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

Abstract

Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocyte-specific gp130 knockout mice (gp130Δhepa) and control animals (gp130f/f) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0–144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130Δhepa animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130Δhepa mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130f/f and gp130Δhepa animals. However, gp130Δhepa livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-β (TGFβ), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC.

A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis

“…In the autochthonous tumour models, the severity of the phenotype also correlates with the extent of liver inflammation, being stronger in Δhep than in Δp/np animals. This is consistent with the fact that increased YAP1 expression promotes hepatocyte proliferation in vivo only upon liver injury or inflammation, that IL6 cooperates with YAP1 in this setting35, and that GP130 is necessary for full-fledged DEN-induced tumourigenesis in the mouse14.…”

“…Increased GP130 expression selectively supports the activation of STAT3 by proinflammatory cytokines of the IL6 family, but not by those of the IL10 family, broadly speaking anti-inflammatory in nature; the importance of the GP130/STAT3 axis in epithelial inflammation and gastrointestinal tumourigenesis22 and of GP130 in liver tumours47144041 has been amply documented. Besides the cell-autonomous proliferation phenotype, RAF1-deficient DIH are much more efficient than controls in attracting macrophages; they also produce higher amounts of CCL2, a STAT3 target gene42, and of CXCL1, upregulated by YAP1 in breast cancer cell lines43.…”

“…In the mouse, Raf1 ablation causes liver apoptosis910, suggesting an essential function in this organ and a potential role in liver cancer development. Contrary to this expectation, patient data show reduced RAF1 expression in human HCCs; based on this, we have investigated the role of RAF1 in HCC using two different mouse models: (1) HCC xenografts and (2) hepatocarcinogenesis induced by the alkylating agent diethylnitrosamine (DEN) and promoted by Phenobarbital (Pb), which mimics human disease in terms of gene expression profiles and critically depends on inflammation11121314. Both models have revealed a tumour suppressor function of RAF1 in HCC, consistent with the reduced RAF1 expression in HCC patients.…”

IL6‐mediated inflammatory loop reprograms normal to epithelial‐mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta–deficient β2‐spectrin+/− mice

“…Chronic activation of proinflammatory pathways is critical to the progression of hepatitis to liver cancer. Among numerous proinflammatory factors, interleukin‐6 (IL6)‐mediated signaling has been extensively studied in the context of chronic liver diseases and HCC development . One study found elevated IL6 levels in 40% of liver cancer patients, which suggests that IL6 is associated with HCC progression .…”

Transforming growth factor‐β in liver cancer stem cells and regeneration

“…Among numerous proinflammatory factors, interleukin‐6 (IL‐6) is the most prominently elevated in almost 40% of liver cancer patients, suggesting that IL‐6 is associated with HCC progression 81, 82, 83, 84, 85, 86, 87. The TGF‐β pathway induced IL‐6 secretion may confer chemotherapeutic resistance in HCC 32.…”