Activated Cdc42‐associated kinase 1 (ACK1) expression is upregulated in hepatocellular carcinoma (HCC) tissues and other tumour tissues. However, the function and regulatory mechanism of ACK1 in HCC remains unclear. In this study, the expression of pTyr284‐ACK1, pSer473‐AKT and PTEN in HCC was detected by immunohistochemistry, and its clinicopathological significance was analysed. Then, ACK1‐targeted small molecule inhibitors AIM‐100 and Dasatinib were used to treat cells SK‐Hep‐1 and HepG2, and changes in activity and biological behaviours of PTEN/AKT/mTOR signalling pathway were observed. The results showed that pTyr284‐ACK1 protein was highly expressed in HCC tissues and was related to the poor prognosis of patients; the expression of pTyr284‐ACK1 protein was positively correlated with pSer473‐AKT and negatively correlated with PTEN. In addition, after treatment either with AIM‐100 or Dasatinib, both proliferation of two cells and migration, invasion of SK‐Hep‐1 cells were all significantly inhibited. Meanwhile, ACK1, pTyr284‐ACK1, pSer473‐AKT, mTOR and EGFR were down‐regulated; PTEN was up‐regulated when analysed by western‐blot in SK‐Hep‐1 cells. These results demonstrated that ACK1 may promote HCC development via PTEN/AKT/mTOR pathway. Targeted inhibition of ACK1 may be a novel therapeutic strategy for HCC.

中文翻译：

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靶向抑制ACK1可通过PTEN / AKT / mTOR途径抑制肝癌细胞的增殖

在肝细胞癌（HCC）组织和其他肿瘤组织中，激活的Cdc42相关激酶1（ACK1）表达被上调。但是，ACK1在肝癌中的功能和调节机制仍不清楚。本研究采用免疫组织化学方法检测肝癌组织中pTyr284‐ACK1，pSer473‐AKT和PTEN的表达，并分析其临床病理意义。然后，将以ACK1为靶点的小分子抑制剂AIM-100和达沙替尼用于处理SK-Hep-1和HepG2细胞，并观察到PTEN / AKT / mTOR信号通路的活性和生物学行为的变化。结果表明，pTyr284‐ACK1蛋白在肝癌组织中高表达，与患者预后不良有关。pTyr284‐ACK1蛋白的表达与pSer473‐AKT正相关，与PTEN负相关。此外，用AIM-100或达沙替尼治疗后，两个细胞的增殖以及SK-Hep-1细胞的迁移，侵袭均被显着抑制。同时，ACK1，pTyr284-ACK1，pSer473-AKT，mTOR和EGFR被下调。通过Western印迹分析SK-Hep-1细胞中的PTEN后，其上调了。这些结果表明ACK1可能通过PTEN / AKT / mTOR途径促进肝癌的发展。ACK1的靶向抑制可能是HCC的新型治疗策略。这些结果表明ACK1可能通过PTEN / AKT / mTOR途径促进肝癌的发展。ACK1的靶向抑制可能是HCC的新型治疗策略。这些结果表明ACK1可能通过PTEN / AKT / mTOR途径促进肝癌的发展。ACK1的靶向抑制可能是HCC的新型治疗策略。