Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, 350122, China.
Funct Integr Genomics. 2023 May 18;23(2):164. doi: 10.1007/s10142-023-01049-5.
Interleukin-1 receptor antagonist (IL-1RA) has been shown to play an important role in cancer progression. However, its pathogenic effects and molecular mechanism in the malignant progression of esophageal squamous cell carcinoma (ESCC) remain largely unknown. This study was designed to explore the function of IL-1RA in ESCC and determine the relationship between IL-1RA and lymph node metastasis in ESCC patients. The clinical relevance of IL-1RA in relation to the clinicopathological features and prognosis of 100 ESCC patients was analyzed. The function and underlying mechanisms of IL-1RA in the growth, invasion, and lymphatic metastasis in ESCC were explored both in vitro and in vivo. The therapeutic effect of anakinra, an IL-1 receptor antagonist, on ESCC was also evaluated in animal experiments. Downregulation of IL-1RA was observed in ESCC tissues and cells and was found to be strongly correlated with pathological stage (P = 0.034) and lymphatic metastasis (P = 0.038). Functional assays demonstrated that upregulation of IL-1RA reduced cell proliferation, migration, and lymphangiogenesis both in vitro and in vivo. Mechanistic studies revealed that overexpression of IL-1RA activated the epithelial-to-mesenchymal transition (EMT) in the ESCC cells through activation of MMP9 and regulation of the expression and secretion of VEGF-C through the PI3K/NF-κB pathway. Anakinra treatment resulted in significant inhibition of tumor growth, lymphangiogenesis, and metastasis. IL-1RA inhibits lymph node metastasis of ESCC by regulating the EMT through activation of matrix metalloproteinase 9(MMP9) and lymphangiogenesis, driven by VEGF-C and the NF-κB signaling pathway. Anakinra may be an effective drug for the inhibition of ESCC tumor formation and lymph node metastasis.
白细胞介素-1 受体拮抗剂 (IL-1RA) 已被证明在癌症进展中发挥重要作用。然而，其在食管鳞状细胞癌 (ESCC) 恶性进展中的致病作用和分子机制在很大程度上仍不清楚。本研究旨在探讨 IL-1RA 在 ESCC 中的作用，并确定 IL-1RA 与 ESCC 患者淋巴结转移之间的关系。分析了 100 例 ESCC 患者中 IL-1RA 与临床病理特征和预后的相关性。在体外和体内研究了 IL-1RA 在 ESCC 生长、侵袭和淋巴转移中的功能和潜在机制。还在动物实验中评估了 IL-1 受体拮抗剂 anakinra 对 ESCC 的治疗效果。在 ESCC 组织和细胞中观察到 IL-1RA 的下调，并且与病理分期（P=0.034）和淋巴转移（P=0.038）强烈相关。功能测定表明，IL-1RA 的上调减少了体外和体内 ESCC 细胞的增殖、迁移和淋巴管生成。机制研究表明，IL-1RA 通过激活 MMP9 和通过 PI3K/NF-κB 通路调节 VEGF-C 的表达和分泌，在上皮间质转化 (EMT) 中激活 ESCC 细胞。阿那白滞素治疗导致肿瘤生长、淋巴管生成和转移的显著抑制。IL-1RA 通过激活基质金属蛋白酶 9（MMP9）和通过 VEGF-C 和 NF-κB 信号通路驱动的淋巴管生成来抑制 ESCC 的淋巴结转移。阿那白滞素可能是抑制 ESCC 肿瘤形成和淋巴结转移的有效药物。
