Original Research Article
Inactivation of p27kip1 promotes chemical hepatocarcinogenesis through enhancing inflammatory cytokine secretion and STAT3 signaling activation
Article first published online: 20 JUN 2013
Copyright © 2013 Wiley Periodicals, Inc.
Journal of Cellular Physiology
Volume 228, Issue 10, pages 1967–1976, October 2013
How to Cite
Guo, J., Ma, Q., Zhou, X., Fan, P., Shan, T. and Miao, D. (2013), Inactivation of p27kip1 promotes chemical hepatocarcinogenesis through enhancing inflammatory cytokine secretion and STAT3 signaling activation. J. Cell. Physiol., 228: 1967–1976. doi: 10.1002/jcp.24357
- Issue published online: 20 JUN 2013
- Article first published online: 20 JUN 2013
- Accepted manuscript online: 4 MAR 2013 11:21AM EST
- Manuscript Accepted: 21 FEB 2013
- Manuscript Received: 10 JAN 2013
- Science and Technology Project of Shaanxi. Grant Number: 2012K16-09-02
- Youth Foundation of the First Affiliated Hospital, Medical College, Xi'an Jiaotong University. Grant Number: 2011YK.20
Although the expression of p27 has been regarded as a prognostic parameter in human liver cancer since the implication of decreased p27 expression levels in the genesis and progression of hepatocellular carcinoma (HCC), the molecular mechanism linking p27 deficiency and HCC development is still unclear. Here, we report an increase in tumorigenesis and progression as well as an enhanced inflammatory response in p27 deficient mice (p27−/−) and hypothesize the possible mechanism. We show that p27−/− mice display increased proliferation and decreased apoptosis of tumor cells, accompanied by an increase in the serum inflammatory cytokines IL-6 and TNF-α. Furthermore, our data indicated that the increased number and signal transducers and activator of transcription 3 (STAT3) phosphorylation status of infiltrated inflammatory cells was accompanied by increased IL-6 and TNF-α mRNA levels in tumor and normal liver tissue in the p27−/− mice. Moreover, using tumor cell and splenocytes co-culture and tumor homologous transplantation, we validated our hypothesis in vitro and in vivo. Collectively, these data demonstrate that the loss of p27 promotes carcinogens-induced HCC genesis and progression via the elevation of inflammatory cytokines and the augmented activation of STAT3 signaling in tumor cells and infiltrated inflammatory cells. Altogether, the loss of the cyclin kinase inhibitor p27, traditionally regarded as a consequence of DNA damage, can in turn promote HCC progression through enhancing the inflammatory response, potentially representing a promising therapeutic target in the prevention of HCC genesis and progression. J. Cell. Physiol. 228: 1967–1976, 2013. © 2013 Wiley Periodicals, Inc.