ß-arrestin2 deficiency protects against hepatic fibrosis in mice and prevents synthesis of extracellular matrix.

Hepatic fibrosis is a disease of the wound-healing response following chronic liver injury, and activated hepatic stellate cells (HSCs) play a crucial role in the progression of hepatic fibrosis. ß-arrestin2 functions as a multiprotein scaffold to coordinate complex signal transduction networks. Although ß-arrestin2 transduces diverse signals in cells, little is known about its involvement in the regulation of liver fibrosis. Our current study utilized a porcine serum-induced liver fibrosis model and found increased expression of ß-arrestin2 in hepatic tissues with the progression of hepatic fibrosis, which was positively correlated with collagen levels. Furthermore, changes in human fibrotic samples were also observed. We next used ß-arrestin2-/- mice to demonstrate that ß-arrestin2 deficiency ameliorates CCl4-induced liver fibrosis and decreases collagen deposition. The in vitro depletion and overexpression experiments showed that decreased ß-arrestin2 inhibited HSCs collagen production and elevated TßRIII expression, thus downregulating the TGF-ß1 pathway components Smad2, Smad3 and Akt. These findings suggest that ß-arrestin2 deficiency ameliorates liver fibrosis in mice, and ß-arrestin2 may be a potential treatment target in hepatic fibrosis.

Targeted blockade of JAK/STAT3 signaling inhibits proliferation, migration and collagen production as well as inducing the apoptosis of hepatic stellate cells.

Protein tyrosine kinases belonging to the Janus kinase (JAK) family are associated with many cytokine receptors, which, on ligand binding, regulate important cellular functions such as proliferation, apoptosis and differentiation. The protective effects of JAK inhibitors on fibrotic diseases such as myelofibrosis and bone marrow fibrosis have been demonstrated in previous studies. The JAK inhibitor SHR0302 is a synthetic molecule that potently inhibits all members of the JAK family, particularly JAK1. However, its effect on hepatic fibrosis has not been investigated to date, to the best of our knowledge. In the present study, the effects of SHR0302 on the activation, proliferation, migration and apoptosis of hepatic stellate cells (HSCs) as well as HSC collagen production were investigated. Our data demonstrated that treatment with SHR0302 (10-9-10-5 mol/l) exerted an inhibitory effect on the activation, proliferation and migration of HSCs. In addition, the expression of collagen I and collagen III were significantly decreased following treatment with SHR0302. Furthermore, SHR0302 induced the apoptosis of HSCs, which was demonstrated by Annexin V/PI staining. SHR0302 significantly increased the activation of caspase-3 and Bax in HSCs whereas it decreased the expression of Bcl-2. SHR0302 also inhibited the activation of Akt signaling pathway. The pharmacological inhibition of the JAK1/signal transducer and activator of transcription (STAT)3 pathway led to the disruption of functions essential for HSC growth. Taken together, these findings provide evidence that SHR0302 may have the potential to alleviate hepatic fibrosis by targeting HSC functions.

Decreased expression of the type III TGF-ß receptor enhances metastasis and invasion in hepatocellullar carcinoma progression.

The transforming growth factor ß (TGF-ß) superfamily of cytokines is multifunctional and involved in the regulation of cell growth and differentiation. TGF-ß can induce an epithelial-mesenchymal transition (EMT) of both epithelial and endothelial cells. This has consequences for cancer progression in regards to both migration and invasion abilities. The type III TGF-ß receptor (TßRIII) is a ubiquitously expressed TGF-ß co-receptor which regulates TGF-ß signaling and the progression of various types of cancer. Previous studies have shown that TßRIII exhibits abnormal expression and plays an essential role in regulating cancer invasion and metastasis, while little is known in regards to its role in hepatocellular carcinoma (HCC) progression. In the present study, we designed the present research to study the role of TßRIII in the invasion and metastasis of HCC and the possible mechanisms involved. The results demonstrated decreased expression of TßRIII in HCC patient tissues and human HCC cell lines. TGF-ß1 stimulation led to the increased migratory ability and reduced expression of TßRIII in HCC cells. In addition, knockdown of TßRIII by small interfering RNA (siRNA) promoted the migration and invasion of HCC cells and induced activation of the Smad2 and Akt pathways. All the results suggest that TßRIII is a novel suppressor of HCC progression.

The emerging roles of ß-arrestins in fibrotic diseases.

ß-Arrestins and ß-arrestin2 are important adaptor proteins and signal transduction proteins that are mainly involved in the desensitization and internalization of G-protein-coupled receptors. Fibrosis is characterized by accumulation of excess extracellular matrix (ECM) molecules caused by chronic tissue injury. If highly progressive, the fibrotic process leads to organ malfunction and, eventually, death. The incurable lung fibrosis, renal fibrosis and liver fibrosis are among the most common fibrotic diseases. Recent studies show that ß-arrestins can activate signaling cascades independent of G-protein activation and scaffold many intracellular signaling networks by diverse types of signaling pathways, including the Hedgehog, Wnt, Notch and transforming growth factor-ß pathways, as well as downstream kinases such as MAPK and PI3K. These signaling pathways are involved in the pathological process of fibrosis and fibrotic diseases. This ß-arrestin-mediated regulation not only affects cell growth and apoptosis, but also the deposition of ECM, activation of inflammatory response and development of fibrotic diseases. In this review, we survey the involvement of ß-arrestins in various signaling pathways and highlight different aspects of their regulation of fibrosis. We also discuss the important roles of ß-arrestins in the process of fibrotic diseases by regulating the inflammation and deposit of ECM. It is becoming more evident that targeting ß-arrestins may offer therapeutic potential for the treatment of fibrotic diseases.