IL-37 mediates the antitumor activity in renal cell carcinoma

Abstract

Interleukin (IL)-37 is a natural suppressor of innate inflammatory and immune responses. IL-37 plays an important role in renal function and antitumor activity. The aim of this study was to investigate the role of IL-37 in renal cell carcinoma (Rcc). Serum IL-37 levels in 120 Rcc patients and 50 healthy controls were measured by enzyme-linked immunosorbent assay (ELISA). The Rcc cell lines A498 and Caki-1 were cultured with 0-100 ng/mL of recombinant human IL-37 protein (rhIL-37). Cancer cells were transfected with or without pcDNA3.1-IL-6 to alter IL-6 expression. Cell migration, proliferation, and apoptosis were tested by wound-healing assay, MTT, and flow cytometry, respectively. Levels of IL-6, pSTAT3 Y705, Bcl-2, cyclin D1, and HIF-1α were detected by qRT-PCR, ELISA, or western blot. Additionally, therapeutic effect of rhIL-37 was also confirmed in SCID mice. The expression of IL-37 was decreased in Rcc patients and was negatively correlated with tumor progression. In vitro, IL-37 markedly inhibited the migration and proliferation, and promoted apoptosis in Rcc cells. Furthermore, the expressions of IL-6, pSTAT3 Y705, HIF-1α, Bcl-2, and cyclin D1 were decreased by IL-37. However, these effects were reversed by the transfection of pcDNA3.1-IL-6. In vivo, tumor growth and gene expressions of IL-6 and HIF-1α were suppressed by IL-37. In conclusion, IL-37 might serve as a novel tumor suppressor in Rcc and exert its antitumor activity through inhibiting IL-6/STAT3 signaling.

Interleukin-37 expression and its potential role in oral leukoplakia and oral squamous cell carcinoma

“…Reduction of inflammation in aged mice via transgenic expression of IL-37 could prevent NRASV12-mediated oncogenesis41. Expression of IL-37 was decreased both in human hepatocellular carcinoma tissues and in renal cell carcinoma, suggesting that IL-37 may be useful for tumour immunotherapy3142. The present study focused on the expression and regulatory role of IL-37 in the local environment of OLK and OSCC.…”

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

“…IL‐37 has been identified as a natural suppressor of innate inflammatory and immune responses 8, 12. Recent studies have indicated that IL‐37 plays a protective role in tumor progression in mouse fibrosarcoma,9 human lung cancer,14, 42 hepatocellular carcinoma,13 breast cancer,43 cervical cancer,44 and renal cell carcinoma 45. Zhang et al15 found that IL‐37 inhibits colon cancer progression via β‐catenin suppression and that a lack of IL‐37 is associated with poor survival.…”

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

“…Previous studies have found that IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to achieve its extracellular functions [41]. Jiang et al reported that serum IL-37 abundance is decreased in Rcc patients and negatively correlates with the disease progression [21]. Although our study only describes the intracellular activity of IL-37b on the Smad3 signaling in HCC, it is conceivable that IL-37b secretion by liver nonparenchymal cells may also play an anticancer effect via extracellular signal transduction.…”

“…High expression of IL-37 in HCC tumor tissues was associated with better overall survival (OS) and disease-free survival (DFS) [19]. In addition, IL-37 has been shown to suppress cell proliferation and invasion of human cervical cancer (CC) and Renal cell carcinoma (Rcc) through inhibiting signal transducer and activator of transcription 3 (STAT3) signaling [20, 21]. In 2016, Ge et al found that the expression of IL-37 was decreased in Non-small cell lung cancer (NSCLC) tissues and the antitumor activity of IL-37 was found by inhibition of angiogenesis in vitro and in vivo [22].…”