School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, PR China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, 710061, PR China.
Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, 710003, PR China.
Cancer Lett. 2021 Aug 10;513:50-62. doi: 10.1016/j.canlet.2021.05.010. Epub 2021 May 18.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Loss of WW-domain containing oxidoreductase (WWOX) has been proven to be associated with malignant metastasis in patients with HCC. In this study, by using a non-biased CRISPR knockout genetic screen targeting 19,050 human genes, we found that toosendanin (TSN) is a novel druggable WWOX candidate agonist for metastatic HCC patients. We also found that TSN exhibited significant anti-proliferative and anti-metastatic effects on HCC cells in a WWOX-dependent manner. Overexpression and knockdown of WWOX in vitro and in vivo confirmed that the suppression of HCC by TSN involved WWOX. TSN regulated Stat3, DVL2, and GSK3β by transforming their interactions with WWOX as demonstrated by a Co-IP assay. TSN accelerated the degradation of β-catenin by promoting the function of APC, AXIN1, CK1, and GSK3β complex. Nuclear translocation of p-Stat3 Y705 and β-catenin was impeded by the TSN-induced blockade of JAK2/Stat3 and Wnt/β-catenin signaling, accompanied by the inhibition of MMPs and C-MYC.
肝细胞癌（HCC）是全球癌症相关死亡的第三大主要原因。已经证明 WW 结构域包含氧化还原酶（WWOX）的缺失与 HCC 患者的恶性转移有关。在这项研究中，我们通过使用针对 19050 个人类基因的无偏 CRISPR 敲除遗传筛选，发现川楝素（TSN）是转移性 HCC 患者的新型可用药 WWOX 候选激动剂。我们还发现，TSN 以 WWOX 依赖的方式对 HCC 细胞表现出显著的抗增殖和抗转移作用。体外和体内过表达和敲低 WWOX 证实，TSN 通过调节其与 WWOX 的相互作用来抑制 HCC。如 Co-IP 测定所示，TSN 通过转化其与 WWOX 的相互作用来调节 Stat3、DVL2 和 GSK3β。TSN 通过促进 APC、AXIN1、CK1 和 GSK3β 复合物的功能，加速 β-连环蛋白的降解。p-Stat3 Y705 和 β-连环蛋白的核易位被 TSN 诱导的 JAK2/Stat3 和 Wnt/β-连环蛋白信号通路阻断所阻碍，同时抑制 MMPs 和 C-MYC。
