The transcriptional regulator NF-κB regulates several signalling pathways, including those that are involved in cell proliferation and apoptosis. In many tumours, activated NF-κB promotes proliferation and inhibits apoptosis, but reports have shown that inhibition of NF-κB actually causes increased proliferation in the skin. In the 6 February issue of Nature, Maya Dajee et al. further explore the role of NF-κB in skin tumorigenesis.
The authors expressed activated oncogene HRAS either alone or with the NF-κB subunit p65 or a stable mutant of IκBα — which causes NF-κB to remain inactive in the cytoplasm — in primary human keratinocytes and grafted these cells onto immunodeficient mice. RAS expression stimulates growth in most cell systems, but in this model it inhibited growth in the skin. Co-expression of RAS and NF-κB subunits also inhibited proliferation. The co-expression of RAS and stabilized IκBα allowed the cell to overcome growth arrest induced by activated RAS, leading to the formation of large squamous-cell carcinomas (SCCs). Tumours from patients with SCC had NF-κB in the cytoplasm and a subset also had increased expression of IκBα and RAS, supporting the relevance of RAS and NF-κB activation in some spontaneous human SCCs.
So, the functions of activated RAS and inactivated NF-κB oppose each other to cause carcinogenesis in the skin, but what other molecules are involved? The expression of integrin receptors — which interact with extracellular-matrix components, such as laminin, and trigger cell proliferation and migration — is associated with tumour-invasive potential. Dajee and colleagues showed that the SCCs with stabilized IκBα and activated RAS also expressed high levels of integrin α6β4 and laminin-5, and that blocking these molecules with specific antibodies inhibited tumour formation. When keratinocytes from patients with a blistering disease caused by mutations in integrin α6β4 and laminin-5 were transduced with stabilized IκBα and activated RAS, no tumours were formed, indicating that integrin and laminin also have a key role in SCC development.
These data highlight the problems of targeting NF-κB as a method of increasing apoptosis in tumours — use of such agents, which are in development, could actually promote tumorigenesis in the skin.
References
ORIGINAL RESEARCH PAPER
Dajee, M. et al. NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639–643 (2003)
FURTHER READING
Karin, M. et al. NF-κB in cancer: from innocent bystander to major culprit. Nature Rev. Cancer 2, 301–310 (2002)
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Hutchinson, E. Getting under the skin. Nat Rev Cancer 3, 153 (2003). https://doi.org/10.1038/nrc1034
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DOI: https://doi.org/10.1038/nrc1034