CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma
Open Access
- 5 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Hematology & Oncology
- Vol. 13 (1), 1-16
- https://doi.org/10.1186/s13045-020-0845-z
Abstract
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.Funding Information
- Major Research Plan (81572552, 81772774, 81772808)
- the project from Shanghai Science and Technology Commission (17411963500)
- Shanghai Science and Technology Commission (17411951000)
- Shanghai Municipal Health Commission (2015ZB0204)
- International Science and Technology Cooperation Project of Shanghai (18410721900)
- Minhang Hospital (2018MHJ05)
- Shanghai Minhang Science and Technology Commission (2019MHZ077)
- fusion grant of Minhang Hospital-College of Pharmacy, Fudan University (RO-MY201805)
- National Natural Science Foundation of China (8180101167)
- National Natural Science Foundation of China (31771472)
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