Abstract
BackgroundSustained adrenergic signaling secondary to chronic stress promotes cancer progression; however, the underlying mechanisms for this phenomenon remain unclear. Hepatocellular carcinoma (HCC) frequently develops within fibrotic livers rich in activated hepatic stellate cells (HSCs). Here, we examined whether the stress hormone norepinephrine (NE) could accelerate HCC progression by modulating HSCs activities.MethodsHCC cells were exposed to conditioned medium (CM) from NE-stimulated HSCs. The changes in cell migration and invasion, epithelial-mesenchymal transition, parameters of cell proliferation, and levels of cancer stem cell markers were analyzed. Moreover, the in vivo tumor progression of HCC cells inoculated with HSCs was studied in nude mice subjected to chronic restraint stress.ResultsCM from NE-treated HSCs significantly promoted cell migration and invasion, epithelial-mesenchymal transition (EMT), and expression of cell proliferation-related genes and cancer stem cell markers in HCC cells. These pro-tumoral effects were markedly reduced by depleting secreted frizzled related protein 1 (sFRP1) in CM. The pro-tumoral functions of sFRP1 were dependent on β-catenin activation, and sFRP1 augmented the binding of Wnt16B to its receptor FZD7, resulting in enhanced β-catenin activity. Additionally, sFRP1 enhanced Wnt16B expression, reinforcing an autocrine feedback loop of Wnt16B/β-catenin signaling. The expression of sFRP1 in HSCs promoted HCC progression in an in vivo model under chronic restraint stress, which was largely attenuated by sFRP1 knockdown.ConclusionsWe identify a new mechanism by which chronic stress promotes HCC progression. In this model, NE activates HSCs to secrete sFRP1, which cooperates with a Wnt16B/β-catenin positive feedback loop. Our findings have therapeutic implications for the treatment of chronic stress-promoted HCC progression.
Highlights
Sustained adrenergic signaling secondary to chronic stress promotes cancer progression; the underlying mechanisms for this phenomenon remain unclear
NE is capable of activating hepatic stellate cells (HSCs) via the α1A-ADR The expression of adrenergic receptors (ADRs) was screened among HSCs (LX2 cells, p-HSC), liver cell line L02, and Hepatocellular carcinoma (HCC) cells (PLC/PRF/5, HepG2, Hep3B, Huh7 SMMC7721, MHCC97H, and HCCLM3)
Nonselective and selective α1-ADR antagonists efficiently suppressed NE-dependent HSC activation, as shown by reduced alpha-smooth muscle actin (α-SMA) and collagen I (COL1A1) expression, reduced cell proliferation, and increased cell apoptosis in LX2 cells (Fig. 1d, e, f, g). In accordance with these changes, the α1-ADR antagonists significantly suppressed NE-induced cyclin D1 expression and remarkably increased the levels of cleaved caspase-3 (Fig. 1h). These results suggest that the stress hormone NE stimulates HSC activation through α1A-ADR signaling
Summary
Sustained adrenergic signaling secondary to chronic stress promotes cancer progression; the underlying mechanisms for this phenomenon remain unclear. Hepatocellular carcinoma (HCC) frequently develops within fibrotic livers rich in activated hepatic stellate cells (HSCs). HCC often arises on a background of inflamed or fibrotic livers rich in activated hepatic stellate cells (HSCs) [9,10,11]. Several neuronal genes were found to be highly expressed in HSCs, including adrenergic receptors [20,21,22,23,24,25,26]. This prompted us to hypothesize that chronic stress could affect HCC progression through stress hormonemodulating HSC activities
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