Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis

Abstract

Aberrantly hyperactivated STAT3 has been found in human liver cancers as an oncogene; however, STAT3 has also been shown to exert hepatoprotective effects during liver injury. The balancing act that STAT3 plays between hepatoprotection and liver tumorigenesis remains poorly defined. In this study, the diethylnitrosamine (DEN)-induced liver tumor model and the chronic carbon tetrachloride (CCl 4 )-induced liver fibrosis model were both used to investigate the role of STAT3 in liver tumorigenesis. Hepatocyte-specific STAT3 knockout mice were resistant to liver tumorigenesis induced by a single DEN injection, whose tumorigenesis was associated with minimal chronic liver inflammation, injury, and fibrosis. In contrast, long-term CCl 4 treatment resulted in severe hepatic oxidative damage, inflammation, and fibrosis but rarely induced liver tumor formation in wild-type mice. Despite the oncogenic function of STAT3 in DEN-induced liver tumor, hepatocyte-specific STAT3 knockout mice were more susceptible to liver tumorigenesis after 16 weeks of CCl 4 injection, which was associated with higher levels of liver injury, inflammation, fibrosis, and oxidative DNA damage compared with wild-type mice. These findings suggest that the hepatoprotective feature of STAT3 prevents hepatic damage and fibrosis under the condition of persistent inflammatory stress, consequently suppressing injurydriven liver tumor initiation. Once liver tumor cells have developed, STAT3 likely acts as an oncogenic factor to promote tumor growth.

Conflicting Roles of Molecules in Hepatocarcinogenesis: Paradigm or Paradox

“…However, both pro- and anti-oncogenic activities of Stat3 in HCC development were observed in hepatocyte-specific Stat3 knockouts, transgenic mice expressing dominant active or negative mutant of Stat3, or tumor-bearing animals treated with Stat3 inhibitors (Lin et al, 2009; Schneller et al, 2011; Wang et al, 2011b). Interestingly, hepatocyte-specific deletion of tyrosine phosphatase Shp2 resulted in a marked increase in DEN-induced HCC incidences, which was compromised by additional removal of Stat3 (Bard-Chapeau et al, 2011).…”

“…Interestingly, hepatocyte-specific deletion of tyrosine phosphatase Shp2 resulted in a marked increase in DEN-induced HCC incidences, which was compromised by additional removal of Stat3 (Bard-Chapeau et al, 2011). However, deleting Stat3 alone also led to enhanced tumorigenesis induced by DEN (Bard-Chapeau et al, 2011) or CCl 4 (Wang et al, 2011b) as compared to wild-type mice.…”

The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma

“…For example, the MDR2 knockout mice, which develop spontaneous biliary fibrosis and resultant chronic inflammation, dysplasia, and HCC, showed a reliance on TNF α -NF- κ B signaling in transformed hepatocytes for their survival and progression to HCC, while other studies utilizing the chemical carcinogen diethylnitrosamine (DEN) demonstrated that decreased NF- κ B signaling in hepatocytes resulted in increased tumorigenesis [59,110]. Similarly, DEN-induced carcinogenesis was minimized in STAT3 knockout mice, but carbon tetrachloride (CCl 4 ) treatment was in contrast shown to induce tumor formation in the same mouse model, thus demonstrating a reliance on liver damage, hepatocyte death, and compensatory proliferation in an inflammatory context to promote tumorigenesis [113]. …”

STAT3 Association with Microtubules and Its Activation Are Independent of HDAC6 Activity

“…STAT3 is constitutively activated in several types of cancers, such as breast cancer, T-cell lymphomas, and liver cancer (Garcia et al, 1997;Mitchell and John, 2005;Wang et al, 2011). Besides its role in activating cancer-related genes, emerging evidence reveals that STAT3 interacts with stathmin to regulate microtubule dynamics and metastasis of cancer cells (Ng et al, 2006;Walker et al, 2011), implicating a potential association STAT3 with microtubules.…”