Interleukin-33 Predicts Poor Prognosis and Promotes Renal Cell Carcinoma Cell Growth Through its Receptor ST2 and the JNK Signaling Pathway

Wu, Changwen; Wu, Yiguo; Cheng, Cheng; Zhou, Hong; Shi, Zimin; Lin, Shuangquan; Li, Jie; He, Xiaoyi; Zhu, Anyi

doi:10.1159/000489766

Cited by 18 publications

(15 citation statements)

References 16 publications

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“…The latter is a highly conserved signal transduction in eukaryotic cells and one of the best-characterized signaling cascades to regulate cell proliferation (Achkar et al, 2018;Liu et al, 2018;Liang and Yang, 2019). A number of studies have demonstrated a role for the increased activity of MAPK signaling cascades in RCC cells and activation of the MAPK pathway was generally recognized for RCC growth (Wu et al, 2018;Zhao et al, 2018). Our current data further support this notion.…”

Section: Discussionsupporting

confidence: 81%

Cell Polarity Protein Pals1-Associated Tight Junction Expression Is a Favorable Prognostic Marker in Clear Cell Renal Cell Carcinoma

Lan

Liu

et al. 2020

Front. Genet.

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Introduction: The Pals1-associated tight junction (PATJ) is a Crumbs (CRB) complex component that regulates epithelial cell apico-basal polarity and directional migration. This study assessed PATJ expression in clear cell renal cell carcinoma (ccRCC) vs. normal tissues and associated with ccRCC progression and prognosis. Methods: The effects of PATJ knockdown were investigated on regulation of normal kidney epithelial cell viability and protein expression in vitro. The PATJ mRNA data in ccRCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and analyzed with UALCAN, LinkedOmics, Kaplan-Meier Plotter, GEPIA, and SurvExpress tools. Immunohistochemistry was performed for PATJ in tissue microarray sections (n = 150 ccRCC and 30 normal renal specimens). Normal human kidney tubular epithelial cell (HKC) cells were transfected with PATJ and negative control siRNA for cell viability CCK-8 assay, flow cytometry, and western blots. Results: The data showed that PATJ mRNA and protein were downregulated in ccRCC tissues and cell lines. Downregulation of PATJ mRNA was associated with male patients, advanced tumor stages, grades, and ccB subtypes as well as poorer overall and diseasefree survival of patients. Furthermore, PATJ protein was also significantly downregulated in ccRCC tissues and associated with advanced tumor pathologic, TNM stages and poorer overall. In vitro, knockdown of PATJ expression promoted HKC proliferation and the activation of mitogen-activated protein kinases (MAPK) pathway proteins. Conclusions: This study revealed that a decrease of PATJ in ccRCC, which was associated with male patients, advanced tumor, and poorer survival, suggesting that PATJ may be a useful prognostic biomarker and therapeutic target for ccRCC. Keywords: cell polarity protein Pals1-associated tight junction, clear cell renal cell carcinoma, prognosis, tumor cell proliferation, mitogen-activated protein kinases Li et al.

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Section: Discussionsupporting

confidence: 81%

Cell Polarity Protein Pals1-Associated Tight Junction Expression Is a Favorable Prognostic Marker in Clear Cell Renal Cell Carcinoma

Lan

Liu

et al. 2020

Front. Genet.

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“…In colon, IBD is a major risk factor of colorectal cancer with 23-fold increased risk among patients with pancolitis (17). In addition, IL-33 up-regulation has been detected in established invasive cancers, which may suggest a role for IL-33/Treg axis in tumor progression in response to damaged tissue homeostasis (9,(18)(19)(20). These observations suggest IL-33 blocking antibodies developed for atopic disorders may show efficacy in cancer treatment.…”

Section: Il-33 and Tregs Are Increased In Cancer-prone Chronic Inflammentioning

confidence: 99%

IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation

Ameri

Tuchayi

Zaalberg

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Chronic inflammation’s tumor-promoting potential is well-recognized; however, the mechanism underlying the development of this immune environment is unknown. Studying the transition from acute, tumor-suppressive to chronic, tumor-promoting allergic contact dermatitis (ACD) revealed how tumor-promoting chronic inflammation develops. Epidermis-derived interleukin (IL)-33 up-regulation and its induction of regulatory T cell (Treg) accumulation in the skin preceded the transition from acute to chronic ACD and triggered the tumor-promoting immune environment in chronic ACD. Mice lacking IL-33 were protected from chronic ACD and its skin cancer sequela compared with wild-type controls (P = 0.0002). IL-33’s direct signaling onto Tregs was required for the development of the tumor-promoting immune environment in the skin. IL-33–Treg signaling was also required for chronic colitis and its associated colorectal cancer development in a colitis model (P < 0.0001). Significantly increased IL-33 and Tregs marked the perilesional skin and colon in patients with cancer-prone chronic inflammatory diseases. Our findings elucidate the role of the IL-33/Treg axis in creating a tumor-promoting immune environment in chronic inflammatory diseases and suggest therapeutic targets for cancer prevention and treatment in high-risk patients.

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“…Such over-expression was associated with advanced tumor-lymph node-metastasis (TNM) stage, resulting in reduced survival and increased risk of recurrence in patients. Mechanistically, it has been shown that IL-33 enhances RCC cell growth in vivo and prevents chemotherapy-induced tumor apoptosis in vitr o via JNK signaling activation in tumor cells ( 149 ). Similarly, both IL-33 and ST2 were up-regulated in ovarian tumors compared to normal ovary and ovarian benign tumors, and the expression levels were further increased in tumor tissues at the metastatic site ( 150 ).…”

Section: Il-33/st2 As a Biomarker Predictive Of Cancer Progression Anmentioning

confidence: 99%

The Pleiotropic Immunomodulatory Functions of IL-33 and Its Implications in Tumor Immunity

et al. 2018

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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.

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Interleukin-33 Predicts Poor Prognosis and Promotes Renal Cell Carcinoma Cell Growth Through its Receptor ST2 and the JNK Signaling Pathway

Cited by 18 publications

References 16 publications

Cell Polarity Protein Pals1-Associated Tight Junction Expression Is a Favorable Prognostic Marker in Clear Cell Renal Cell Carcinoma

Cell Polarity Protein Pals1-Associated Tight Junction Expression Is a Favorable Prognostic Marker in Clear Cell Renal Cell Carcinoma

IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation

The Pleiotropic Immunomodulatory Functions of IL-33 and Its Implications in Tumor Immunity

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