Adenovirus-mediated Smad4 gene transfer inhibit.s tumor growth and metastasis of human pancreatic carcinoma

胰腺癌是最难以治愈的肿瘤之一，因为它具有高度的侵袭性和转移性。我们之前生成了一个拮抗剂。HOF在人胰腺癌的侵袭转移过程中发挥了重要作用。这HGF-antagonist。NK4对HGF和C-MET受体的相互作用具有竞争性抑制作用。此外，NK4还能抑制不同细胞的增殖和迁移。血管生成因子刺激的内皮细胞类型。在我们之前的研究中，腺病毒介导的NK4基因治疗抑制了c-MET高表达的人胰腺癌细胞系的生长、侵袭性和转移。然而，有少数胰腺癌细胞系c-MET表达水平较低，因此我们重点研究Smad 4/DPC4。SMAD4是响应tgf - β相关配体激活的信号转导通路中的关键辅助因子，调节细胞生长和分化。Smad4已被报道表达对胰腺肿瘤侵袭和血管生成的抑制作用。腺病毒介导的SMAD4纯合子人胰腺肿瘤细胞系的基因转移可以恢复SMAD4蛋白的表达和功能。因此，腺病毒介导的smad4基因治疗可能是治疗胰腺癌的另一个有吸引力的选择。我们现在正在准备重组腺病毒用于胰腺癌细胞系的细胞生长和侵袭性。分析腺病毒- nk4感染胰腺癌细胞在裸鼠体内的肿瘤生长情况。

Pancreatic cancer is one, of the most difficult neoplasms to treat curatively, because of its highly invasive and metastatic potential. We previously generated an antagonist. for HOF which played an important role in invasion and metastasis of human pancreatic cancer. This HGF-antagonist., NK4 has competitive inhibitory effects on interaction between HGF and C-MET receptor. Furthermore, NK4 inhibits proliferation and migration of distinct. type of endotbelial cells stimulated by angiogenic factor. In our privios study, adnovirus-mediated NK4 gene therapy suppressed the growth, invasiveness and metastasis of human pancreatic cancer cell lines with high expression of c-MET. However, there are a few pancreatic cancer cell lines with low level of c-MET expression, so we focused on Smad 4/DPC4. SMAD4 is a critical cofactor in signal transduction pathways activated in response to transforming growth factor-beta (TGF-beta)-related ligands, regulating cell growth and differentiation. Smad4 has been reported to express the inhibitory effects of on pancreatic tumour invasion and angiogenesis. Adenovirus mediated gene transfer in a panel of SMAD4 homozygouscleleted human pancreatic tumor cell lines should restore SMAD4 protein ex-pression and function. Thus adenovirus mediated Smad 4 gene therapy may be another attractive option for the treatment of pancreatic cancer. We are now preparing recombinat aclenovirus for cell growth and invasiveness of pancreatic cancer cell lines. The tumor growth of adenovirus-NK4 infected pancreatic cancer cells in nude mice will be analyzed.