Akioka Takahiro, Kimura Shoichi, Katayama Yuichi, Fujii Masato, Kiwaki Takumi, Kawaguchi Makiko, Fukushima Tsuyoshi, Sato Yuichiro, Mukai Shoichiro, Kamoto Toshiyuki, Sawada Atsuro
Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Section of Oncopathology and Morphological Pathology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Biomedicines. 2025 Mar 28;13(4):811. doi: 10.3390/biomedicines13040811.
Increased expression of MET and hepatocyte growth factor (HGF)-related molecules has been positively correlated with poor prognosis in renal cell carcinoma (RCC). In the current study, the expression and phosphorylation of MET in metastatic RCC (mRCC) are determined by immunohistochemistry, and the therapeutic effect of MET and HGF activation-targeting agents for RCC cell lines is analyzed. Immunohistochemistry was performed for 76 formalin-fixed paraffin-embedded specimens (primary tumor: 32, metastatic site: 44). The therapeutic effect of capmatinib (MET-I) and SRI-31215 (inhibitor of HGF-activating proteases: HGFA-I) was determined based on the inhibition of MET phosphorylation, cell proliferation, and cell migration in 786-O and caki-1 cell lines. Increased expression and phosphorylation of MET were observed in both primary tumor and metastatic sites; however, phosphorylation was significantly upregulated in metastatic sites ( = 0.0001). In an assay of RCC cell lines, the strongest inhibition of MET phosphorylation, cell proliferation, and migration was confirmed with the combined used of MET-I and HGFA-I. Phosphorylation of MET was significantly upregulated in metastasis, which suggested the importance of downregulation in the treatment of mRCC. Our findings suggest that dual inhibition of MET and HGF activation may offer a promising strategy for mRCC treatment, warranting further clinical validation.
MET和肝细胞生长因子（HGF）相关分子的表达增加与肾细胞癌（RCC）的不良预后呈正相关。在本研究中，通过免疫组织化学确定转移性RCC（mRCC）中MET的表达和磷酸化，并分析针对RCC细胞系的MET和HGF激活靶向药物的治疗效果。对76个福尔马林固定石蜡包埋标本（原发肿瘤：32个，转移部位：44个）进行免疫组织化学检测。基于对786-O和caki-1细胞系中MET磷酸化、细胞增殖和细胞迁移的抑制作用，确定卡马替尼（MET-I）和SRI-31215（HGF激活蛋白酶抑制剂：HGFA-I）的治疗效果。在原发肿瘤和转移部位均观察到MET表达和磷酸化增加；然而，转移部位的磷酸化显著上调（P = 0.0001）。在RCC细胞系检测中，证实MET-I和HGFA-I联合使用对MET磷酸化、细胞增殖和迁移的抑制作用最强。MET磷酸化在转移中显著上调，这表明下调在mRCC治疗中的重要性。我们的研究结果表明，双重抑制MET和HGF激活可能为mRCC治疗提供一种有前景的策略，值得进一步临床验证。
