Potential conflict of interest: Nothing to report.
Growth arrest and DNA damage 45G down-regulation contributes to janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma
Article first published online: 18 NOV 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 59, Issue 1, pages 178–189, January 2014
How to Cite
Zhang, L., Yang, Z., Ma, A., Qu, Y., Xia, S., Xu, D., Ge, C., Qiu, B., Xia, Q., Li, J. and Liu, Y. (2014), Growth arrest and DNA damage 45G down-regulation contributes to janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma. Hepatology, 59: 178–189. doi: 10.1002/hep.26628
This work received support by grants from the National Natural Science Foundation of China (no. 81201542), the Natural Science Foundation of Shanghai (no. 12ZR1430100), the Chinese National Key Project (no. 2013ZX10002-011), and the State Key Laboratory of Oncogenes and Related Genes (no. 91-12-03).
- Issue published online: 20 DEC 2013
- Article first published online: 18 NOV 2013
- Accepted manuscript online: 29 JUL 2013 09:29AM EST
- Manuscript Accepted: 7 JUL 2013
- Manuscript Received: 25 FEB 2013
Growth arrest and DNA damage 45G (GADD45G), a stress sensor with multiple implications in various biological processes, is down-regulated in a broad spectrum of cancers. However, little is known about the biological effects of GADD45G on hepatocellular carcinoma (HCC) cells and the related mechanisms. In the present study, we found that GADD45G was commonly down-regulated in oncogene-transformed mouse liver cells and in human and mouse HCC. Ectopic expression of GADD45G robustly elicited senescence in HCC cells and suppressed tumor growth in vivo. Furthermore, GADD45G-induced senescence occurred in HCC cells independently of p53, p16INK4a (p16), and retinoblastoma (Rb). Instead, the prompt inhibition of Janus kinase 2 (Jak2), tyrosine kinase 2 (Tyk2), and signal transducer and activator of transcription 3 (Stat3) activation was observed in cells undergoing senescence. Impairment of Jak-Stat3 activation caused by GADD45G expression was associated with activation of SH2 domain-containing protein tyrosine phosphatase-2 (Shp2). Expression of constitutively activated Stat3 or human telomerase reverse transcriptase (hTERT), as well as knockdown of Shp2f, efficiently counteracted GADD45G-induced senescence. More important, in clinical HCC specimens, we found that GADD45G expression was inversely correlated with phosphorylated Stat3 expression in tumor cells and disease progression. Conclusion: GADD45G functions as a negative regulator of the Jak-Stat3 pathway and inhibits HCC by inducing cellular senescence. The decrease or absence of GADD45G expression may be a key event for tumor cells or premalignant liver cells to bypass cellular senescence. (Hepatology 2014;58:178–189)