CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma

• Published in: Journal of hematology and oncology 2020-02, Vol.13 (1), p.11-11, Article 11
• Main Authors: Ma, Xiao-Lu, Hu, Bo, Tang, Wei-Guo, Xie, Su-Hong, Ren, Ning, Guo, Lin, Lu, Ren-Quan
• Format: Article
• Language: English
• Subjects: 5'-Nucleotidase - genetics; AKT protein; AKT signaling; Analysis; Animal models; Biochemistry; c-Myc protein; Cancer; Cancer stem cells; Cancer therapies; Carcinoma; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; CD73; CD73 antigen; Cell differentiation; Cell Line, Tumor; Development and progression; Drug resistance; Experiments; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic research; Glycogen; Glycogen synthase kinase 3; Glycogen synthesis; GPI-Linked Proteins - genetics; Hematology; Hepatocellular carcinoma; Humans; Immunoprecipitation; Infection; Kinases; Laboratory animals; Lenvatinib; Lenvatinib resistance; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Medical prognosis; Metastasis; Myc protein; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; Polysaccharides; Proteins; Rap1 protein; Sox9 protein; SOX9 Transcription Factor - analysis; SOX9 Transcription Factor - genetics; Spheroids; Stem cells; Studies; Transcription; Tumors; Ubiquitin
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-020-0845-z

Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation. We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73- counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis. Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.