CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma
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/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. Metho...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2020-02-01
|
Series: | Journal of Hematology & Oncology |
Subjects: | |
Online Access: | https://doi.org/10.1186/s13045-020-0845-z |
id |
doaj-fcfaa8db368b48aca1c82262a6b69515 |
---|---|
record_format |
Article |
spelling |
doaj-fcfaa8db368b48aca1c82262a6b695152021-02-07T12:03:36ZengBMCJournal of Hematology & Oncology1756-87222020-02-0113111610.1186/s13045-020-0845-zCD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinomaXiao-Lu Ma0Bo Hu1Wei-Guo Tang2Su-Hong Xie3Ning Ren4Lin Guo5Ren-Quan Lu6Department of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan UniversityDepartment of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityDepartment of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan UniversityDepartment of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan UniversityDepartment of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan UniversityDepartment of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan UniversityDepartment of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan UniversityAbstract 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/P110β 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 3β. 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.https://doi.org/10.1186/s13045-020-0845-zHepatocellular carcinomaCancer stem cellsCD73AKT signalingLenvatinib resistance |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiao-Lu Ma Bo Hu Wei-Guo Tang Su-Hong Xie Ning Ren Lin Guo Ren-Quan Lu |
spellingShingle |
Xiao-Lu Ma Bo Hu Wei-Guo Tang Su-Hong Xie Ning Ren Lin Guo Ren-Quan Lu CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma Journal of Hematology & Oncology Hepatocellular carcinoma Cancer stem cells CD73 AKT signaling Lenvatinib resistance |
author_facet |
Xiao-Lu Ma Bo Hu Wei-Guo Tang Su-Hong Xie Ning Ren Lin Guo Ren-Quan Lu |
author_sort |
Xiao-Lu Ma |
title |
CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma |
title_short |
CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma |
title_full |
CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma |
title_fullStr |
CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma |
title_full_unstemmed |
CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma |
title_sort |
cd73 sustained cancer-stem-cell traits by promoting sox9 expression and stability in hepatocellular carcinoma |
publisher |
BMC |
series |
Journal of Hematology & Oncology |
issn |
1756-8722 |
publishDate |
2020-02-01 |
description |
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/P110β 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 3β. 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. |
topic |
Hepatocellular carcinoma Cancer stem cells CD73 AKT signaling Lenvatinib resistance |
url |
https://doi.org/10.1186/s13045-020-0845-z |
work_keys_str_mv |
AT xiaoluma cd73sustainedcancerstemcelltraitsbypromotingsox9expressionandstabilityinhepatocellularcarcinoma AT bohu cd73sustainedcancerstemcelltraitsbypromotingsox9expressionandstabilityinhepatocellularcarcinoma AT weiguotang cd73sustainedcancerstemcelltraitsbypromotingsox9expressionandstabilityinhepatocellularcarcinoma AT suhongxie cd73sustainedcancerstemcelltraitsbypromotingsox9expressionandstabilityinhepatocellularcarcinoma AT ningren cd73sustainedcancerstemcelltraitsbypromotingsox9expressionandstabilityinhepatocellularcarcinoma AT linguo cd73sustainedcancerstemcelltraitsbypromotingsox9expressionandstabilityinhepatocellularcarcinoma AT renquanlu cd73sustainedcancerstemcelltraitsbypromotingsox9expressionandstabilityinhepatocellularcarcinoma |
_version_ |
1724281867770789888 |