Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Cell Death Dis. 2022 Apr 21;13(4):391. doi: 10.1038/s41419-022-04816-7.
Cholangiocarcinoma (CCA) is a subtype of bile duct cancer usually diagnosed late with a low survival rate and no satisfactorily systemic treatment. Recently, regorafenib has been accepted as a second-line treatment for CCA patients. In this study, we investigated the potential signal transduction pathways mediated by regorafenib. We established a transcriptomic database for regorafenib-treated CCA cells using expression microarray chips. Our data indicate that regorafenib inhibits yes-associated protein 1 (YAP1) activity in various CCA cells. In addition, we demonstrated that YAP1 regulates epithelial-mesenchymal transition (EMT)-related genes, including E-cadherin and SNAI2. We further examined YAP1 activity, phosphorylation status, and expression levels of YAP1 downstream target genes in the regorafenib model. We found that regorafenib dramatically suppressed these events in CCA cells. Moreover, in vivo results revealed that regorafenib could significantly inhibit lung foci formation and tumorigenicity. Most importantly, regorafenib and amphiregulin (AREG) neutralize antibody exhibited synergistic effects against CCA cells. In a clinical setting, patients with high YAP1 and EMT expression had a worse survival rate than patients with low YAP1, and EMT expression did. In addition, we found that YAP1 upregulated the downstream target amphiregulin in CCA. Our findings suggest that AREG neutralizing antibody antibodies combined with regorafenib can reverse the CCA metastatic phenotype and EMT in vitro and in vivo. These findings provide novel therapeutic strategies to combat the metastasis of CCA.
胆管癌（CCA）是一种胆管癌的亚型，通常诊断较晚，生存率低，且尚无令人满意的系统治疗方法。最近，regorafenib 已被接受为 CCA 患者的二线治疗药物。在本研究中，我们研究了 regorafenib 介导的潜在信号转导通路。我们使用表达微阵列芯片为 regorafenib 处理的 CCA 细胞建立了转录组数据库。我们的数据表明，regorafenib 抑制了各种 CCA 细胞中的 yes 相关蛋白 1（YAP1）活性。此外，我们证明 YAP1 调节上皮-间充质转化（EMT）相关基因，包括 E-钙粘蛋白和 SNAI2。我们进一步检查了 regorafenib 模型中 YAP1 活性、磷酸化状态和 YAP1 下游靶基因的表达水平。我们发现 regorafenib 可显著抑制 CCA 细胞中的这些事件。此外，体内结果表明，regorafenib 可显著抑制肺灶形成和致瘤性。最重要的是，regorafenib 和 amphiregulin（AREG）中和抗体对 CCA 细胞表现出协同作用。在临床环境中，YAP1 和 EMT 表达高的患者比 YAP1 和 EMT 表达低的患者生存率更差。此外，我们发现 YAP1 在 CCA 中上调下游靶基因 amphiregulin。我们的研究结果表明，AREG 中和抗体与 regorafenib 联合使用可以逆转 CCA 的转移表型和 EMT 表型，无论是在体外还是在体内。这些发现为对抗 CCA 的转移提供了新的治疗策略。
