IL‐37 inhibits invasion and metastasis in non‐small cell lung cancer by suppressing the IL‐6/STAT3 signaling pathway

Jiang, Mingfang; Wang, Ye; Zhang, Hua; Ji, Youxin; Zhao, Peng; Sun, Rongli; Zhang, Chunyu

doi:10.1111/1759-7714.12628

Cited by 45 publications

(39 citation statements)

References 33 publications

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“…Similarly, Jiang et al found that serum IL‐37 level was decreased in NSCLC patients compared with healthy control. This low IL‐37 expression level was significantly associated with advanced TNM stage …”

Section: Il‐37 In Tumormentioning

confidence: 93%

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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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Section: Il‐37 In Tumormentioning

confidence: 93%

“…53 level was significantly associated with advanced TNM stage. 54 A significant decrease in tumor growth was observed with IL-37 overexpression in a murine NSCLC model. 52 Tumor angiogenesis plays a crucial role for carcinogenesis and metastasis in NSCLC.…”

Section: Lung Cancermentioning

confidence: 95%

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

Liu

2018

Cancer Reports

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“…However, only limited studies have used cancer patient samples to investigate IL-37. 16,19,20 Furthermore, given its expression and role in immune cells, the expression of IL-37 in immune cells and its regulatory effects need to be investigated in cancer patients.…”

Section: Publicationmentioning

confidence: 99%

“…Indeed, the protective role of IL‐37 in cancer has been reported when IL‐37 was transfected into cancer cells, or when recombinant IL‐37 was administered in animal models of cancers (summarized in review papers by Ding et al and Abulkhir et al). However, only limited studies have used cancer patient samples to investigate IL‐37 . Furthermore, given its expression and role in immune cells, the expression of IL‐37 in immune cells and its regulatory effects need to be investigated in cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Interleukin‐37 is highly expressed in regulatory T cells of melanoma patients and enhanced by melanoma cell secretome

Osborne

Domenico

Luo

et al. 2019

Molecular Carcinogenesis

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Immune suppression is one of the 10 hallmarks of cancer. Interleukin‐37 (IL‐37), a member of the IL‐1 family, inhibits both innate and adaptive immunity, and has been shown to modulate immune responses in various disease conditions. Yet, IL‐37 has rarely been investigated in cancer patients, and its biological role in cancer remains to be elucidated. In this study, we investigated the gene expression of IL‐37 in age‐ and sex‐matched blood samples of healthy individuals and melanoma patients, and demonstrated upregulation of IL‐37 messenger RNA (mRNA) in the blood samples of melanoma patients. By further analyzing immune cell subsets responsible for the upregulated IL‐37 expression, we discovered that IL‐37 mRNA was highly expressed in T cells and granulocytes, with the highest expression in regulatory T (Treg) cells in healthy individuals, and that IL‐37 mRNA was upregulated in lymphocytes (T, B, and natural killer cells) in melanoma patient blood. Among all cell subsets, Treg cells from melanoma patients exhibited the highest IL‐37 gene expression levels. We provided evidence that melanoma‐conditioned media induces IL‐37 mRNA and protein expression in multiple lymphocyte populations, particularly in Treg cells. We further confirmed that the IL‐1‐mediated secretome from human melanoma cells, specifically transforming growth factor‐β, induces IL‐37 mRNA expression in human Treg cells. Our results suggest a potential immunosuppressive role for IL‐1 and IL‐37 in melanoma tumorigenesis. Highly elevated IL‐37 in specific lymphocyte populations could serve as a biomarker for tumor‐induced immunosuppression.

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“…In previous studies, IL-37 has been demonstrated to inhibit the proliferation and invasion of cervical cancer cells through STAT3, and promoted cell apoptosis through Bcl-2-like protein 11 (15,16). In non-small cell lung cancer and renal cell carcinoma, IL-37 played an anticancer role through STAT3 (17). In gallbladder carcinoma, IL-37 acted as a tumor suppressor by inhibiting cell migration and invasion (18).…”

Section: Introductionmentioning

confidence: 99%

Decreased IL‑37 expression in hepatocellular carcinoma tissues and liver cancer cell lines

Guo

et al. 2020

Oncol Lett

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The role of IL-37 in cancer is currently largely unknown. The present study aimed to investigate IL-37 expression in hepatocellular carcinoma (HCC), paracancerous tissues (PT) and liver cancer cell lines, and their associations between IL-37 and NF-κB. A total of 65 HCC and 65 PT tissues were collected. The expression of IL-37 and NF-κB in tissues was detected by immunohistochemistry (IHC) and the data was analyzed using SPSS software. In the in vitro studies, IL-37 gene was transfected into HepG2 and MHCC97H cell lines with Lipofectamine 3000, and the protein regulation of NF-κB by IL-37 was verified by immunofluorescence (IF) and western blotting. In HCC, the positive expression rates of IL-37 and NF-kB were 21.5 and 95.4%, respectively. In PT, strong positive staining of IL-37and weak positive staining of NF-κB were observed. The normal expression levels of IL-37 and NF-κB, the increased IL-37 and decreased NF-κB induced by IL-37 gene transfection were observed through IF in cell lines. In terms of clinical significance, the difference in IL-37 expression between HCC and PT was statistically significant (χ 2 =55.05; P<0.001). IL-37 expression in HCC but not PT was negatively associated with serum AFP (χ 2 =6.522; P=0.039). IL-37 expression in PT was associated with sex (χ 2 =13.12; P=0.003) and tumor size (χ 2 =7.996; P=0.045). NF-κB expression in PT was associated with age, sex and BCLC stage. Notably, there was a negative correlation between IL-37 and NF-κB in HCC (r=-0.277; P=0.029) but not in PT (P>0.05). IL-37 overexpression downregulated the NF-κB protein by 56.50% in HepG2 cells (P<0.05) and 30.52% in MHCC97H cells (P<0.05). In conclusion, the expression of IL-37 in HCC and PT was specifically associated with serum AFP and tumor size, respectively. IL-37 expression was negatively correlated with NF-κB protein expression in HCC tissues and liver cancer cell lines.

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IL‐37 inhibits invasion and metastasis in non‐small cell lung cancer by suppressing the IL‐6/STAT3 signaling pathway

Cited by 45 publications

References 33 publications

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

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

Interleukin‐37 is highly expressed in regulatory T cells of melanoma patients and enhanced by melanoma cell secretome

Decreased IL‑37 expression in hepatocellular carcinoma tissues and liver cancer cell lines

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