Cancer Biology More Aggressive Tumors with Ras and Without NF-B

Mutations that activate Ras, a protein involved in activating the mitogen-activated protein kinase (MAPK) cascade that regulates cell proliferation, are found in many human cancers. Signaling through the NF-B pathway is also involved in controlling proliferation, especially through regulation of apoptosis (see Bolotin and Fuchs). Dajee et al. found a correlation in the characteristics of human squamous cell carcinomas (SCCs) and human skin cells transfected with activated Ras and a stable inhibitor of NF-B IBα (referred to as Ras-IBα cells). Similar to SCCs in humans, these transfected cells were neoplastic and invasive when grafted into immune-deficient mice. At the molecular level, both SCCs and Ras-IBα cells exhibited increased levels of the NF-B subunit p65 in the cytoplasm and increased phosphorylation of MAPK targets. In these cells, activated Ras can promote G₁ arrest through stimulation of cyclin-dependent kinase (CDK) inhibitors and reduction in the levels of CDK4. In the Ras-IBα cells, these responses to activated Ras were blocked, and the cells proceeded through the cell cycle. Similarly, activated Ras inhibited IBα-induced increase in apoptosis in response to tumor necrosis factor. Thus, the Ras-IBα cells were more likely to replicate and less likely to undergo programmed cell death than cells expressing only activated Ras or stabilized IBα. In addition to similarities in signaling, SCCs and Ras-IBα cells also had high levels of expression of laminin 5 and integrin α6β4. Function-blocking antibodies to either protein prevented tumorigenesis of the Ras-IBα cells. Likewise, tumors did not form if Ras and IBα were coexpressed in cells deficient for either laminin 5 or α6β4 integrin, confirming the importance of matrix interactions in tumorigenesis.

D. Bolotin, E. Fuchs, More than skin deep. Nature 421, 594-595 (2003). [Online Journal]

M. Dajee, M. Lazarov, J. Y. Zhang, T. Cai, C. L. Green, A. J. Russell, M. P. Marinkovich, S. Tao, Q. Lin, Y. Kubo, P. A. Khavari, NF-B blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639-643 (2003). [Online Journal]