RETRACTED ARTICLE: Aberrant mannosylation profile and FTX/miR-342/ALG3-axis contribute to development of drug resistance in acute myeloid leukemia

Abstract

Drug-resistance is a major problem in acute myeloid leukemia (AML) chemotherapy. Aberrant changes in specific N-glycans have been observed in leukemia multidrug resistance (MDR). MicroRNAs (miRNAs) and long non coding RNAs (lncRNAs) act as key players in the development of AML resistance to chemotherapy. In the present study, the N-glycan profiles of membrane proteins were analyzed from adriamycin (ADR)-resistant U937/ADR cells and sensitive line U937 cells using mass spectrometry (MS). The composition profiling of high-mannose N-glycans differed in U937/ADR and U937 cell lines. Lectin microarray showed that the strong binding of membrane proteins was observed for MAN-M and ConA lectins, which were specific for mannose. These binding were also validated by flow cytometry. Importantly, the alteration of high-mannose N-glycan was further confirmed by detecting the enzyme level of ALG family. The altered level of ALG3 was found corresponding to the drug-resistant phenotype of AML cell lines both in vitro and in vivo. Mechanistically, miR-342 was found to be dysregulated and inversely correlated to ALG3 expression, targeting its 3′-UTR. LncRNA FTX was a direct target of miR-342 and positively modulated ALG3 expression by competitively binding miR-342 in AML cell lines. Functionally, we found that FTX directly interacted with miR-342 to regulate ALG3 expression and function, including ADR-resistant cell growth and apoptosis. The observation suggested that high-mannose N-glycans and mannosyltransferase ALG3 affected drug-resistance in AML cells. FTX/miR-342/ALG3 axis could potentially be used for the targets to overcome therapeutic resistance in AML.

Role of microRNAs, circRNAs and long noncoding RNAs in acute myeloid leukemia

“…In accord with Zhang et al's study, its expression was abnormally upregulated following doxorubicin-based chemotherapy and knockdown of UCA1 helped overcome chemoresistance in pediatric AML by suppressing glycolysis via binding miR-125a [189]. FTX is another lncRNA involved in chemoresistance, and it controlled the expression of ALG3 by binding miR-342 [193]. HOXA cluster antisense RNA 2 (HOXA-AS2) was significantly upregulated in BM samples from AML patients after treatment with adriamycin-based chemotherapy and sponged miR-520c-3p to contribute to chemoresistance in AML [195].…”

“…An oncogenic activity of lncRNA was also shown by HOTAIR that regulating the expression of c-Kit in AML cells through competitively binding miR-193a, an important tumor-suppressor miRNA to predict a poor clinical outcome [190]. HOTAIRM1, a lncRNA located in the HOXA genomic region, is related to myeloid differentiation which sequestered miR-20a, miR-106b and ↑in AML cell lines and CN-AML with biallelic CEBPA p27kip1 Role in promoting cells proliferation is to sequester hnRNP I to inhibit the expression of the cell cycle regulator p27kip1 [167] ↑in HL-60 and HL-60/ADR miR-125a Poor chemotherapy overcome [189] HOTAIR ↑in de novo AML patients miR-193a;c-Kit Increase AML cells proliferation, inhibited apoptosis and infiltration of leukemic blasts and number of AML cells colony formation, and shorten overall survival time [190] ↑in LSC p15 Promote the self-renewal of leukemia stem cells [191] CCAT1 ↑in HL60 and AML PB miR-155, c-Myc Upregulated c-Myc expression to increased cells proliferation and differentiation by its competing endogenous RNA (ceRNA) activity on miR-155 [192] FTX ↑in U937 and THP-1 miR-342, ALG3 Drug resistance [193] PANDAR ↑ANDARLINK Predict adverse prognosis in AML [181] HOXA-AS2 ↑in APL TRAIL-mediated pathway Lead to fine-tuning of apoptosis during ATRA-induced myeloid differentiation [194] ↑00PERLINK \l "_ENREF_200" \o "Zhao H, 2013 #197" or><adriamycin-based chemotherapy and in U/A and T/A cells miR-520c-3p/ S100A4 Axis Knockdown of lncRNA HOXA-AS2 inhibited ADR cell proliferation and chemoresistance of AML by the miR-520c-3p/ S100A4 Axis, and promoted apoptosis [195] HOTAIRM1 is an oncogenic lncRNA that upregulated c-Myc via its ceRNA activity on miR-155 to repress monocytic differentiation and promote cell growth [192]. The host non-coding transcript of miR-223 of linc-223, found downregulated in AML, is a functional lncRNA which regulated proliferation and differentiation of AML cells by binding miR-125-5p [203].…”

Novel variants and clinical symptoms in four new ALG3‐CDG patients, review of the literature, and identification of AAGRP‐ALG3 as a novel ALG3 variant with alanine and glycine‐rich N‐terminus

“…Recently and in line with this, ALG3 was also detected in cellular compartments apart from the ER, albeit the function of this protein in the cytosol and nucleus remains unclear (Hacker, Schultheiss, & Kurzik‐Dumke, ; Hacker, Schultheiss, Doring, & Kurzik‐Dumke, ). Furthermore, ALG3 seems to be associated with cervical cancer (Yang et al, ) and was also found to affect drug‐resistance in acute myeloid leukemia cells (Liu et al, ).…”

LncRNA FTX activates FOXA2 expression to inhibit non–small‐cell lung cancer proliferation and metastasis

“…Liu et al showed that FTX could compete with miR‐374a to inhibit epithelial‐mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells or inhibit their proliferation by binding to an E3 ligase MDM2 . Another study reported that FTX could activate ALG3 expression by eliminating interference of miR‐342 in acute myeloid leukaemia (AML) . However, whether lncRNA FTX participates in lung cancer progression and the possibility for FTX to act as a prognostic marker remain unclear.…”