Abstract
Although microRNAs have been elaborated to participate in various physiological and pathological processes, their functions in TRAIL resistance of acute myeloid leukemia (AML) remain obscure. In this study, we detected relatively lower expression levels of miR-424&27a in TRAIL-resistant and semi-resistant AML cell lines as well as newly diagnosed patient samples. Overexpression of miR-424&27a, by targeting the 3′UTR of PLAG1, enhanced TRAIL sensitivity in AML cells. Correspondingly, knockdown of PLAG1 sensitized AML cells to TRAIL-induced apoptosis and proliferation inhibition. We further found that PLAG1 as a transcription factor could reinforce Bcl2 promoter activity, causing its upregulation at the mRNA level. Both downregulated PLAG1 and elevated expression of miR-424&27a led to Bcl2 downregulation and augmented cleavage of Caspase8, Caspase3 and PARP in the presence of TRAIL. Restoration of Bcl2 could eliminate their effects on AML TRAIL sensitization. Overall, we propose that miR-424&27a and/or PLAG1 might serve as novel therapeutic targets in AML TRAIL therapy.
Highlights
Advances have been achieved in stemcell transplantation and standard chemotherapy of acute myeloid leukemia (AML) over the past few decades, chemoresistance and therapy-related mortality still play a vital role in therapeutic failure and poor outcomes [1,2,3]
Eventhough K562/A02 was semi-resistant to TRAIL, its miR-424 and miR-27a expression levels were only slightly higher than that of K562. These results suggest that decreased expression of miR-424 and miR-27a may contribute to TRAIL resistance of AML cells
We presented that miR-424 and miR-27a were downregulated in TRAIL-resistant AML cells
Summary
Advances have been achieved in stemcell transplantation and standard chemotherapy of acute myeloid leukemia (AML) over the past few decades, chemoresistance and therapy-related mortality still play a vital role in therapeutic failure and poor outcomes [1,2,3]. Compared with less invasive and/ or normal lung and liver cells, miR-221&222 were overexpressed in aggressive non-small cell lung cancer and hepatocarcinoma, which facilitated their functions on inducing TRAIL resistance by targeting PTEN and TIMP3 tumor suppressors [19]. These data indicate that miRNAs exerted effects on both AML development and TRAIL resistance of tumors. We proposed that upregulation of either miR-424 or miR-27a would improve TRAIL sensitivity of AML cells by transcriptional repression of Bcl through directly targeting the 3′UTR region of PLAG1
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