CD24 Regulates Sorafenib Resistance Via Activating Autophagy In Hepatocellular Carcinoma

Hepatocellular carcinoma is one of most common solid cancers worldwide.Sorafenib is indicated as a treatment for advanced hepatocellular carcinoma(HCC).Despite this encouraging advance,drug resistance to sorafenib remains a serious concern as the overall survival(OS)of HCC patients after sorafenib treatment is only 2-3 months longer than placebo.And the precise mechanisms of drug resistance are largely unknown.CD24 is a glycoprotein expressing on the surface of most B lymphocytes and several tumor types,including prostate cancer,cervical cancer,non–small cell lung carcinoma,gastric cancer,and breast cancer.The encoded protein is anchored via a glycosyl phosphatidylinositol(GPI)linked to the cell surface and contributes to a wide range of downstream signaling networks.The recent study indicated that the overexpression of CD24 may be related to drug resistance.For example,CD24 high versus low cells express differential gene regulatory networks,differential sensitivity to the drug imatinib mesylate,and differential self-renewal capacity;The study of Goldman A showed that CD44 and CD24 molecules accumulated on the membrane liposomes in the mouse model of breast cancer and induced chemotherapeutic tolerance by regulating the activation of Src family kinases.Autophagy is a process of cell self-degradation,which plays an important role in adapting to metabolic stress,maintaining the integrity of genome and maintaining the stability of the internal environment.Apoptosis tolerance is an important mechanism of drug resistance in tumor therapy.Autophagy can prevent apoptosis induced by anti-tumor agents and promote tumor resistance.At present,autophagy is recognized as an important factor in promoting drug resistance in tumor cells.Whether autophagy is involved in CD24 mediated drug-resistance of sorafeinib is also a major issue in this study.In this study,we collected 70 HCC tumor tissues and adjacent tissues,13 of which were secondary sorafenib resistant tumors.Real-time fluorescence quantitative polymerase chain reaction and immunohistochemistry were used to detect the expression of CD24 in HCC tumor tissues and adjacent tissues.Sorafenib resistance HCC cell lines used to study the mechanisms of drug resistance.To explore the role of CD24 molecules in the drug resistance process of sorafenib by overexpressing or knocking down the molecules of CD24.To understand the mechanism of CD24 induced sorafenib-resistance,we carried out a whole transcriptome shotgun sequencing(RNA-Seq)to determine the continually cellular transcriptome change between Huh7/SR and Huh7/SR sh CD24.The inhibitors and activators used to regulate the PP2A/AKT/m TOR signal pathway and autophagy pathway.Mouse tumor-bearing test used to verify the molecular mechanism of cd24 regulation of sorafenib resistance in vivo.Here,we found that a cell surface molecule,CD24,is overexpressed in tumor tissues and sorafenib-resistant hepatocellular carcinoma cell lines.Moreover,there is a positive correlations between CD24 expression levels and sorafenib resistance.In sorafenib-resistant HCC cell lines,depletion of CD24 caused a notable increase of sorafenib sensitivity.In addition,we found that CD24 related sorafenib resistance was accompanied by the activation of autophagy and can be blocked by the inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown.In further research,we found that CD24 overexpression also leads to an increase in PP2 A protein production and induces the deactivation of the m TOR/AKT pathway,which enhances the level of autophagy.These results demonstrate that CD24 regulates sorafenib resistance via activating autophagy in HCC.This is the first report to describe the relationships among CD24,autophagy,and sorafenib resistance.In conclusion,the combination of autophagy modulation and CD24 targeted therapy is a promising therapeutic strategy in the treatment of HCC.