IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.
A link between inflammation and cancer has long been suspected, but its molecular nature remained ill defined. A key player in inflammation is transcription factor NF-kappaB whose activity is triggered in response to infectious agents and proinflammatory cytokines via the IkappaB kinase (IKK) complex. Using a colitis-associated cancer model, we show that although deletion of IKKbeta in intestinal epithelial cells does not decrease inflammation, it leads to a dramatic decrease in tumor incidence without affecting tumor size. This is linked to increased epithelial apoptosis during tumor promotion. Deleting IKKbeta in myeloid cells, however, results in a significant decrease in tumor size. This deletion diminishes expression of proinflammatory cytokines that may serve as tumor growth factors, without affecting apoptosis. Thus, specific inactivation of the IKK/NF-kappaB pathway in two different cell types can attenuate formation of inflammation-associated tumors. In addition to suppressing apoptosis in advanced tumors, IKKbeta may link inflammation to cancer.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla 92093, USA.
Florian R
FR
Greten
Lars
L
Eckmann
Tim F
TF
Greten
Jin Mo
JM
Park
Zhi-Wei
ZW
Li
Laurence J
LJ
Egan
Martin F
MF
Kagnoff
Michael
M
Karin
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003092:Colitis / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000209:etiology / Q000378:metabolism*; D020895:Enterocytes / Q000201:enzymology / Q000378:metabolism; D051550:I-kappa B Kinase; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D022423:Myeloid Cells / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*
D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse