Department of Biochemistry and Molecular Biology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China.
Department of Cell Biology and Genetics, The School of Basic Medical Sciences; 3Fujian Provincial Key Laboratory of Neuroglia and Disease, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China.
Oncol Rep. 2019 Jul;42(1):399-413. doi: 10.3892/or.2019.7155. Epub 2019 May 9.
Annexin A2 (ANXA2) acts as a calcium‑dependent phospholipid‑binding protein that is widely expressed in vertebrate cells and has abnormally high expression in various tumor cells. However, the detailed molecular mechanism underlying the effects of ANXA2 on glioma cells remains unclear. The present study aimed to investigate the role and underlying molecular mechanisms of ANXA2 in glioma cell proliferation. The results revealed that knockdown of ANXA2 inhibited the proliferation of U251 and U87 glioma cell lines and decreased phosphorylated (p) signal transducer and activator of transcription 3 (STAT3)(Y705) and cyclin D1 expression, leading to impedance of the G1‑to‑S phase transition. Furthermore, it was suggested that ANXA2 may regulate pSTAT3(Y705) levels through direct binding with STAT3, thereby affecting STAT3‑cyclin D1 pathway‑mediated cell proliferation. When ANXA2 was re‑expressed in ANXA2‑knockdown cells, the expression of pSTAT3(Y705) and cyclin D1 was restored. Furthermore, overexpression of ANXA2 significantly promoted the proliferation of U251 cells, as determined by an MTT assay and a tumor formation assay in nude mice, but had no statistically significant effect on colony formation rate, cell cycle progression or the STAT3‑cyclin D1 pathway, suggesting that endogenous ANXA2 may be redundant. Additionally, the present study provided evidence that the overexpression of ANXA2 enhanced the expression of pSTAT3(Y705) in the presence of epidermal growth factor (EGF), indicating that the proliferation‑promoting effect of ANXA2 may be due to the accumulation and synergistic effect of paracrine EGF. Taken together, the present results indicated that ANXA2 may affect the proliferation of human glioma cells through the STAT3‑cyclin D1 pathway via direct interaction with STAT3 in U251 and U87 glioma cells. ANXA2 was redundant in this pathway, but positive synergy was revealed to exist between ANXA2 and EGF.
膜联蛋白 A2（ANXA2）作为一种钙依赖性磷脂结合蛋白，广泛表达于脊椎动物细胞中，并且在各种肿瘤细胞中表达异常升高。然而，ANXA2 对神经胶质瘤细胞影响的详细分子机制尚不清楚。本研究旨在探讨 ANXA2 在神经胶质瘤细胞增殖中的作用及其潜在的分子机制。结果显示，敲低 ANXA2 抑制了 U251 和 U87 神经胶质瘤细胞系的增殖，并降低了磷酸化（p）信号转导和转录激活因子 3（STAT3）（Y705）和细胞周期蛋白 D1 的表达，从而抑制 G1 期至 S 期的转变。此外，研究结果表明，ANXA2 可能通过与 STAT3 的直接结合来调节 pSTAT3（Y705）水平，从而影响 STAT3-细胞周期蛋白 D1 通路介导的细胞增殖。当在 ANXA2 敲低细胞中重新表达 ANXA2 时，pSTAT3（Y705）和细胞周期蛋白 D1 的表达得到恢复。此外，过表达 ANXA2 可显著促进 U251 细胞的增殖，通过 MTT 检测和裸鼠肿瘤形成实验证实，但对集落形成率、细胞周期进程或 STAT3-细胞周期蛋白 D1 通路没有统计学意义的影响，表明内源性 ANXA2 可能是冗余的。此外，本研究还提供了证据表明，在表皮生长因子（EGF）存在的情况下，过表达 ANXA2 增强了 pSTAT3（Y705）的表达，表明 ANXA2 的促增殖作用可能是由于旁分泌 EGF 的积累和协同作用。综上所述，本研究结果表明，在 U251 和 U87 神经胶质瘤细胞中，ANXA2 可能通过与 STAT3 的直接相互作用，通过 STAT3-细胞周期蛋白 D1 通路影响人神经胶质瘤细胞的增殖。在该通路中，ANXA2 是冗余的，但 ANXA2 和 EGF 之间存在正协同作用。
