Regulation Of TGF-β And Hippo Signaling By Musculin Protein In Liver Cancer Cells

The incidence rate of liver cancer is very high in China,and new cancer cases are expected to surpass 1 million by 2025,making liver cancer a serious health challenge.Current treatment options for liver cancer mainly include surgical resection,radiotherapy,chemotherapy and targeted therapy,but suffer from high recurrence rates and short patient survival.In order to improve the treatment of liver cancer with high recurrence rate and short survival,many recent studies have been devoted to the study of targeted treatment modalities for liver cancer,such as the study of exosomes and nanocarriers,in order to provide a new theoretical basis for the study of hepatoma targeted therapeutics by virtue of these targets.Therefore,it is urgent to deeply understand the molecular mechanisms underlying liver cancer development and seek for new molecular targets for cancer intervention.TGF-β and Hippo signaling pathways play important biological roles in liver cancer development,regulating cancer cell growth and migration,amongst others.As one of the basic helix loop helix(b HLH)transcription factor family members,Musculin has been reported to regulate the development of specific tumors,such as lymphoma and rhabdomyosarcoma.However,whether and how Musculin exerts a role in liver cancer remain elusive.We found in this thesis that TGF-β signaling activation could stimulate the expression of Musculin in hepatoma cells,whereas inhibition of TGF-βsignaling reduced Musculin expression.Investigations by dual luciferase reporter assays and target gene expression tests revealed that stably overexpression of Musculin in liver cancer cells could inhibit TGF-β signaling and the transcriptional activity of the downstream Smad proteins,thus forming a negative feedback regulatory loop.Furthermore,Musculin also inhibited the expressions of luciferase reporters and target genes which were stimulated by YAP.Functionally,Musculin was able to ameliorate TGF-β or YAP-induced proliferation and migration of liver cancer cells.Finally,the expression of Musculin was decreased in liver cancer tissues from clinical patients compared with normal liver tissues.The above results demonstrated that Musculin was a novel regulator of both TGF-β signaling and Hippo signaling,and consequently regulating liver cancer cell growth and migration.These findings can not only provide further understanding of TGF-β and Hippo signaling abnormalities in liver cancer development,but also be a potentially new molecular target for liver cancer intervention.