The Mechanism Of Thyroid Hormones In Inhibiting Hepatocellular Carcinoma Progression Through Regulation Of Thyroid Hormone Responsive

Primary hepatic carcinoma(PHC)has a high incidence and mortality rate worldwide,and hepatocellular carcinoma(HCC)is the most common primary hepatic carcinoma,accounting for approximately 75%-85%of the total cases.HCC is very malignant with insidious onset and no specific symptoms in the early stage.Most HCC is diagnosed at an advanced stage and the opportunity for surgical resection is lost,making it the third cause of cancer death worldwide.In the past decade,there have been great developments in the diagnosis and treatment of HCC,such as advances in surgical techniques and imaging technologies,especially the availability of targeted therapeutics and immune treatment,which have revolutionized the treatment paradigm for HCC.Currently,the treatment of HCC is mainly a comprehensive treatment model based on surgical resection,yet the overall survival of HCC patients is still unsatisfactory.The development of other effective and practicable treatments is critical to improving the prognosis of HCC patients.Thyroid hormones(THs),known as 3,5,3’-triiodo-L-tyrosine(3.5,3’-triiodo-L-thyronine,T3)and 3,5,3’,5’-tetraiodo-L-tyrosine(3,5,3’,5’-tetraiodo-L-tyrosine,T4),have been suggested to be engaged in a multitude process of both physiology and pathology,including cell growth,proliferation metabolism,tumorigenesis,and progression.Clinical case-control studies have shown that hypothyroidism is a permissive risk factor for HCC.Mechanistic studies have shown that thyroid hormone T3 exhibits a durable inhibitory effect on HCC progression by activating the local T3/TRβ axis,switching from Warburg to oxidative,and inducing cell differentiation.These results indicate that thyroid hormones play an important role in inhibiting HCC development and progression.As regulators of the response to thyroid hormones,thyroid hormone responsive(THRSP)is involved in the physiological functions of thyroid hormones and in the regulation of lipid biosynthesis mainly in tissues that synthesize fatty acids.In addition,THRSP has been reported as a potential prognostic marker and an important mediator of HCC progression.However,the specific molecular mechanisms by which THRSP regulates HCC progression and whether THRSP mediates the inhibitory effects of thyroid hormones on HCC are still unclear.As an important hallmark of cancer,metabolic reprogramming is critical for cancer cells to drive their malignant behavior including tumor progression and microenvironmental maintenance.Glycolysis,an essential component of metabolic reprogramming,plays an invaluable component in supporting the robust biosynthesis and energy requirements of cancer cells,driving tumorigenesis,angiogenesis,invasion,distant metastasis,immune escape,and drug resistance Multiple signaling pathways have participated in the glycolytic process of HCC,such as the PI3K/Akt pathway and the AMPK pathway.Considering the importance of glycolysis in the progression of HCC,the study of key enzymes targeting the glycolytic pathway offers potential approaches for the treatment of HCC.In this thesis,we analyzed The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)data to acquire the significantly differential genes in tissue sequencing and then identify the target gene THRSP.Clinical data suggest that THRSP is significantly downregulated in HCC tissues and THRSP expression level is an independent risk factor for overall survival and recurrence-free survival in HCC patients.Mechanistically,the exogenous addition of T3 enhanced the expression of THRSP and inhibited the proliferation,invasion,migration,and cellular glycolysis levels of HCC cells.In addition,THRSP can regulate downstream gene enolase 2(ENO2)expression by inhibiting PI3K/AKT pathway,glycolysis(Glycolysis/Gluconeogenesis)pathway,and activating the AMPK pathway.The transcription factor HIF-1α can target the promoter of ENO2 and regulate its expression and high expression of ENO2 is associated with poor prognosis in HCC patients.More importantly,the combination of T3 and the multi-kinase inhibitor lenvatinib not only inhibited the progression of HCC but also enhanced the sensitivity and anti-tumor activity of targeted therapy for HCC.In conclusion,T3 inhibits HCC progression by regulating THRSP expression,and THRSP is expected to be a potential therapeutic target for HCC.In this study,we confirmed the effects of T3 and THRSP on HCC biological behavior and systematically elucidated the mechanism for the first time.Furthermore,we revealed that T3 can be combined with multi-kinase inhibitors to enhance the effect of HCC treatment.