Department of Gastroenterological Surgery, Kanazawa University, Kanazawa, Japan.
Department of Human Pathology, Kanazawa University, Kanazawa, Japan.
Anticancer Res. 2020 Sep;40(9):5211-5219. doi: 10.21873/anticanres.14524.
BACKGROUND/AIM: CBP is a transcriptional coactivator in the Wnt/β-catenin pathway that is related to cell kinetics and differentiation. This study aimed to characterize β-catenin-activated hepatocellular carcinoma (HCC) and evaluate the direct effects of PRI-724 (a selective inhibitor of Wnt/β-catenin/CBP signaling) on HCC.
Immunohistochemistry for β-catenin was performed in 199 HCC resected samples. Moreover, using cultured HCC cell lines, cell kinetics and its related proteins were analyzed after treatment of cells with C-82 (active form of PRI-724).
Nuclear β-catenin expression was found in 18% of HCC cases and the tumor sizes in these positive samples were larger. In HCC cell lines with a constitutively activated β-catenin, C-82 inhibited cell proliferation. C-82 led to an increase in the percentage of cells in the G/G phase of the cell cycle. The percentage of cells in the sub-G phase also increased. Moreover, C-82 treatment significantly decreased the expression of cell proliferating markers and increased the expression of apoptosis-related proteins.
PRI-724(C-82) may be a novel drug for β-catenin-activated HCC therapy.
背景/目的：CBP 是 Wnt/β-catenin 通路中的转录共激活因子，与细胞动力学和分化有关。本研究旨在表征β-catenin 激活的肝细胞癌 (HCC)，并评估 PRI-724（一种选择性 Wnt/β-catenin/CBP 信号通路抑制剂）对 HCC 的直接作用。
对 199 例 HCC 切除样本进行β-catenin 的免疫组织化学染色。此外，在培养的 HCC 细胞系中，用 C-82（PRI-724 的活性形式）处理细胞后，分析细胞动力学及其相关蛋白。
在 18%的 HCC 病例中发现了核β-catenin 表达，这些阳性样本的肿瘤体积更大。在β-catenin 持续激活的 HCC 细胞系中，C-82 抑制细胞增殖。C-82 导致细胞周期 G/G 期的细胞百分比增加。亚 G 期的细胞百分比也增加。此外，C-82 处理显著降低了细胞增殖标志物的表达，增加了凋亡相关蛋白的表达。
PRI-724（C-82）可能是治疗β-catenin 激活的 HCC 的一种新型药物。
