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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Silencing LINC00987 ameliorates adriamycin resistance of acute myeloid leukemia via miR-4458/HMGA2 axis
Yue Liu1, Xiao-Ya Zhu2, Li-Li Liao3
1Institute of Biomedicine, Department of Cellular Biology, Jinan University, No. 601 Huangpu Ave West, Shipai Street, Tianhe District, Guangzhou, Guangdong, 510632, China.
Background:
Most patients with acute myeloid leukemia (AML) eventually develop drug resistance, leading to a poor prognosis. Dysregulated long gene non coding RNAs (lincRNAs) have been implicated in chemoresistance in AML. Unfortunately, the effects of lincRNAs which participate in regulating the Adriamycin (ADR) resistance in AML cells remain unclear. Thus, the purpose of this study is to determine LINC00987 function in ADR-resistant AML.
Methods:
In this study, ADR-resistant cells were constructed. LINC00987, miRNAs, and HMGA2 mRNA expression were measured by qRT-PCR. P-GP, BCRP, and HMGA2 protein were measured by Western blot. The proliferation was analyzed by MTS and calculated IC50. Soft agar colony formation assay and TUNEL staining were used to analyze cell colony formation and apoptosis. Xenograft tumor experiment was used to analyze the xenograft tumor growth of ADR-resistant AML.
Results:
We found that higher expression of LINC00987 was observed in AML patients and associated with poor overall survival in AML patients. LINC00987 expression was increased in ADR-resistant AML cells, including ADR/MOLM13 and ADR/HL-60 cells. LINC00987 downregulation reduces ADR resistance in ADR/MOLM13 and ADR/HL-60 cells in vitro and in vivo, while LINC00987 overexpression enhanced ADR resistance in MOLM13 and HL-60 cells. Additionally, LINC00987 functions as a competing endogenous RNA for miR-4458 to affect ADR resistance in ADR/MOLM13 and ADR/HL-60 cells. HMGA2 is a target of miR-4458. LINC00987 knockdown and miR-4458 overexpression reduced HMGA2 expression. HMGA2 overexpression enhanced ADR resistance, which reversed the function of LINC00987 silencing in suppressing ADR resistance of ADR/MOLM13 and ADR/HL-60 cells.
Conclusions:
Downregulation of LINC00987 weakens ADR resistance by releasing miR-4458 to deplete HMGA2 in ADR/MOLM13 and ADR/HL-60. Therefore, LINC00987 may act as the therapeutic target for treating chemoresistant AML.
Insights
LINC00987 promotes Adriamycin resistance in acute myeloid leukemia (AML) by sponging miR-4458 and upregulating HMGA2. Downregulating LINC00987 may offer a new therapeutic strategy for chemoresistant AML.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Acute myeloid leukemia (AML) frequently develops drug resistance, leading to poor patient outcomes.
- Long non-coding RNAs (lincRNAs) are increasingly recognized for their role in chemoresistance within AML.
- The specific function of lincRNAs in Adriamycin (ADR) resistance in AML remains largely unknown.
Purpose of the Study:
- To investigate the role of LINC00987 in Adriamycin (ADR) resistance in acute myeloid leukemia (AML) cells.
- To elucidate the molecular mechanism by which LINC00987 influences chemoresistance in AML.
Main Methods:
- Construction of ADR-resistant AML cell lines.
- Quantification of LINC00987, miRNA, and HMGA2 mRNA expression via qRT-PCR.
- Assessment of P-GP, BCRP, and HMGA2 protein levels using Western blot.
- Evaluation of cell proliferation, IC50, colony formation, apoptosis, and xenograft tumor growth.
Main Results:
- LINC00987 expression is elevated in AML patients and correlates with poorer survival.
- LINC00987 expression significantly increases in ADR-resistant AML cells.
- LINC00987 downregulation reduces ADR resistance in vitro and in vivo, while overexpression enhances it.
- LINC00987 acts as a competing endogenous RNA for miR-4458, leading to HMGA2 upregulation and increased ADR resistance.
Conclusions:
- LINC00987 downregulation mitigates ADR resistance by enabling miR-4458 to reduce HMGA2 levels.
- LINC00987 emerges as a potential therapeutic target for overcoming chemoresistance in AML.
- Targeting the LINC00987/miR-4458/HMGA2 axis could be a promising strategy for treating drug-resistant AML.
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