Zhang Jing, Guo Hua, Zhu Jin-Shui, Yang Yu-Chen, Chen Wei-Xiong, Chen Ni-Wei
Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China.
Oncol Lett. 2014 May;7(5):1401-1408. doi: 10.3892/ol.2014.1963. Epub 2014 Mar 11.
The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway plays an important role in cell proliferation, transformation, apoptosis, tumor growth and angiogenesis. Paclitaxel is commonly used to treat multiple human malignancies; however, the underlying mechanisms of paclitaxel in gastric cancer (GC) have not been fully investigated. In the present study, specimens from 45 GC and 36 chronic gastritis patients were collected, and the correlations of PI3K, phosphorylated-Akt (p-Akt) and hypoxia-inducible factor-1α (HIF-1α) expression with the clinicopathological characteristics of GC were analyzed by immunohistochemistry. The human SGC-7901 GC cells under hypoxic conditions were pretreated with the PI3K inhibitor, LY294002 (40 μM), and paclitaxel (0.1 μM). The expression levels of PI3K, p-Akt and HIF-1α were detected by quantitative polymerase chain reaction and western blotting. Cell proliferative activity and apoptosis were evaluated by the Cell Counting Kit-8 assay and flow cytometry. As a result, the rates of positive expression of PI3K, p-Akt and HIF-1α were significantly higher in GC compared with chronic gastritis patients (each P<0.01), and were positively associated with the tumor-node-metastasis (TNM) staging, lymph node metastases, lymphatic infiltration and vascular infiltration (each P<0.01), but inversely correlated with tumor differentiation (P<0.01) in patients with GC. Under hypoxic conditions, the combined inhibition of the PI3K/Akt pathway with paclitaxel markedly reduced the proliferative activity and induced cell apoptosis in GC cells compared with the single treatment of PI3K inhibitor or paclitaxel (each P<0.01), and was accompanied by a decreased expression of HIF-1α. Overall, our findings indicate that the increased expression of the PI3K/Akt/HIF-1α pathway was closely correlated with tumor differentiation, TNM staging, lymph node metastases and lymphatic and vascular infiltration. The inhibition of the PI3K/Akt pathway enhanced the therapeutic efficacy of paclitaxel in GC cells under hypoxic conditions, suggesting that the PI3K/Akt/HIF-1α pathway may act as an important therapeutic target for paclitaxel treatment of GC.
磷脂酰肌醇-3-激酶（PI3K）/Akt信号通路在细胞增殖、转化、凋亡、肿瘤生长和血管生成中发挥重要作用。紫杉醇常用于治疗多种人类恶性肿瘤；然而，紫杉醇在胃癌（GC）中的潜在机制尚未得到充分研究。在本研究中，收集了45例GC患者和36例慢性胃炎患者的标本，采用免疫组织化学方法分析PI3K、磷酸化Akt（p-Akt）和缺氧诱导因子-1α（HIF-1α）表达与GC临床病理特征的相关性。对缺氧条件下的人SGC-7901 GC细胞用PI3K抑制剂LY294002（40μM）和紫杉醇（0.1μM）进行预处理。通过定量聚合酶链反应和蛋白质印迹法检测PI3K、p-Akt和HIF-1α的表达水平。采用细胞计数试剂盒-8法和流式细胞术评估细胞增殖活性和凋亡情况。结果显示，与慢性胃炎患者相比，GC患者中PI3K、p-Akt和HIF-1α的阳性表达率显著更高（均P<0.01），且与肿瘤-淋巴结-转移（TNM）分期、淋巴结转移、淋巴浸润和血管浸润呈正相关（均P<0.01），但与GC患者的肿瘤分化呈负相关（P<0.01）。在缺氧条件下，与单独使用PI3K抑制剂或紫杉醇相比，紫杉醇联合抑制PI3K/Akt通路显著降低了GC细胞的增殖活性并诱导细胞凋亡（均P<0.01），同时伴有HIF-1α表达降低。总体而言，我们的研究结果表明，PI3K/Akt/HIF-1α通路的表达增加与肿瘤分化、TNM分期、淋巴结转移以及淋巴和血管浸润密切相关。抑制PI3K/Akt通路增强了紫杉醇在缺氧条件下对GC细胞的治疗效果，提示PI3K/Akt/HIF-1α通路可能是紫杉醇治疗GC的重要治疗靶点。
