Like its relatives, STAT3 is inactive in nonstimulated cells, but is rapidly activated by various cytokines and growth factors, such as IL 6 and EGF family members, as well as hepatocyte growth factor. STAT3 activation requires phosphorylation AZ 3146 of a critical tyrosine residue, which mediates its dimerization that is a prerequisite for nucleus entry and DNA binding. The phosphorylation of STAT3 at Tyr705 is most commonly mediated by Janus kinases, especially JAK2, but its activity is also subject to fine tuning by other mechanisms, including serine phosphorylation and reversible acetylation. Activation of STAT3 also turns on strong negative feedback loops involving SHP phosphatases and suppressor of cytokine signaling 3.
These feedback mechanisms dampen STAT3 activity and ensure that cytokine induced STAT3 activation is a transient event in normal cells. However, in cancer cells STAT3 is often found to be constitutively activated. We have examined a large number of human HCC specimens and detected phosphorylated STAT3 in approximately 60% of them, with STAT3 positive tumors being more aggressive. BMS-536924 These findings are consistent with those of other studies in which STAT3 was found to be activated in the majority of HCCs with poor prognosis and not in surrounding non tumor tissue or in normal liver. However, the events that lead to STAT3 activation in human HCC are not known. Interestingly, activating mutations in the gene encoding the gp130 signaling subunit of IL 6 receptor family members were identified in benign hepatic adenomas.
When combined with a catenin activating mutation, these mutations, which cause STAT3 activation, lead to HCC development. Nevertheless, STAT3 activating mutations are rare in human cancers. Most likely, as discussed above for NF ?B, STAT3 in cancer cells is activated by cytokines and growth factors that are produced within the tumor microenvironment. Indeed, the expression of IL 6, one of the major STAT3 activating cytokines, is elevated in human liver diseases and HCC. In addition, many HCC risk factors, including HCV infection and hepatosteatosis, cause oxidative stress and just like JNK, STAT3 can also be activated in response to ROS accumulation.
As discussed below, NF ?Binduced expression of anti oxidants prevents inadverNF ?B, STAT3 and liver cancer 164 npg Cell Research | Vol 21 No 1 | January 2011 tent activation of STAT3 by ROS accumulation, but it needs to be determined whether NF ?B activity is downregulated during human hepatocarcinogenesis to allow STAT3 activation. Nevertheless, the majority of STAT3 positive HCCs do not exhibit NF ?B activation and most NF ?B positive HCCs do not show activated STAT3. However, the main cause of STAT3 activation in human HCC could simply be the elevated expression of IL 6 and related cytokines, such as IL 11 and IL 22. STAT3 promotes HCC development in mouse models Germ line ablation of Stat3 results in early embryonic lethality. In fact, loss of STAT3 is lethal even to embryonic stem cells, underscoring a critical role for STAT3 in cell growth and/or survival. To overcome these problems, a number of tissue specific Stat3 knockout mouse strains were generated to allow STAT3 deletion in differentiat