Huang Po-Yu, Hung Tung-Wei, Hsieh Yi-Hsien, Wu Pei-Jen, Chen Pei-Ni, Lee Chu-Che, Tsai Jen-Pi
Division of Nephrology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan.
Institute of Medical Sciences, Tzu Chi University, Hualian, Taiwan.
Int J Med Sci. 2025 Apr 22;22(10):2308-2317. doi: 10.7150/ijms.112117. eCollection 2025.
Ellagic acid (EA) exerts anti-carcinogenic activity in various types of cancer. Matrix metalloproteinases (MMPs) are critical mediators in the pathogenesis of renal cell carcinoma (RCC) metastasis. Using experiments, this study aims to investigate the mechanisms by which EA inhibits RCC migration and invasion. The findings show that EA treatment inhibited RCC cell migration and invasion without reducing cell viability in normal human kidney cells (HK2 cells) and RCC cells (786-O and ACHN). A human proteinase array showed that EA treatment decreased MMP1 mRNA and protein expression levels in 786-O and ACHN cell lines. MMP1 expression is elevated in RCC tissues and correlates with tumor grade, stage, and overall survival in RCC patients. Our molecular docking model indicates a strong interaction between EA and MMP1. The addition of recombinant human MMP1 (Rh-MMP1) to RCC cells increased their migration and invasion; co-treatment with Rh-MMP1 and EA effectively reversed these effects. EA reduced the expression of the transcription factor RUNX2 in both RCC cell lines and knockdown of RUNX2 significantly decreased the migration and invasion abilities of EA-treated 786-O cells. High expression of RUNX2 in RCC patients is associated with higher tumor grade, stage, and poorer survival and correlates positively with MMP1 expression level. These results suggest that EA suppresses RUNX2 targeting of MMP1 expression, thereby conferring anti-invasive properties on RCC cells.
鞣花酸（EA）在多种癌症中发挥抗癌活性。基质金属蛋白酶（MMPs）是肾细胞癌（RCC）转移发病机制中的关键介质。本研究通过实验旨在探究EA抑制RCC迁移和侵袭的机制。研究结果表明，EA处理可抑制RCC细胞迁移和侵袭，而不降低正常人肾细胞（HK2细胞）和RCC细胞（786 - O和ACHN）的细胞活力。人蛋白酶阵列显示，EA处理可降低786 - O和ACHN细胞系中MMP1的mRNA和蛋白表达水平。MMP1在RCC组织中表达升高，且与RCC患者的肿瘤分级、分期及总生存期相关。我们的分子对接模型表明EA与MMP1之间存在强烈相互作用。向RCC细胞中添加重组人MMP1（Rh - MMP1）可增加其迁移和侵袭能力；Rh - MMP1与EA联合处理可有效逆转这些作用。EA降低了两种RCC细胞系中转录因子RUNX2的表达，敲低RUNX2可显著降低EA处理的786 - O细胞的迁移和侵袭能力。RCC患者中RUNX2的高表达与更高的肿瘤分级、分期及更差的生存率相关，且与MMP1表达水平呈正相关。这些结果表明，EA通过抑制RUNX2对MMP1表达的靶向作用，从而赋予RCC细胞抗侵袭特性。
