CD73 promotes hepatocellular carcinoma progression and metastasis via activating PI3K/AKT signaling by inducing Rap1-mediated membrane localization of P110 and predicts poor prognosis
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Open Access
- 10 April 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Hematology & Oncology
- Vol. 12 (1), 1-17
- https://doi.org/10.1186/s13045-019-0724-7
Abstract
BackgroundHepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide because of rapid progression and high incidence of metastasis or recurrence. Accumulating evidence shows that CD73-expressing tumor cell is implicated in development of several types of cancer. However, the role of CD73 in HCC cell has not been systematically investigated and its underlying mechanism remains elusive.MethodsCD73 expression in HCC cell was determined by RT-PCR, Western blot, and immunohistochemistry staining. Clinical significance of CD73 was evaluated by Cox regression analysis. Cell counting kit-8 and colony formation assays were used for proliferation evaluation. Transwell assays were used for motility evaluations. Co-immunoprecipitation, cytosolic and plasma membrane fractionation separation, and ELISA were applied for evaluating membrane localization of P110 and its catalytic activity. NOD/SCID/c(null) (NOG) mice model was used to investigate the in vivo functions of CD73.ResultsIn the present study, we demonstrate that CD73 was crucial for epithelial-mesenchymal transition (EMT), progression and metastasis in HCC. CD73 expression is increased in HCC cells and correlated with aggressive clinicopathological characteristics. Clinically, CD73 is identified as an independent poor prognostic indicator for both time to recurrence and overall survival. CD73 knockdown dramatically inhibits HCC cells proliferation, migration, invasion, and EMT in vitro and hinders tumor growth and metastasis in vivo. Opposite results could be observed when CD73 is overexpressed. Mechanistically, adenosine produced by CD73 binds to adenosine A2A receptor (A2AR) and activates Rap1, which recruits P110 to the plasma membrane and triggers PIP3 production, thereby promoting AKT phosphorylation in HCC cells. Notably, a combination of anti-CD73 and anti-A2AR achieves synergistic depression effects on HCC growth and metastasis than single agent alone.ConclusionsCD73 promotes progression and metastasis through activating PI3K/AKT signaling, indicating a novel prognostic biomarker for HCC. Our data demonstrate the importance of CD73 in HCC in addition to its immunosuppressive functions and revealed that co-targeting CD73 and A2AR strategy may be a promising novel therapeutic strategy for future HCC management.Keywords
Funding Information
- Major Research Plan (87172263, 81572064, 81672839, 81472676)
- key developing disciplines of Shanghai Municipal Commission of Health and Family Planning (2015ZB0201)
- National Key Research and Development Program of China (2016YFF0101405)
- Shanghai Science and Technology Commission (1411970200, 14DZ1940302, 14140902301)
- Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020103)
- National High Technology Research and Development Program (863 Program) of China (2015AA020401)
- the State Key Program of National Natural Science of China (81530077)
- Specialized Research Fund for the Doctoral Program of Higher Education and Research Grants Council Earmarked Research Grants Joint Research Scheme (20130071140008)
- the Projects from Shanghai Science and Technology Commission (14DZ1940300, 14411970200)
- the Strategic Priority Research Program of the Chinese Academy of Science (XDA12020105)
- Projects from Shanghai Science and Technology Commission (16411952100)
- Young Scientists Fund (81602543, 8180101167)
- Sailing Program from the Shanghai and Technology Commission (16YF1401400)
- Zhongshan Hospital Science Foundation (2016ZSQN30, 2017ZSQN18, 2017ZSYQ26)
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