Abstract
microRNAs (miRNA), as tumor suppressors or oncogenes, are involved in modulating cancer cell behavior, including cell proliferation and apoptosis. The miR-140-5p acts as a tumor suppressor in several tumors, but the role of miR-140-5p in chronic myeloid leukemia (CML) remains unclear. Here, we investigated the suppression of miR-140-5p in CML patients and CML cell lines using quantitative PCR (qPCR) and fluorescence in situ hybridization (FISH). Overexpression miR-140-5p in CML cells significantly inhibited cell proliferation as revealed by the CCK-8 assay and promoted cell apoptosis as revealed by flow cytometry. Moreover, the sine oculis homeobox 1 (SIX1) gene had been confirmed as a direct target of miR-140-5p using bioinformatics analysis and luciferase reporter assays. Overexpression of miR-140-5p decreased the SIX1 protein level in CML cells. SIX1 mRNA and protein levels were significantly up-regulated in CML patients and CML cell lines. Knockdown of SIX1 expression significantly inhibited CML cell proliferation and promoted cell apoptosis. Furthermore, SIX1 as a transcriptional factor positively regulated pyruvate kinase isozyme type M2 (PKM2) expression and played an important role in the Warburg effect. In addition, these findings indicated that miR-140-5p functions as a tumor suppressor and plays a critical role in CML cell apoptosis and metabolism by targeting SIX1. Moreover, the miR-140-5p/SIX1 axis may be a potential therapeutic target in CML.
Highlights
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by fusion of the Abelson murine leukemia (ABL) gene on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22, which results in the expression of an oncoprotein, termed BCR-ABL1 tyrosine kinase [1–3]
The results showed that miR-140-5p expression was down-regulated in both CML cell lines (Figure 1C)
Since we found that miR-140-5p was down-regulated in both CML patients’ peripheral blood mononuclear cells (PBMCs) and CML cell lines, we investigated whether miR-140-5p played a role in CML cells
Summary
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by fusion of the Abelson murine leukemia (ABL) gene on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22, which results in the expression of an oncoprotein, termed BCR-ABL1 tyrosine kinase [1–3]. MiRNAs are small non-coding RNAs which negatively regulate gene expression by targeting mRNAs at the UTR. It has previously been demonstrated that miRNAs serve important roles in numerous biological processes, including cell growth, cell cycle progression, apoptosis, migration, and invasion [5]. Dysregulated miRNAs may act as either oncogenes or tumor suppressors, depending on the biological function of their targets [6]. Accumulating evidence has suggested that miRNAs play an important role in CML development and progression. Certain miRNAs, such as miR-362-5p [7], miR-320a [8], miR-15-5p [9] and miR-486 [10], have been confirmed to act as oncogenes or tumor
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