An Inflammatory Path to Cancer

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Science  11 Dec 2009:
Vol. 326, Issue 5959, pp. 1461
DOI: 10.1126/science.326.5959.1461-c

Switching normal cells into a transformed phenotype that is characterized by uncontrolled growth is central to the development of cancer. Iliopoulos et al. describe an epigenetic switch: a stable phenotypic change, retained through multiple generations in proliferating cells, which is not due to changes in DNA sequence. Immortalized cells from mammary epithelial tissue were transformed by overexpressing Src, a protein tyrosine kinase; activation of Src for just 5 min produced cells that adopted a transformed phenotype and maintained it for at least 12 generations. Activating Src led to an increase in activity of the transcription factor NF-κB, a central mediator of inflammatory responses. A key target of NF-κB in this system was Lin28, an RNA-binding protein that inhibits the accumulation of the microRNA let-7. In turn, let-7 reduces levels of interleukin-6 (IL-6), an inflammatory cytokine thought to contribute to human cancers. IL-6 signals through its receptor to activate NF-κB, thus creating a positive feedback loop. Disruption of any step in the loop resulted in loss of transformation. The authors note that the signaling events defined in this study are known to be associated with certain human cancers. Thus, the epigenetic switch they describe could allow a transient inflammation to produce a long-lasting cancerous effect analogous to mutation of a tumor suppressor gene or activation of an oncogene.

Cell 139, 693 (2009).

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