Small interfering RNA expression vector targeting hypoxia-inducible factor 1 alpha inhibits tumor growth in hepatobiliary and pancreatic cancers
Small interfering RNA expression vector targeting hypoxia-inducible factor 1 alpha inhibits tumor growth in hepatobiliary and pancreatic cancers
复制标题
DOI：
10.1038/sj.cgt.7700871
复制
发表时间：
2006-02-01
影响因子：
6.4
通讯作者：
Nakajima, Y
中科院分区：
文献类型：
--
作者：
Mizuno, T;Nagao, M;Nakajima, Y
肝胆癌和胰腺癌是低血供肿瘤，可在缺氧条件下增殖。最近的报告表明，缺氧诱导因子1 α（HIF 1 α）在这些癌症的生存中发挥着重要作用。鉴于这些发现，抑制HIF 1 α通路可能被证明是治疗这些癌症的有力工具。为了抑制HIF 1 α的表达，我们在这项研究中使用了小干扰RNA（siRNA）表达载体。siRNA表达载体的瞬时转染显著降低了HIF 1 α mRNA水平（对照的13%）和蛋白水平（对照的41%），并显著抑制了癌细胞系的生长（P < 0.05）。VEGF、Glut 1和aldorase A的表达也显著降低（P < 0.05），我们发现这些载体诱导凋亡，但不诱导细胞周期阻滞。在使用裸鼠的皮下肿瘤模型中，与对照相比，稳定表达siRNA的转染的MIA PaCa-2细胞几乎不形成肿瘤（P < 0.05）。因此，本研究证明了siRNA表达载体在靶向HIF 1 α中的有用性，并指出了在胰腺癌和肝胆癌治疗中的潜在临床作用。
Hepatobiliary and pancreatic carcinomas are hypovascular tumors that can proliferate under hypoxic conditions. Recent reports have demonstrated that hypoxia-inducible factor 1 alpha (HIF1 alpha) plays an important role in the survival of these cancers. Given these findings, the inhibition of the HIF1 alpha pathway might prove to be a powerful tool in the treatment of these cancers. To inhibit HIF1 alpha expression, we used small interference RNA ( siRNA) expression vectors in this study. The transient transfection of siRNA expression vectors significantly reduced both HIF1 alpha mRNA levels (13% of control) and protein levels (41% of control) and significantly inhibited the growth of cancer cell lines (P < 0.05). VEGF, Glut1, and aldorase A expressions were also significantly reduced by transfection with these vectors (P < 0.05), and we found that these vectors induced apoptosis but not cell cycle arrest. In a subcutaneous tumor model using nude mice, transfected MIA PaCa-2 cells, stably expressing siRNAs, barely formed tumors compared to control (P < 0.05). This study thus demonstrates the usefulness of siRNA expression vector in targeting HIF1 alpha and points to a potential clinical role in the treatment of pancreatic and hepatobiliary carcinomas.