Increased Expression of Micro-RNA-23a Mediates Chemoresistance to Cytarabine in Acute Myeloid Leukemia

被引：19

作者：

Hatzl, Stefan ^{[1
]}

Perfler, Bianca ^{[1
]}

Wurm, Sonja ^{[1
]}

Uhl, Barbara ^{[1
]}

Quehenberger, Franz ^{[2
]}

Ebner, Susanne ^{[3
]}

Troppmair, Jakob ^{[3
]}

Reinisch, Andreas ^{[1
]}

Woelfler, Albert ^{[1
]}

Sill, Heinz ^{[1
]}

Zebisch, Armin ^{[1
,4
]}

机构：

[1] Med Univ Graz, Div Hematol, Auenbruggerpl 38, A-8036 Graz, Austria

[2] Med Univ Graz, Inst Med Informat Stat & Documentat, A-8036 Graz, Austria

[3] Med Univ Innsbruck, Dept Visceral Transplant & Thorac Surg, Daniel Swarovski Res Lab, A-6020 Innsbruck, Austria

[4] Med Univ Graz, Otto Loewi Res Ctr Vasc Biol Immunol & Inflammat, Div Pharmacol, Univ Pl 4, A-8010 Graz, Austria

来源：

CANCERS | 2020年 / 12卷 / 02期

基金：

奥地利科学基金会;

关键词：

micro-RNA-23a; acute myeloid leukemia; therapeutic resistance; cytarabine; KINASE INHIBITOR PROTEIN; STEM-CELLS; MIR-23A PROMOTES; REAL-WORLD; CANCER; THERAPY; MICRORNAS; MICROENVIRONMENT; CHEMOTHERAPY; PATHOGENESIS;

D O I：

10.3390/cancers12020496

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Resistance to chemotherapy is one of the primary obstacles in acute myeloid leukemia (AML) therapy. Micro-RNA-23a (miR-23a) is frequently deregulated in AML and has been linked to chemoresistance in solid cancers. We, therefore, studied its role in chemoresistance to cytarabine (AraC), which forms the backbone of all cytostatic AML treatments. Initially, we assessed AraC sensitivity in three AML cell lines following miR-23a overexpression/knockdown using MTT-cell viability and soft-agar colony-formation assays. Overexpression of miR-23a decreased the sensitivity to AraC, whereas its knockdown had the opposite effect. Analysis of clinical data revealed that high miR-23a expression correlated with relapsed/refractory (R/R) AML disease stages, the leukemic stem cell compartment, as well as with inferior overall survival (OS) and event-free survival (EFS) in AraC-treated patients. Mechanistically, we demonstrate that miR-23a targets and downregulates topoisomerase-2-beta (TOP2B), and that TOP2B knockdown mediates AraC chemoresistance as well. Likewise, low TOP2B expression also correlated with R/R-AML disease stages and inferior EFS/OS. In conclusion, we show that increased expression of miR-23a mediates chemoresistance to AraC in AML and that it correlates with an inferior outcome in AraC-treated AML patients. We further demonstrate that miR-23a causes the downregulation of TOP2B, which is likely to mediate its effects on AraC sensitivity.

引用

页数：19