Che Ying, Lu Xiaolong, Wang Xueting, Liu Zhien, Guan Liyang, Li Xin, Du Zaixing, Ren Hang, Wang Jihong, Zhou Zunchun, Lv Li
Department of Pharmacology, Dalian Medical University, Dalian, 116044, Liaoning, China.
School of Life Sciences, Liaoning Normal University, Dalian, 116081, Liaoning, China.
Cancer Cell Int. 2024 Aug 14;24(1):290. doi: 10.1186/s12935-024-03468-1.
rAj-Tspin, a soluble recombinant peptide from Apostichopus japonicus, can inhibit the integrin β1 (ITGB1)/FAK/AKT signaling pathway in hepatocellular carcinoma (HCC) via cell epithelial-mesenchymal transition (EMT) and apoptosis. Zyxin (ZYX) is a focal adhesion protein that is considered a novel mediator of EMT and apoptosis. However, the inhibitory mechanisms of rAj-Tspin in HCC and whether it is related to ZYX are unclear. We examined the antitumor effect of rAj-Tspin on the Huh7 human HCC cell line and on a nude mouse model generated via subcutaneous injection or orthotopic intrahepatic transplantation of Huh7 cells. Our results revealed that rAj-Tspin strikingly reduced the viability and promoted the apoptosis of Huh7 cells and inhibited HCC tumor growth in nude mice. rAj-Tspin inhibited ITGB1 and ZYX protein expression in vivo and in vitro in a dose-dependent manner. Mechanistically, the FAK/AKT signaling pathway and the proliferation and invasion of HCC cells were suppressed upon ITGB1 and ZYX knockdown. Moreover, the effect of ITGB1 overexpression on the growth of HCC cells was inhibited by rAj-Tspin. In contrast, the promoting effect of ITGB1 overexpression could be inhibited by ZYX knockdown. ZYX knockdown had no effect on ITGB1 expression. These findings suggest that ZYX is required for the indispensable role of ITGB1 in rAj-Tspin-alleviated HCC and provide an important therapeutic target for HCC. In summary, the anti-HCC effect of rAj-Tspin potentially involves the regulation of the ITGB1/ZYX/FAK/AKT pathway, which in turn impacts EMT and apoptosis.
rAj-Tspin是一种来自日本刺参的可溶性重组肽，它可以通过细胞上皮-间质转化（EMT）和凋亡来抑制肝细胞癌（HCC）中的整合素β1（ITGB1）/黏着斑激酶（FAK）/蛋白激酶B（AKT）信号通路。桩蛋白（ZYX）是一种黏着斑蛋白，被认为是EMT和凋亡的新型介质。然而，rAj-Tspin在HCC中的抑制机制以及它是否与ZYX相关尚不清楚。我们研究了rAj-Tspin对Huh7人肝癌细胞系以及通过皮下注射或原位肝内移植Huh7细胞建立的裸鼠模型的抗肿瘤作用。我们的结果显示，rAj-Tspin显著降低了Huh7细胞的活力，促进了其凋亡，并抑制了裸鼠体内HCC肿瘤的生长。rAj-Tspin在体内和体外均以剂量依赖性方式抑制ITGB1和ZYX蛋白表达。机制上，ITGB1和ZYX敲低后，FAK/AKT信号通路以及HCC细胞的增殖和侵袭受到抑制。此外，rAj-Tspin抑制了ITGB1过表达对HCC细胞生长的影响。相反，ZYX敲低可抑制ITGB1过表达的促进作用。ZYX敲低对ITGB1表达没有影响。这些发现表明，ZYX是ITGB1在rAj-Tspin缓解HCC中发挥不可或缺作用所必需的，为HCC提供了一个重要的治疗靶点。总之，rAj-Tspin的抗HCC作用可能涉及对ITGB1/ZYX/FAK/AKT通路的调节，进而影响EMT和凋亡。
