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.