Activation of the transforming growth factor‐β/SMAD transcriptional pathway underlies a novel tumor‐promoting role of sulfatase 1 in hepatocellular carcinoma

Abstract

In vitro studies have proposed a tumor suppressor role for Sulfatase1 (SULF1) in hepatocellular carcinoma (HCC), however high expression in human HCC has been associated with poor prognosis. The reason underlying this paradoxical observation remains to be explored. Using a transgenic (Tg) mouse model overexpressing Sulf1 (Sulf1-Tg) we assessed the effects of SULF1 on the diethylnitrosamine (DEN) model of liver carcinogenesis. Sulf1-Tg mice show higher incidence of large and multifocal tumors with DEN injection compared to wild type (WT) mice. Lung metastases were found in 75% of Sulf1-Tg mice but not in WT mice. Immunohistochemistry (IHC), immunoblotting and reporter assays all show a significant activation of the TGFβ/SMAD transcriptional pathway by SULF1 both in vitro and in vivo. This effect of SULF1 on TGFβ/SMAD pathway is functional; overexpression of SULF1 promotes TGFβ-induced gene expression and epithelial-mesenchymal-transition (EMT), and enhances cell migration/invasiveness. Mechanistic analyses demonstrate that inactivating mutation of the catalytic site of SULF1 impairs the above actions of SULF1 and diminishes the release of TGFβ from the cell surface. And we also show that SULF1expression decreases the interaction between TGF-β1 and its HSPG sequestration receptor TGFβR3. Finally, using gene expression from human HCCs, we show that patients with high SULF1 expression have poorer recurrence-free survival (HR 4.1 (1.9–8.3); p=0.002) compared to patients with low SULF1. We also found strong correlations of SULF1 expression with TGFβ expression and with several TGFβ-related EMT genes in human HCC. CONCLUSION In summary, our study proposes a novel role of SULF1 in HCC tumor progression through augmentation of the TGFβ pathway, thus defining SULF1 as a potential biomarker for tumor progression and a novel target for drug development for HCC.

Transcriptional Induction of Periostin by a Sulfatase 2–TGFβ1–SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma

“…DEN is a genotoxic drug and its use has been well established in mouse models for hepatocarcinogenesis (16). At 14 days of age, mice received a single intraperitoneal injection of DEN (15 mg/kg body weight).…”

Decreased Expression of Sulfatase 2 in the Brains of Alzheimer’s Disease Patients: Implications for Regulation of Neuronal Cell Signaling

“…Thus, whereas SULF1 mitigates FGF2 signaling, SULF2 enhances FGF2 signaling [23]. However, in contrast to their opposing effects on FGF signaling, both SULF1 and SULF2 activate Wnt and TGFβ signaling which are important signaling pathways in development, differentiation, and carcinogenesis [24, 25]. …”

Sulfatase 1: a new Jekyll and Hyde in hepatocellular carcinoma?

“…This conclusion is supported by Dhanasekaran and coworkers, who in a recent study (16) provided convincing data in support of the oncogenic role of SULF1 in hepatocarcinogenesis and unraveled some of the molecular mechanisms involved. These authors used a transgenic mouse model overexpressing SULF1 (Sulf1-Tg) to evaluate the effects of SULF1 on the diethylnitrosamine (DENA) model of hepatocarcinogenesis.…”

“…The analysis by Dhanasekaran and coworkers (16) of genes involved in TGF-β signaling showed higher expression of Smad2 and Smad6 in Sulf1-Tg than in WT mice. Also, an increase in phosphorylation of Smad2/3 in peritumoral liver tissues and, at a higher extent, in tumors of Sulf1-Tg mice than WT mice occurred.…”

“…In order to identify the molecular players responsible for the oncogenic role of SULF1, Dhanasekaran and coworkers (16) evaluated by transcriptome analysis of non-DENA treated liver tissues the pathways and biological processes activated in Sulf1-Tg compared to WT mice. They observed the up-regulation of biological processes involving cytoskeletal remodeling, cell adhesion, and muscle development in Sulf1-Tg mice.…”