Carcinogenesis Advance Access published online on October 6, 2009
Carcinogenesis, doi:10.1093/carcin/bgp238
MK2 regulates the early stages of skin tumor promotion
1 Department of Dermatology, Aarhus University Hospital, 8000 Aarhus, Denmark
2 Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", 16672 Vari, Greece
3 Institute of Biochemistry, Hannover Medical School, 30625 Hannover, Germany
Correspondence to: Lars Iversen, MD, DMSc, Department of Dermatology, Aarhus University Hospital, P.P. Oerumsgade 11, 8000 Aarhus C, Denmark., Telephone no. +45 89491848, Fax no. +45 89491850, E-mail: lars.iversen{at}ki.au.dk
The association between inflammation and tumorigenesis is well recognized. Mitogen-activated protein kinase-activated protein kinase-2 (MK2) is known to play a pivotal role in inflammatory processes. Here we studied the effect of MK2-deficiency and TNF-
-deficiency on skin tumor development in mice using the two-stage chemical carcinogenesis model. We found that MK2-/- mice developed significantly fewer skin tumors compared with both TNF--/- and wild-type mice when induced by initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and by promotion with 12-O-tetradecanoylphorbol-13-acetat (TPA). The TPA-induced inflammatory response was reduced in both, TNF--/- mice and MK2-/- mice, but most pronounced in TNF--/- mice, indicating that a reduced inflammatory response was not the only explanation for the inhibited tumorigenesis seen in MK2-/- mice. Interestingly, increased numbers of apoptotic cells were detected in the epidermis of MK2-/- mice compared with TNF--/- and wild-type mice, suggesting an additional role of MK2 in the regulation of apoptosis. This was further supported by a): increased levels of the tumor suppressor protein p53 in MK2-/- mice after DMBA/TPA treatment compared with controls, b): reduced phosphorylation (activation) of the negative p53 regulator, murine double minute 2 (Mdm2) in MK2-/- mouse keratinocytes in vitro and c): a significant decrease in the DMBA/TPA induced apoptosis in cultured MK2-/- keratinocytes transfected with p53 siRNA. Taken together, these findings demonstrate a dual role of MK2 in the early stages of tumor promotion through regulation of both the inflammatory response and apoptosis of DNA-damaged cells. These results also identify MK2 as a putative target for future skin carcinoma therapy.
Received April 30, 2009; revised September 2, 2009; accepted September 26, 2009.