Li Z, Yang N H, Li B, Sun C Y
The Second Affiliated Hospital of Soochow University, Suzhou 215004, China Department of Hepatobiliary Surgery, the Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.
Department of Hepatobiliary Surgery, the Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.
Zhonghua Gan Zang Bing Za Zhi. 2023 Apr 20;31(4):408-414. doi: 10.3760/cma.j.cn501113-20230225-00080.
To investigate the effect of 1-acyl-sn-glycerol-3-phosphate acyltransferaseδ (APGAT4) on the growth and lenvatinib resistance of hepatocellular carcinoma (HCC), and provide novel targets for HCC treatment. Using the bioinformatics methods to screen out upregulated genes in lenvatinib resistant cell lines from GEO dataset and survival related genes from TCGA dataset. Immumohistochemical staining was used to detect the expression AGPAT4 in HCC tissues, and its correlation with patients' survival. CCK8, EdU, cell cycle, and cell apoptosis assays were used to investigate the impact of role AGPAT4 on the proliferation and lenvatinib reistance of HCC cells. AGPAT4 stable knockdown cell line and subcutaneous nude mouse model were established to test the therapeutic effects of Lenvatinib. Analysis of variance was used to compare the differences between data sets. APGAT4 was the common factor that predicted poor survival and Lenvatinib resistance. The mRNA and protein levels of APGAT4 were significantly upregulated in HCC tissues compared to the para-tumor tissues ( < 0.05). Using siRNA could significantly knocked down the mRNA and protein expression of APGAT4 in HCC cell lines Hep3B and HCCLM3. Compared with the control group, the proliferation ability of HCC cell lines (Hep3B and HCCLM3) in APGAT4 knockdown group was significantly inhibited, and the cell cycle was arrested in G2/M phase ( < 0.05). In addition, compared to the control group, HCC cell lines (Hep3B and HCCLM3) in APGAT4 knockdown group showed significant decrease in the Lenvatinib half maximal inhibitory concentration, and were more sensitive to lenvatinib-induced apoptosis ( < 0.05). In HCC subcutaneous nude mouse model, compared to the control group, the growth of tumor in APGAT4 knockdown group was significantly suppressed, and more apoptosis cells were induced ( < 0.05). APGAT4 promotes the growth and Lenvatinib resistance of HCC, which is a potential target for HCC treatment. Targeting APGAT4 treatment is conducive to inhibit the growth and Lenvatinib resistance of HCC.
探讨1-酰基-sn-甘油-3-磷酸酰基转移酶δ（APGAT4）对肝细胞癌（HCC）生长及仑伐替尼耐药的影响，为HCC治疗提供新靶点。利用生物信息学方法从GEO数据集中筛选出仑伐替尼耐药细胞系中上调的基因，从TCGA数据集中筛选出生存相关基因。采用免疫组织化学染色检测HCC组织中AGPAT4的表达及其与患者生存的相关性。运用CCK8、EdU、细胞周期及细胞凋亡检测等方法研究AGPAT4对HCC细胞增殖及仑伐替尼耐药的影响。建立AGPAT4稳定敲低细胞系及皮下裸鼠模型以检测仑伐替尼的治疗效果。采用方差分析比较数据集之间的差异。APGAT4是预测生存不良及仑伐替尼耐药的共同因素。与癌旁组织相比，HCC组织中APGAT4的mRNA和蛋白水平显著上调（<0.05）。使用小干扰RNA可显著敲低HCC细胞系Hep3B和HCCLM3中APGAT4的mRNA和蛋白表达。与对照组相比，APGAT4敲低组HCC细胞系（Hep3B和HCCLM3）的增殖能力显著受到抑制，细胞周期阻滞于G2/M期（<0.05）。此外，与对照组相比，APGAT4敲低组HCC细胞系（Hep3B和HCCLM3）的仑伐替尼半数最大抑制浓度显著降低，对仑伐替尼诱导的凋亡更敏感（<0.05）。在HCC皮下裸鼠模型中，与对照组相比，APGAT4敲低组肿瘤生长显著受到抑制，诱导产生更多凋亡细胞（<0.05）。APGAT4促进HCC的生长及仑伐替尼耐药，是HCC治疗的潜在靶点。靶向APGAT4治疗有利于抑制HCC的生长及仑伐替尼耐药。
