IL-37bΔ1-45 suppresses the migration and invasion of endometrial cancer cells by targeting the Rac1/NF-κB/MMP2 signal pathway

• Published in: Laboratory investigation 2021-06, Vol.101 (6), p.760-774
• Main Authors: Wang, Xishuang, Wei, Zengtao, Tang, Zhongyun, Xue, Chenyue, Yu, Huayun, Zhang, Derui, Li, Yulan, Liu, Xihong, Shi, Yongyu, Zhang, Lining, Chen, Guoling, Zhou, Huaiyu, Wang, Jianing, Wang, Xiaoyan
• Format: Article
• Language: English
• Subjects: 13/89; 38/77; 631/250/127/1213; 631/67/1244; 82/51; 82/80; 96/21; Actin; Actins - metabolism; Adult; Aged; Animals; Cancer; Carcinoma; Carcinoma, Endometrioid - drug therapy; Carcinoma, Endometrioid - metabolism; Cell Line, Tumor; Cell proliferation; Cervical cancer; Cervix; Depolymerization; Endometrial cancer; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - metabolism; Endometriosis; Endometrium; Epithelial-Mesenchymal Transition - drug effects; Estrogens; Female; Gelatinase A; Gynecological diseases; Humans; Inflammation; Interleukin 1; Interleukin-1 - metabolism; Interleukin-1 - pharmacology; Interleukin-1 - therapeutic use; Interleukins; Isoforms; Laboratory Medicine; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix metalloproteinases; Medicine; Medicine & Public Health; Mesenchyme; Metalloproteinase; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; NF-kappa B - metabolism; NF-κB protein; Pathogenesis; Pathology; Peritoneum; Progesterone; Proteins; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Reproductive system; Signal Transduction - drug effects; Tumors; Uterine cancer; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-021-00544-2

Endometrial carcinoma is one of the most common malignancies in the female reproductive system. Interleukin-37 (IL-37) is a newly discovered anti-inflammatory factor belonging to the IL-1 family. IL-37 has five different isoforms, and IL-37b is the most biologically functional subtype. In recent years, the protective roles of IL-37 in different cancers, including lung and liver cancers, have been successively reported. IL-37 also plays an important role in some gynecological diseases such as endometriosis, adenomyosis, and cervical cancer. However, the role and mechanism of IL-37b, especially the mature form of IL-37b, in endometrial carcinoma have not been elucidated. The present study demonstrated that IL-37 protein was downregulated in endometrial carcinoma cells compared with the control endometrium. IL-37b did not affect the proliferation and colony-forming ability of endometrial cancer cells. A mature form of IL-37b (IL-37bΔ1-45) effectively suppressed the migration and invasion of endometrial cancer cells by decreasing the expression of matrix metalloproteinase 2 (MMP2) via Rac1/NF-κB signal pathway. However, it did not affect epithelial–mesenchymal transition (EMT) or filamentous actin (F-actin) depolymerization of endometrial cancer cells. IL-37bΔ1-45 attenuated tumor metastasis in a peritoneal metastatic xenograft model of endometrial cancer. To sum up, these results suggested IL-37b could be involved in the pathogenesis of endometrial carcinoma and provide a novel target for the diagnosis and treatment of endometrial carcinoma.