Zhang Wei, Tan Yongsheng, Ma Heping
Department of Intervention Division, Inner Mongolia Autonomous Region People's Hospital, Hohhot, Inner Mongolia 010017, P.R. China.
Oncol Lett. 2017 Nov;14(5):5409-5417. doi: 10.3892/ol.2017.6858. Epub 2017 Aug 31.
Gastric cancer (GC), one of the types of tumor most prone to malignancy, is characterized by high lethality. Numerous molecular mediators of GC have been identified, including transcription factors, signaling molecules and non-coding RNAs. Recently, inhibition of angiogenesis has emerged as a potential strategy for GC therapy. In the present study, the levels of vascular endothelial growth factor (VEGF), peroxisome proliferator-activated receptor-α (PPARα) and miR-21 in GC patients and individuals without cancer, and the correlation between VEGF and miR-21, and PPARα and miR-21 expression were analyzed. In addition, the GC MKN45 cell line was treated with apatinib (a tyrosine kinase inhibitor) and aspirin (an activator of the transcription factor, PPARα) to investigate the effects of these compounds on tumorigenesis. Furthermore, the present study attempted to elucidate the molecular mechanisms of alteration of GC tumorigenesis by aspirin and apatinib. The results of the current study demonstrated that there was a higher expression of VEGF and miR-21 in GC tissues compared with that in morphologically adjacent normal tissues whereas PPARα expression was decreased. These results were confirmed , as treatment of MKN45 cells with VEGF resulted in a significant increase in miR-21 expression and a significant reduction in PPARα protein expression. Furthermore, the inhibitory effects of VEGF on PPARα mRNA and protein expression were demonstrated to be mediated by miR-21. Suppression of PPARα protein expression attenuated the inhibitory effects of miR-21 on the level of PPARα mRNA, thereby enhancing tumorigenesis in gastric cancer. Treatment of MKN45 cells with aspirin reduced the levels of phosphorylated AKT by activating PPARα, whereas treatment with apatinib inhibited the phosphorylation of vascular endothelial growth factor receptor 2 and phosphoinositide-3 kinase in MKN45 cells. Finally, treatment of MKN45 cells with apatinib and aspirin suppressed tumorigenesis by inhibiting cell proliferation, migration, invasion and colony formation. Taken together, the results of the present study indicate that treatment with a combination of aspirin and apatinib may be a potential therapeutic strategy for GC treatment.
胃癌（GC）是最易发生恶性病变的肿瘤类型之一，具有高致死率的特点。已鉴定出众多胃癌的分子介质，包括转录因子、信号分子和非编码RNA。最近，抑制血管生成已成为胃癌治疗的一种潜在策略。在本研究中，分析了胃癌患者和非癌症个体中血管内皮生长因子（VEGF）、过氧化物酶体增殖物激活受体-α（PPARα）和miR-21的水平，以及VEGF与miR-21、PPARα与miR-21表达之间的相关性。此外，用阿帕替尼（一种酪氨酸激酶抑制剂）和阿司匹林（转录因子PPARα的激活剂）处理胃癌MKN45细胞系，以研究这些化合物对肿瘤发生的影响。此外，本研究试图阐明阿司匹林和阿帕替尼改变胃癌肿瘤发生的分子机制。当前研究结果表明，与形态学上相邻的正常组织相比，胃癌组织中VEGF和miR-21的表达更高，而PPARα表达降低。这些结果得到了证实，因为用VEGF处理MKN45细胞导致miR-21表达显著增加，PPARα蛋白表达显著降低。此外，VEGF对PPARα mRNA和蛋白表达的抑制作用被证明是由miR-21介导的。PPARα蛋白表达的抑制减弱了miR-21对PPARα mRNA水平的抑制作用，从而增强了胃癌的肿瘤发生。用阿司匹林处理MKN45细胞通过激活PPARα降低了磷酸化AKT的水平，而用阿帕替尼处理抑制了MKN45细胞中血管内皮生长因子受体2和磷酸肌醇-3激酶的磷酸化。最后，用阿帕替尼和阿司匹林处理MKN45细胞通过抑制细胞增殖、迁移、侵袭和集落形成抑制了肿瘤发生。综上所述，本研究结果表明，联合使用阿司匹林和阿帕替尼可能是胃癌治疗的一种潜在治疗策略。
