Interconnections between autophagy and the coagulation cascade in hepatocellular carcinoma.

[severe combined immunodeficiency]

Autophagy has an important role in tumor biology of hepatocellular carcinoma (HCC ). Recent studies demonstrated that tissue factor (TF ) combined with coagulation factor VII (FVII ) has a pathological role by activating a G-protein-coupled receptor called protease-activated receptor 2 (PAR 2 ) for tumor growth . The present study aimed to investigate the interactions of autophagy and the coagulation cascade in HCC . Seventy HCC patients who underwent curative liver resection were recruited . Immunohistochemical staining and western blotting were performed to determine TF , FVII , PAR 2 and light chain 3 (LC 3 A /B ) expressions in tumors and their contiguous normal regions . We found that the levels of autophagic marker LC 3 A /B-II and coagulation proteins (TF , FVII and PAR 2 ) were inversely correlated in human HCC tissues . Treatments with TF , FVII or PAR 2 agonist downregulated LC 3 A /B-II with an increased level of mTOR in Hep 3 B cells ; in contrast , knockdown of TF , FVII or PAR 2 increased LC 3 A /B . Furthermore , mTOR silencing restored the impaired expression of LC 3 A /B-II in TF -, FVII- or PAR 2 -treated Hep 3 B cells and activated autophagy . Last , as an in vivo correlate , we administered TF , FVII or PAR 2 agonist in a NOD /severe combined immunodeficiency xenograft model and showed decreased LC 3 A /B protein levels in HepG 2 tumors with treatments . Overall , our present study demonstrated that TF , FVII and PAR 2 regulated autophagy mainly via mTOR signaling . The interaction of coagulation and autophagic pathways may provide potential targets for further therapeutic application in HCC .