 exerts dual-functioning, pro- as well as anti-tumorigenic effects depending on the tumor type, expression levels, cellular context, and cytokine milieu. A better understanding of the distinct roles of IL-33 in epithelial, stromal, and immune cell compartments will benefit the development of a targeting strategy for this IL-33/ST2 axis for cancer immunotherapy.

• IL-33
• ST2
• cancer immunotherapy
• cellular context
• immune editing

Interleukin (IL)-33 is a member of the IL-1 superfamily and is a crucial cytokine playing the role of a dual-function molecule. IL-33 mediates its function by interacting with its receptor suppression of tumorigenicity 2 (ST2), which is constitutively expressed on T helper (Th)1 cells, Th2 cells, and other immune cells. Previously, we summarized findings on IL-33 and performed an intensive study of the correlation between IL-33 and tumor. IL-33 enables anti-tumor immune responses through Th1 cells and natural killer (NK) cells and plays a role in tumor immune escape in cancers via Th2 cells and regulatory T cells. Herein, we discuss the contradictory role of IL-33 in immune cells in different cancer, and our summaries may be helpful for better understanding of the development of research on IL-33 and tumor immunity.

• IL-33
• cancer
• immune cells
• immunity

• GPNMB
• IL-33
• cancer stem cells
• metastasis
• tumor associated macrophages

Osteosarcoma is the most common primary tumor of bone. Interleukin-33 (IL-33) is a pro-inflammatory cytokine that also participates in tumor progression. This study aimed to investigate the role of IL-33 in human osteosarcoma cell viability, proliferation, apoptosis, and epithelial-mesenchymal transition (EMT) in vitro and the molecular mechanisms involved.

The normal osteoblast cell line, hFOB 1.19, and the human osteosarcoma cell lines SOSP-9607, SAOS2, MG63, and U2OS were studied. The expression of IL-33 mRNA and protein in human osteosarcoma cell lines were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. The effects of IL-33 on human osteosarcoma cell viability, apoptosis, EMT, and the signaling pathways were studied using the MTT assay, flow cytometry, qRT-PCR, and Western blot.

IL-33 was upregulated in human osteosarcoma cell lines, including U2OS cells. The use of an IL-33 gene plasmid promoted osteosarcoma cell viability, inhibited cell apoptosis, increased the expression of Bcl-2, and reduced the expression of Bax. IL-33 reduced the level of E-cadherin and increased the levels of N-cadherin and matrix metalloproteinase-9 (MMP-9) in osteosarcoma cells at the mRNA and protein level. The use of the IL-33 plasmid increased the protein expression levels of p-AKT and the p-AKT/AKT ratio in osteosarcoma cells, and IL-33 siRNA reversed these findings.

IL-33 was highly expressed in human osteosarcoma cells. Down-regulation of IL-33 reduced cell viability and EMT of osteosarcoma cells, and induced cell apoptosis through activation of the PI3K/AKT signaling pathway.

• Alternative splicing
• Tumor specific-antigens (TSAs)
• immune system
• immunotherapy
• neoantigens
• tumor cells

• Alternative Splicing
• Animals
• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/immunology
• Cell Communication
• Humans
• Lymphocytes/immunology
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/pathology
• Tumor Microenvironment

• National Natural Science Foundation of China

Breast cancer stem cells (BCSC) play critical roles in the acquisition of resistance to endocrine therapy in estrogen receptor (ER)-positive (ER + ve) breast cancer (BC). The resistance results from complex alterations involving ER, growth factor receptors, NOTCH, Wnt/β-catenin, hedgehog, YAP/TAZ, and the tumor microenvironment. These mechanisms are likely converged on regulating BCSCs, which then drive the development of endocrine therapy resistance. In this regard, hormone therapies enrich BCSCs in ER + ve BCs under both pre-clinical and clinical settings along with upregulation of the core components of “stemness” transcriptional factors including SOX2, NANOG, and OCT4. SOX2 initiates a set of reactions involving SOX9, Wnt, FXY3D, and Src tyrosine kinase; these reactions stimulate BCSCs and contribute to endocrine resistance. The central contributions of BCSCs to endocrine resistance regulated by complex mechanisms offer a unified strategy to counter the resistance. ER + ve BCs constitute approximately 75% of BCs to which hormone therapy is the major therapeutic approach. Likewise, resistance to endocrine therapy remains the major challenge in the management of patients with ER + ve BC. In this review we will discuss evidence supporting a central role of BCSCs in developing endocrine resistance and outline the strategy of targeting BCSCs to reduce hormone therapy resistance.

• ER-positive breast cancer
• breast cancer stem cells
• endocrine therapy resistance
• hormone and growth factor signaling
• microenvironment

• NA Canadian Institutes of Health Research

MiR-873/CDK3 has been shown to play a critical role in ERα signaling and tamoxifen resistance. Thus, targeting this pathway may be a potential therapeutic approach for the treatment of ER positive breast cancer especially tamoxifen resistant subtype. Here we report that Norcantharidin (NCTD), currently used clinically as an ani-cancer drug in China, regulates miR-873/CDK3 axis in breast cancer cells. NCTD decreases the transcriptional activity of ERα but not ERβ through the modulation of miR-873/CDK3 axis. We also found that NCTD inhibits cell proliferation and tumor growth and miR-873/CDK3 axis mediates cell proliferation suppression of NCTD. More important, we found that NCTD sensitizes resistant cells to tamoxifen. NCTD inhibits tamoxifen induced the transcriptional activity as well ERα downstream gene expressions in tamoxifen resistant breast cancer cells. In addition, we found that NCTD restores tamoxifen induced recruitments of ERα co-repressors N-CoR and SMRT. Knockdown of miR-873 and overexpression of CDK3 diminish the effect of NCTD on tamoxifen resistance. Our data shows that NCTD regulates ERα signaling and tamoxifen resistance by targeting miR-873/CDK3 axis in breast cancer cells. This study may provide an alternative therapy strategy for tamoxifen resistant breast cancer.

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents, Hormonal/pharmacology
• Apoptosis
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Bridged Bicyclo Compounds, Heterocyclic/pharmacology
• Cell Proliferation
• Cyclin-Dependent Kinase 3/genetics
• Cyclin-Dependent Kinase 3/metabolism
• Drug Resistance, Neoplasm/drug effects
• Estrogen Receptor alpha/genetics
• Estrogen Receptor alpha/metabolism
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, Nude
• MicroRNAs/genetics
• Signal Transduction
• Tamoxifen/pharmacology
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays

• National Natural Science Foundation of China

• EMT
• IL-33
• Liver CSCs
• Tobacco smoke
• p38 MAPK

• Animals
• Apoptosis
• Cell Proliferation
• Cell Transformation, Neoplastic/drug effects
• Cell Transformation, Neoplastic/metabolism
• Cell Transformation, Neoplastic/pathology
• Epithelial-Mesenchymal Transition
• Humans
• Interleukin-33/genetics
• Interleukin-33/metabolism
• Liver Neoplasms, Experimental/chemically induced
• Liver Neoplasms, Experimental/metabolism
• Liver Neoplasms, Experimental/pathology
• Male
• Mice
• Mice, Inbred BALB C
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Phosphorylation
• Signal Transduction
• Tumor Cells, Cultured
• p38 Mitogen-Activated Protein Kinases/genetics
• p38 Mitogen-Activated Protein Kinases/metabolism

• No. 81602839, 81773431, 81573139, 81803210 National Natural Science Foundation of China
• BK20161029, SBK2018041176 Natural Science Foundation of Jiangsu Province
• (PAPD) Priority Academic Program Development of Jiangsu Higher Education Institutions

• Interleukin-33
• parotid gland
• pleomorphic adenoma
• sST2
• salivary gland
• tumor

• IL-33
• cancer
• cytokine
• immunology
• therapy

• Adaptive Immunity
• Adjuvants, Immunologic/administration & dosage
• Animals
• Antineoplastic Agents, Immunological/pharmacology
• Antineoplastic Agents, Immunological/therapeutic use
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/metabolism
• Cancer Vaccines/therapeutic use
• Carcinogenesis/immunology
• Dendritic Cells/immunology
• Dendritic Cells/metabolism
• Disease Models, Animal
• Epithelial Cells/immunology
• Epithelial Cells/metabolism
• Humans
• Immunity, Innate
• Immunotherapy/methods
• Interleukin-1 Receptor-Like 1 Protein/immunology
• Interleukin-1 Receptor-Like 1 Protein/metabolism
• Interleukin-33/administration & dosage
• Interleukin-33/antagonists & inhibitors
• Interleukin-33/immunology
• Interleukin-33/metabolism
• Killer Cells, Natural/immunology
• Killer Cells, Natural/metabolism
• Myeloid-Derived Suppressor Cells/immunology
• Myeloid-Derived Suppressor Cells/metabolism
• Neoplasms/immunology
• Neoplasms/therapy
• Signal Transduction/immunology
• Tumor Microenvironment/immunology

Soluble IL‐33 (interleukin (IL)‐1‐like cytokine) acts as endogenous alarm signal (alarmin). Since alarmins, besides activating immune system, act to restore tissue homeostasis, we investigated whether IL‐33 exerts beneficial effects on oral stem cell pull.

Clonogenicity, proliferation, differentiation and senescence of stem cells derived from human periodontal ligament (PDLSCs) and dental pulp (DPSCs) were determined after in vitro exposure to IL‐33. Cellular changes were detected by flow cytometry, Western blot, immunocytochemistry and semiquantitative RT‐PCR.

IL‐33 stimulated proliferation, clonogenicity and expression of pluripotency markers, OCT‐4, SOX‐2 and NANOG, but it inhibited ALP activity and mineralization in both PDLSCs and DPSCs. Higher Ki67 expression and reduced β‐galactosidase activity in IL‐33‐treated cells were demonstrated, whereas these trends were more conspicuous in osteogenic medium. However, after 7‐day IL‐33 pretreatment, differentiation capacity of IL‐33‐pretreated cells was retained, and increased ALP activity was observed in both cell types. Results showed that IL‐33 regulates NF‐κB and β‐catenin signalling, indicating the association of these molecules with changes observed in IL‐33‐treated PDLSCs and DPSCs, particularly their proliferation, pluripotency‐associated marker expression and osteogenesis.

IL‐33 treatment impairs osteogenesis of PDLSCs and DPSCs, while increases their clonogenicity, proliferation and pluripotency marker expression. After exposure to IL‐33, osteogenic capacity of cells stayed intact. NF‐κB and β‐catenin are implicated in the effects achieved by IL‐33 in PDLSCs and DPSCs.

• dental pulp
• interleukin-33
• osteogenesis
• periodontal ligament
• pluripotency
• stem cell

Interleukin-33 (IL-33) is a IL-1 family member of cytokines exerting pleiotropic activities. In the steady-state, IL-33 is expressed in the nucleus of epithelial, endothelial, and fibroblast-like cells acting as a nuclear protein. In response to tissue damage, infections or necrosis IL-33 is released in the extracellular space, where it functions as an alarmin for the immune system. Its specific receptor ST2 is expressed by a variety of immune cell types, resulting in the stimulation of a wide range of immune reactions. Recent evidences suggest that different IL-33 isoforms exist, in virtue of proteolytic cleavage or alternative mRNA splicing, with potentially different biological activity and functions. Although initially studied in the context of allergy, infection, and inflammation, over the past decade IL-33 has gained much attention in cancer immunology. Increasing evidences indicate that IL-33 may have opposing functions, promoting, or dampening tumor immunity, depending on the tumor type, site of expression, and local concentration. In this review we will cover the biological functions of IL-33 on various immune cell subsets (e.g., T cells, NK, Treg cells, ILC2, eosinophils, neutrophils, basophils, mast cells, DCs, and macrophages) that affect anti-tumor immune responses in experimental and clinical cancers. We will also discuss the possible implications of diverse IL-33 mutations and isoforms in the anti-tumor activity of the cytokine and as possible clinical biomarkers.

• IL-33
• IL-33 isoforms
• cancer
• immune cell subsets
• tumor immunology

• IL-33
• NSCLC
• TLR4
• gram-negative bacteria

• il-33
• st2
• cd8⁺ t cells
• dendritic cells
• antitumor immunity

• Animals
• Humans
• Interleukin-33/immunology
• Neoplasms/immunology
• Neoplasms/therapy

• P50 CA090386 NCI NIH HHS
• R01 CA208354 NCI NIH HHS
• R01 CA149669 NCI NIH HHS
• P30 CA060553 NCI NIH HHS
• R01 CA222963 NCI NIH HHS

Lung adenocarcinoma is one of the leading causes of cancer-related death worldwide. We showed transcriptomic profiles in three pairs of tumors and adjacent non-tumor lung tissues using next-generation sequencing (NGS) to screen protein-coding RNAs and microRNAs. Combined with meta-analysis from the Oncomine and Gene Expression Omnibus (GEO) databases, we identified a representative genetic expression signature in lung adenocarcinoma. There were 9 upregulated genes, and 8 downregulated genes in lung adenocarcinoma. The analysis of the effects from each gene expression on survival outcome indicated that 6 genes (AGR2, SPDEF, CDKN2A, CLDN3, SFN, and PHLDA2) play oncogenic roles, and 7 genes (PDK4, FMO2, CPED1, GNG11, IL33, BTNL9, and FABP4) act as tumor suppressors in lung adenocarcinoma. In addition, we also identified putative genetic interactions, in which there were 5 upregulated microRNAs with specific targets - hsa-miR-183-5p-BTNL9, hsa-miR-33b-5p-CPED1, hsa-miR-429-CPED1, hsa-miR-182-5p-FMO2, and hsa-miR-130b-5p-IL33. These 5 microRNAs have been shown to be associated with tumorigenesis in lung cancer. Our findings suggest that these genetic interactions play important roles in the progression of lung adenocarcinoma. We propose that this molecular change of genetic expression may represent a novel signature in lung adenocarcinoma, which may be developed for diagnostic and therapeutic strategies in the future.

• bioinformatics
• lung adenocarcinoma
• messenger RNA
• microRNA
• next-generation sequencing