Shi Guang, Zhang Hong, Yu Qiong, Hu Chunmei, Ji Youbo
Department of Hematology and Oncology, the Second Hospital of Jilin University, Changchun 130041, People's Republic of China.
Department of Clinical Medicine, Changchun Medical College, Changchun 130031, People's Republic of China.
Onco Targets Ther. 2019 Jul 5;12:5335-5354. doi: 10.2147/OTT.S198750. eCollection 2019.
Intrahepatic cholangiocarcinoma (CCA) is the second most prevalent type primary liver malignancy, accompanied by an increasing global incidence and mortality rate. Research has documented the contribution of the GATA binding protein-1 (GATA1) in the progression of liver cancer. Here, we aim to investigate the role of GATA1 in CCA stem cells via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Initially, microarray-based gene expression profiling was employed to identify the differentially expressed genes associated with CCA. Subsequently, an investigation was conducted to explore the potential biological significance behind the silencing of GATA1 and the regulatory mechanism between GATA1 and PI3K/AKT pathway. CCA cell lines QBC-939 and RBE were selected and treated with siRNA against GATA1 or/and a PI3K/AKT pathway inhibitor LY294002. In vivo experiment was also conducted to confirm in vitro findings. GATA1 exhibited higher expression in CCA samples and was predicted to affect the progression of CCA through blockade of the PI3K/AKT pathway. siRNA-mediated downregulation of GATA1 and LY294002 treatment resulted in reduced proliferation, migration and invasion abilities of CCA stem cells, together with impeded tumor growth, and led to increased cell apoptosis and primary cilium expression. Additionally, the siRNA-mediated GATA1 downregulation had an inhibitory effect on the PI3K/AKT pathway. LY294002 was manifested to enhance the inhibitory effects of GATA1 inhibition on CCA progression. These in vitro findings were reproduced in vivo on siRNA against GATA1 or LY294002 injected nude mice. Altogether, the present study highlighted that downregulation of GATA1 via blockade of the PI3K/AKT pathway could inhibit the CCA stem cell proliferation, migration and invasion, and tumor growth, and promote cell apoptosis, primary cilium expression.
肝内胆管癌（CCA）是第二常见的原发性肝脏恶性肿瘤，全球发病率和死亡率呈上升趋势。研究已证明GATA结合蛋白1（GATA1）在肝癌进展中的作用。在此，我们旨在通过磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）途径研究GATA1在CCA干细胞中的作用。首先，采用基于微阵列的基因表达谱分析来鉴定与CCA相关的差异表达基因。随后，进行研究以探索GATA1沉默背后的潜在生物学意义以及GATA1与PI3K/AKT途径之间的调控机制。选择CCA细胞系QBC-939和RBE，并用针对GATA1的小干扰RNA（siRNA）或/和PI3K/AKT途径抑制剂LY294002进行处理。还进行了体内实验以证实体外研究结果。GATA1在CCA样本中表达较高，预计通过阻断PI3K/AKT途径影响CCA的进展。siRNA介导的GATA1下调和LY294002处理导致CCA干细胞的增殖、迁移和侵袭能力降低，同时抑制肿瘤生长，并导致细胞凋亡增加和初级纤毛表达增加。此外，siRNA介导的GATA1下调对PI3K/AKT途径具有抑制作用。LY294002被证明可增强GATA1抑制对CCA进展的抑制作用。这些体外研究结果在注射了针对GATA1的siRNA或LY294002的裸鼠体内得到了重现。总之，本研究强调通过阻断PI3K/AKT途径下调GATA1可抑制CCA干细胞的增殖、迁移和侵袭以及肿瘤生长，并促进细胞凋亡和初级纤毛表达。
