Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-β and STAT3 activation

Abstract

The molecular mechanisms underlying the development of hepatocellular carcinoma are not fully understood. Liver-specific signal transducer and activator of transcription (STAT) 5A/B–null mice (STAT5-LKO) were treated with carbon tetrachloride (CCl4), and histological analyses revealed liver fibrosis and tumors. Transforming growth factor (TGF)–β levels and STAT3 activity were elevated in liver tissue from STAT5-LKO mice upon CCl4 treatment. To define the molecular link between STAT5 silencing and TGF-β up-regulation, as well as STAT3 activation, we examined STAT5-null mouse embryonic fibroblasts and primary hepatocytes. These cells displayed elevated TGF-β protein levels, whereas messenger RNA levels remained almost unchanged. Protease inhibitor studies revealed that STAT5 deficiency enhanced the stability of mature TGF-β. Immunoprecipitation and immunohistochemistry analyses demonstrated that STAT5, through its N-terminal sequences, could bind to TGF-β and that retroviral-mediated overexpression of STAT5 decreased TGF-β levels. To confirm the in vivo significance of the N-terminal domain of STAT5, we treated mice that expressed STAT5 lacking the N terminus (STAT5-ΔN) with CCl4. STAT5-ΔN mice developed CCl4-induced liver fibrosis but no tumors. In conclusion, loss of STAT5 results in elevated TGF-β levels and enhanced growth hormone–induced STAT3 activity. We propose that a deregulated STAT5–TGF-β–STAT3 network contributes to the development of chronic liver disease.

Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis

“…[42][43][44] For example, Fujii et al 45 reported that treatment with CCl 4 for 15 weeks induced liver fibrosis and well-differentiated HCC in male A/J strain mice. Furthermore, Hosui et al 46 reported that chronic injection of CCl 4 for 8 weeks induced HCC in 10% of liver-specific STAT5 knockout mice but not in wild-type mice. The present study shows that after 16-week CCl 4 treatment, no HCC development was found in wild-type mice but approximately 60% of STAT3 HepϪ/Ϫ mice developed multiple surface nodular tumors ( Figure 6).…”

STAT5a-targeting miRNA enhances chemosensitivity to cisplatin and 5-fluorouracil in human colorectal cancer cells

“…As STAT3 has been the focus of cancer research, STAT3 inhibitors are being investigated, and a growing number of preclinical studies are ongoing. Therefore, more and more researchers have begun to focus on STAT5 (15)(16)(17)(18)(19). Evidence reveals that inhibition of STAT5 affects biological behavior of cancer cells.…”

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

“…28 A recent study has suggested that STAT5 might have a crucial role in hepatic tumorigenesis. 29 However, its role in cancer development is still controversial as it might also act as a tumor inducer [30][31][32][33] as well as a tumor suppressor. 29,34 No STAT5 activation was detected in gp130 f/f livers 40 weeks after DEN treatment (Figure 7b, Supplementary Figure 7c).…”

“…As STAT5 activation has been shown to trigger tumor growth in a TGFβ-dependent manner, 29 we examined the TGFβ pathway in more detail. We found significantly decreased TGFβ expression in gp130…”