LIM 和 SH3 蛋白 1 通过 PI3K/AKT 通路调节人胶质母细胞瘤的细胞生长和化疗敏感性。
LIM and SH3 protein 1 regulates cell growth and chemosensitivity of human glioblastoma via the PI3K/AKT pathway.
机构信息
Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
Department of Clinical Medicine, Medical College of Soochow University, Suzhou, China.
出版信息
BMC Cancer. 2018 Jul 6;18(1):722. doi: 10.1186/s12885-018-4649-2.
BACKGROUND
LIM and SH3 protein 1 (LASP1) is upregulated in several types of human cancer and implicated in cancer progression. However, the expression and intrinsic function of LASP1 in glioblastoma (GBM) remains unclear.
METHOD
Oncomine and The Cancer Genome Atlas (TCGA) database was analyzed for the expression and clinical significance of LASP1 in GBM. LASP1 mRNA and protein level were measured by qRT-PCR and western blotting. The effect of LASP1 on GBM proliferation was examined by MTT assay and colony formation assay, the effect of LASP1 on sensitivity of Temozolomide was measured by flow cytometry and subcutaneous tumor model. The association between LASP1 and PI3K/AKT signaling was assessed by western blotting.
RESULTS
Oncomine GBM dataset analysis indicated LASP1 is significantly upregulated in GBM tissues compared to normal tissues. GBM dataset from The Cancer Genome Atlas (TCGA) revealed that high LASP1 expression is related to poor overall survival. LASP1 mRNA and protein in clinical specimens and tumor cell lines are frequently overexpressed. LASP1 knockdown dramatically suppressed U87 and U251 cell proliferation. Silencing LASP1 potentiated cell chemosensitivity to temozolomide in vitro, LASP1 knockdown inhibited tumor growth and enhanced the therapeutic effect of temozolomide in vivo. TCGA dataset analysis indicated LASP1 was correlated with PI3K/AKT signaling pathway, and LASP1 deletion inhibited this pathway. Combination treatment with PI3K/AKT pathway inhibitor LY294002 dramatically accelerated the suppression effect of temozolomide.
CONCLUSION
LASP1 may function as an oncogene in GBM and regulate cell proliferation and chemosensitivity in a PI3K/AKT-dependent mechanism. Thus, the LASP1/PI3K/AKT axis is a promising target and therapeutic strategy for GBM treatment.
背景
LIM 和 SH3 蛋白 1（LASP1）在多种人类癌症中上调，并与癌症进展有关。然而，LASP1 在胶质母细胞瘤（GBM）中的表达和内在功能仍不清楚。
方法
通过 Oncomine 和癌症基因组图谱（TCGA）数据库分析 LASP1 在 GBM 中的表达和临床意义。通过 qRT-PCR 和 Western blot 测量 LASP1 mRNA 和蛋白水平。通过 MTT 测定和集落形成测定检测 LASP1 对 GBM 增殖的影响，通过流式细胞术和皮下肿瘤模型测定 LASP1 对替莫唑胺敏感性的影响。通过 Western blot 评估 LASP1 与 PI3K/AKT 信号通路的关联。
结果
Oncomine GBM 数据集分析表明，与正常组织相比，LASP1 在 GBM 组织中显著上调。来自癌症基因组图谱（TCGA）的 GBM 数据集表明，高 LASP1 表达与总生存期差相关。临床标本和肿瘤细胞系中的 LASP1 mRNA 和蛋白经常过表达。LASP1 敲低显着抑制 U87 和 U251 细胞增殖。沉默 LASP1 增强了细胞对替莫唑胺的体外化疗敏感性，LASP1 敲低抑制了肿瘤生长并增强了替莫唑胺的体内治疗效果。TCGA 数据集分析表明，LASP1 与 PI3K/AKT 信号通路相关，LASP1 缺失抑制了该通路。与 PI3K/AKT 通路抑制剂 LY294002 联合治疗可显著加速替莫唑胺的抑制作用。
结论
LASP1 可能在 GBM 中作为癌基因发挥作用，并通过 PI3K/AKT 依赖性机制调节细胞增殖和化疗敏感性。因此，LASP1/PI3K/AKT 轴是 GBM 治疗的有前途的靶点和治疗策略。
Zotero 插件