IL-37 suppresses hepatocellular carcinoma growth by converting pSmad3 signaling from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/P21 tumor-suppressive signaling

Li, Rui; Tang, Chengyong; Shen, Ai; Luo, Huating; Wei, Xufu; Zheng, Daofeng; Sun, Chao; Li, Zhongtang; Zhu, Di; Li, Tingting; Wu, Zhongjun

doi:10.18632/oncotarget.13196

Cited by 31 publications

(31 citation statements)

References 39 publications

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“…Current studies indicate that, many cytokines, including IL‐17, IL‐6 and IL‐37, could regulate the function of HCC cells by an autocrine manner . We next examined whether HBX could promote the secretion of IL‐34 to mediate the biological function of HCC cells.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, when knocking down of IL‐34 by shRNA, the proliferation and migration efficiency of HCC cells mediated by HBX was decreased. Previous studies show that multiple autocrine cytokines, including IL‐17 and IL‐37 , could regulate the biological function of hepatoma cells . We next investigated whether HBX could promote the secretion of IL‐34 from HCC cells and the secreted IL‐34 in turn had an effect on HCC cells.…”

Section: Discussionmentioning

confidence: 99%

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Interleukin‐34 mediated by hepatitis B virus X protein via CCAAT/enhancer‐binding protein α contributes to the proliferation and migration of hepatoma cells

et al. 2019

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Objectives Interleukin‐34 (IL‐34) is associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). However, the role and associated mechanisms of IL‐34 in HBV‐related HCC remain unclear. In this study, the expression, biological function and associated mechanisms of IL‐34 in HBV‐related HCC cells were investigated. Methods IL‐34 expression induced by HBV and HBV X (HBX) gene was measured in hepatoma cells. The role of CCAAT/enhancer‐binding protein α (CEBP/α) in HBX‐induced IL‐34 expression was examined. The signal pathways involved in the expression of CEBP/α and IL‐34 induced by HBX were assessed. The role of IL‐34 in the proliferation and migration of HCC cells, and related mechanisms were explored. Results Dependent on HBX, HBV increased IL‐34 expression in hepatoma cells, and HBX upregulated and interacted with CEBP/α to enhance the activity of IL‐34 promoters. CEBP/α mediated by HBX was associated with the activation of PI3‐K and NF‐κB pathways to promote IL‐34 expression. Via CSF1‐R and CD138, IL‐34 promoted the proliferation and migration of hepatoma cells, and contributed to the activation of ERK and STAT3 pathways and the upregulation of Bcl‐xl and c‐Myc mediated by HBX. Conclusion We demonstrate that IL‐34 contributes to HBX‐mediated functional abnormality of HCC cells and provides a novel insight into the molecular mechanism of carcinogenesis mediated by HBX.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interleukin‐34 mediated by hepatitis B virus X protein via CCAAT/enhancer‐binding protein α contributes to the proliferation and migration of hepatoma cells

et al. 2019

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“…Acting as a dual‐function cytokine, intracellular IL‐37 can regulate cellular behavior. Overexpression of IL‐37 in human hepatocellular carcinoma (HCC) cell lines HepG2 and SMMC‐7721 significantly suppressed HCC cell growth and proliferation through converting Smad3 phospho‐isoform . Intracellular mature IL‐37 can directly bind to Rac1 and subsequently suppress the migration ability of A549 and BEL‐7402 cell .…”

Section: Il‐37 Receptor and Signalingmentioning

confidence: 99%

“…Another study mainly focused on the direct effect of IL‐37 on hepatocarcinogenesis . They observed a reduction of IL‐37 expression in the tumor area.…”

Section: Il‐37 In Tumormentioning

confidence: 99%

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IL‐37: An anti‐inflammatory cytokine with antitumor functions

Liu

2018

Cancer Reports

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Background IL‐37 is a newly identified IL‐1 family cytokine. Unlike other members in IL‐1 family, IL‐37 has been demonstrated to be an anti‐inflammatory cytokine in many inflammatory and autoimmune diseases. IL‐37 is regarded as a dual‐function cytokine as both the extracellular and intracellular IL‐37 are biologically functional. Extracellular IL‐37 can bind to IL‐18Rα and IL‐1R8 to form a triple complex, regulating the downstream STAT3 and PTEN signaling. Intracellular IL‐37 can interact with Smad3, translocate into nucleus, and regulate downstream target gene expressions. Recently, the role of IL‐37 in tumor development has been extensively studied. Recent findings IL‐37 has been found to play an antitumor role in various types of tumors, such as non‐small cell lung cancer, hepatocellular carcinoma, and renal cell carcinoma. Many mechanism studies have been carried out to elaborate the possible effects of IL‐37 on tumor growth, immune responses, and tumor angiogenesis. More importantly, the function of IL‐37 may be dependent on its concentration and receptor expression. It can form dimers at high concentrations to be inactivated, thus inhibiting its anti‐inflammatory function. We focused on the role of IL‐37 in various tumor types and provided the hypothesis regarding the underlying mechanisms. Conclusion IL‐37 may affect tumor development through multiple mechanisms: (1) IL‐37 directly influences tumor cell viability; (2) IL‐37 regulates the immune response to promote the antitumor immunity; and (3) IL‐37 suppresses tumor angiogenesis in the tumor microenvironment. Future studies are warranted to further investigate the mechanisms of these multifaceted functions of IL‐37 in animal models and cancer patients.

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The indirect antiangiogenic effect of IL-37 in the tumor microenvironment

Zhu

Teo

et al. 2020

Journal of Leukocyte Biology

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IL-37, a newly identified IL-1 family cytokine, has been shown to play an important role in inflammatory diseases, autoimmune diseases, and carcinogenesis. IL-37 has been suggested to suppress tumoral angiogenesis, whereas some publications showed that IL-37 promoted angiogenesis through TGF-signaling in both physiologic and pathologic conditions. Therefore, the function of IL-37 in tumoral angiogenesis is not clear and the underlying mechanism is not known.In this current study, we investigated the direct role of IL-37 on endothelial cells, as well as its indirect effect on angiogenesis through functioning on tumor cells both in vitro and in vivo. We found that IL-37 treatment directly promoted HUVEC migration and tubule formation, indicating IL-37 as a proangiogenic factor. Surprisingly, the supernatants from IL-37 overexpressing tumor cell line promoted HUVEC apoptosis and inhibited its migration and tubule formation. Furthermore, we demonstrated that IL-37 suppressed tumor angiogenesis in a murine orthotopic hepatocellular carcinoma model, suggesting its dominant antiangiogenesis role in vivo. Moreover, microarray and qPCR analysis demonstrated that IL-37 reduced the expressions of proangiogenic factors and increased the expressions of antiangiogenic factors by tumor cells. Matrix metalloproteinase (MMP)2 expression was significantly decreased by IL-37 in both cell lines and murine tumor models. MMP9 and vascular endothelial growth factor expressions were also reduced in murine tumors overexpressing IL-37, as well as in cell lines overexpressing IL-37 under hypoxic conditions. In conclusion, although IL-37 could exert direct proangiogenic effects on endothelial cells, it plays an antiangiogenic role via modulating proangiogenic and antiangiogenic factor expressions by tumor cells in the tumor microenvironment.

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IL-37 suppresses hepatocellular carcinoma growth by converting pSmad3 signaling from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/P21 tumor-suppressive signaling

Cited by 31 publications

References 39 publications

Interleukin‐34 mediated by hepatitis B virus X protein via CCAAT/enhancer‐binding protein α contributes to the proliferation and migration of hepatoma cells

Interleukin‐34 mediated by hepatitis B virus X protein via CCAAT/enhancer‐binding protein α contributes to the proliferation and migration of hepatoma cells

IL‐37: An anti‐inflammatory cytokine with antitumor functions

The indirect antiangiogenic effect of IL-37 in the tumor microenvironment

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