Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China.
Department of Pathology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China.
Cell Biochem Funct. 2020 Jul;38(5):642-650. doi: 10.1002/cbf.3522. Epub 2020 Mar 12.
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. SIGNIFICANCE OF THE STUDY: Hepatocellular carcinoma (HCC) is a common malignant tumour with high mortality. Our study showed that ACK1 and pTyr284-ACK1 are highly expressed in HCC and may promote HCC development through the PTEN/AKT/mTOR signalling pathway. Targeted inhibition of ACK1 expression with small inhibitors AIM-100 and Dasatinib may weaken tumour cells ability of proliferation, migration and invasion. Our results suggested that downregulation of ACK1 may be a potential therapeutic strategy for HCC.
激活的 Cdc42 相关激酶 1（ACK1）在肝癌（HCC）组织和其他肿瘤组织中表达上调。然而，ACK1 在 HCC 中的功能和调控机制尚不清楚。在本研究中，通过免疫组织化学检测 HCC 中 pTyr284-ACK1、pSer473-AKT 和 PTEN 的表达，并分析其临床病理意义。然后，用 ACK1 靶向小分子抑制剂 AIM-100 和 Dasatinib 处理 SK-Hep-1 和 HepG2 细胞，观察 PTEN/AKT/mTOR 信号通路活性和生物学行为的变化。结果表明，pTyr284-ACK1 蛋白在 HCC 组织中高表达，与患者预后不良相关；pTyr284-ACK1 蛋白的表达与 pSer473-AKT 呈正相关，与 PTEN 呈负相关。此外，用 AIM-100 或 Dasatinib 处理后，SK-Hep-1 细胞的增殖、迁移和侵袭均受到显著抑制。同时，Western blot 分析显示 SK-Hep-1 细胞中 ACK1、pTyr284-ACK1、pSer473-AKT、mTOR 和 EGFR 下调，PTEN 上调。这些结果表明，ACK1 可能通过 PTEN/AKT/mTOR 通路促进 HCC 的发展。靶向抑制 ACK1 可能是 HCC 的一种新的治疗策略。
肝癌（HCC）是一种常见的恶性肿瘤，死亡率高。我们的研究表明，ACK1 和 pTyr284-ACK1 在 HCC 中高表达，可能通过 PTEN/AKT/mTOR 信号通路促进 HCC 的发展。用小分子抑制剂 AIM-100 和 Dasatinib 靶向抑制 ACK1 表达可能会削弱肿瘤细胞的增殖、迁移和侵袭能力。我们的研究结果表明，下调 ACK1 可能是 HCC 的一种潜在治疗策略。
