期刊
JOURNAL OF HEMATOLOGY & ONCOLOGY
卷 13, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13045-020-0845-z
关键词
Hepatocellular carcinoma; Cancer stem cells; CD73; AKT signaling; Lenvatinib resistance
资金
- National Natural Science Foundation of China [81572552, 81772774, 81772808, 8180101167, 31771472]
- Shanghai Science and Technology Commission [17411963500, 17411951000]
- construction project for important weak discipline from Shanghai Municipal Health Commission [2015ZB0204]
- International Science and Technology Cooperation Project of Shanghai [18410721900]
- Minhang Hospital [2018MHJ05]
- Minhang Science and Technology Commission [2019MHZ077]
- Minhang HospitalCollege of Pharmacy, Fudan University [RO-MY201805]
Background 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/P110 beta cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. Methods 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. Results 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 3 beta. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis. Conclusions 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.
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