Reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model.
Reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model.
复制标题
DOI：
--
复制
发表时间：
2003-11
期刊：
影响因子：
--
通讯作者：
S. J. Kim;Marjorie Johnson;Kristen L. Koterba;M. H. Herynk;H. Uehara;G. Gallick
中科院分区：
文献类型：
--
作者：
S. J. Kim;Marjorie Johnson;Kristen L. Koterba;M. H. Herynk;H. Uehara;G. Gallick
目的肝细胞生长因子/分散因子受体蛋白酪氨酸激酶c-Met的表达在前列腺肿瘤进展过程中频繁升高。然而，c-Met表达降低是否抑制肿瘤生长和转移尚未确定。实验设计将表达c-Met核酶的腺病毒感染到高度转移的人前列腺癌细胞PC3-LN4中，可以降低c-Met的表达。在体外，研究了c-Met、Akt和细胞外信号调节激酶1/2的表达和磷酸化、Src的表达和活性、血管内皮生长因子的表达，以及对细胞迁移和侵袭的影响。在体外和体内感染细胞后，观察裸鼠前列腺肿瘤的形成和局部淋巴结转移。结果与pU1（对照）病毒相比，表达ad -c-Met的核酶感染PC3-LN4细胞可降低稳态c-Met水平，降低Src激酶活性，降低血管内皮生长因子表达，减少迁移和侵袭。在体外感染Ad-c-Met后，观察到明显的致瘤性抑制（组织学证实的肿瘤仅在10只小鼠中出现）和随后的淋巴结转移。同样，基因治疗实验导致8只小鼠中有7只完全抑制肿瘤生长。结论在原位裸鼠模型中，c-Met表达的降低可显著抑制PC3-LN4细胞的肿瘤生长和淋巴结转移。因此，靶向c-Met信号通路可能对控制人类前列腺癌的肿瘤生长和转移具有重要意义。
PURPOSE The expression of c-Met, the receptor protein tyrosine kinase for hepatocyte growth factor/scatter factor, frequently increases during prostate tumor progression. However, whether reduced c-Met expression inhibits tumor growth and metastasis has not been ascertained. EXPERIMENTAL DESIGN c-Met expression was reduced by infection of an adenovirus expressing a c-Met ribozyme into the highly metastatic human prostate cancer cell line PC3-LN4. In vitro, effects on c-Met, Akt, and extracellular signal-regulated kinase 1/2 expression and phosphorylation, Src expression and activity, and vascular endothelial growth factor expression were determined, as were effects on cell migration and invasion. Prostate tumor formation and metastasis to regional lymph nodes in nude mice were examined after both ex vivo and in vivo infection of cells. RESULTS Infection of PC3-LN4 cells with the Ad-c-Met-expressing ribozyme decreased steady-state c-Met levels, decreased Src kinase activity, decreased vascular endothelial growth factor expression, and decreased migration and invasion versus the pU1 (control) virus. Significant inhibition of tumorigenicity (histologically confirmed tumors in only 1 of 10 mice) and consequent lymph node metastasis were observed upon ex vivo infection of Ad-c-Met. Similarly, gene therapy experiments led to complete inhibition of tumor growth in 7 of 8 mice. CONCLUSIONS Reduction in c-Met expression substantially inhibits both tumor growth and lymph node metastasis of PC3-LN4 cells in orthotopic nude mouse models. Therefore, targeting the c-Met signaling pathways may be important in controlling tumor growth and metastasis in human prostate cancers.