MicroRNA-451-modulated hnRNP A1 takes a part in granulocytic differentiation regulation and acute myeloid leukemia.

Li Song,Rui Su,Ming-Tai Chen,Jia Yu,Jia-Nan Gong,Yan-Ni Ma,Jun-Wu Zhang,Chao Shen,Xiao-Shuang Wang,Hai-Shuang Lin,Hua Han

doi:10.18632/oncotarget.19325

Abstract

Myelopoiesis is under the control of a complex network containing various regulation factors. Deregulation of any important regulation factors may result in serious consequences including acute myeloid leukemia (AML). In order to find out the genes that may take a part in AML development, we analyzed data from AML cDNA microarray (GSE2191) in the NCBI data pool and noticed that heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is abnormally over-expressed in AML patients. Then we investigated the function and mechanisms of hnRNP A1 in myeloid development. A gradually decreased hnRNP A1 expression was detected during granulocytic differentiation in ATRA-induced-NB4 and HL-60 cells and cytokines-induced hematopoietic stem and progenitor cells. By function-loss and winning experiments we demonstrated hnRNP A1's inhibition role via inhibiting expression of C/EBPα, a key regulator of granulocytic differentiation, in the granulocytic differentiation. During granulocytic differentiation the decrease of hnRNP A1 reduces inhibition on C/EBPα expression, and the increased C/EBPα promotes the differentiation. We also demonstrated that miR-451 promotes granulocytic differentiation via targeting to and down-regulating hnRNP A1, and hnRNP A1 positively regulates c-Myc expression. Summarily, our results revealed new function and mechanisms of hnRNP A1 in normal granulocytiesis and the involvement of a feed-back loop comprising c-Myc, miR-451 and hnRNP A1 in AML development.

Highlights

Heterogeneous nuclear ribonucleoprotein A1 is an important RNA binding protein that exerts its activities on a wide range of cellular processes [1]
The results are presented as a table of genes ordered by significance (Supplementary Table 1). From these results we noticed that hnRNP A1 is abnormally up-regulated in the acute myeloid leukemia (AML) patients compared to the health controls (Figure 1A), which suggested that hnRNP A1 might function as an oncogene in AML development
Decreased hnRNP A1 expression was detected during all-trans-retinoic acid (ATRA)induced granulocytic differentiation in NB4 and HL-60 cells

Summary

Introduction

Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is an important RNA binding protein that exerts its activities on a wide range of cellular processes [1]. In breast cancer [8, 9], gliomas [10], colorectal cancer [11], and lung cancer [12, 13], the expression of hnRNP A1 abnormally increased. It can promote tumor invasion and connect to poor prognosis in hepatocellular carcinoma [14] and is correlated with the pathogenesis and prognosis of erythroleukemia [15] and prostate cancer [16]. Human Let-7a [25] and IL-6 [26], which play roles in the regulation of cell pluripotency maintenance and differentiation, are regulated by hnRNP A1

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Results

Conclusion