Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene

Speaker:陳俊成                          Time:2003/10/22 14:00~15:00

Commentator:周楠華老師                  Place:Room 601

Abstract:

Hypoxia, a reduction in partial pressure of O₂

, is a common feature of most solid tumors. Much emphasis has been placed in recent years on hypoxia-induced neoangiogenesis, a biological process characterized by migration of endothelial cells toward the tumor mass in order to restore a regular supply of oxygen. Here, the authors suppose another view about hypoxia--it allows single neoplastic cells to escape hypoxia by invading surrounding tissues where oxygen and nutrients are not limited. In this study, different cells were cultured in normoxic or hypoxic conditions. Through Western and Northern blot analyses, they proved that hypoxia could induce the expression and increase the levels of the Met protein. Luciferase assay was performed to conform that hypoxia activates the met promoter. Tumor frozen sections were stained with antibodies against the hypoxic marker hypoxia-induced factor-1α and the Met receptor to prove that Met was oveexpressed in hypoxic regions of tumors. Scatter assay, matrigel invasion assay and collagen invasion assay were done to ensure that hypoxia can enhance hypotocyte growth factor (HGF) - induced cell motility and synergize with HGF in inducing invasion. Finally, they knocked down Met expression by RNA interference to strengthen that Met induction by hypoxia is responsible for the observed invasive phenotype. In conclusion, these data show that hypoxia upregulates Met expression, resulting in promoting tumor invasion. 

References:

1. Pennacchietti, S. et al. Hypoxia promotes invasive growth byt ranscripti-onal activation of the met protooncogene. Cancer Cell 3, 347–361 (2003)

2. Rofstad, E.K. et al. Hypoxia promotes lymph node metastasis in human melanoma xenografts by up-regulating the urokinase-type plasminogen actinovel vator receptor. Cancer Res. 62, 1847–1853 (2002).

3. Harris, A.L. Hypoxia - a key regulatory factor in tumor growth. Nature Rev. Cancer 2, 38–47 (2002).