Over the past several decades, great improvement has been made in understanding the pathogenesis of ALL. However, the detailed mechanisms underlying the malignant progression and recurrence of ALL cells remain not entirely clear. This study focused on a novel modulatory pathway MAGI2-AS3/miR-452-5p/FOXN3 during ALL development. We demonstrated that MAGI2-AS3 and FOXN3 were up-regulated, and miR-345-5p was down-regulated in ALL specimens and cells. MAGI2-AS3 sequestered miR-345-5p to facilitate FOXN3 expression, which contributed to ALL cell growth, apoptosis inhibition and glycolysis.
MAGI2-AS3, located on chromosome 7q21.11, is reported to modulate the progression of a series of malignancies[21]. MAGI2-AS3 affects the malignant properties of tumors through various mechanisms, such as ceRNAs, epigenomic or transcriptional regulations. For instance, MAGI2-AS3 could favor colorectal cancer cell growth and metastasis by sponging miR-3163[22]. MAGI2-AS3 increased MAGI2 level via suppressing DNA demethylation of MAGI2, delaying proliferation and migration of breast cancer cells[23]. Additionally, MAGI2-AS3 transcriptionally down-regulated HOXB7, which slowed the development of esophageal cancer[24]. Recently, the carcinogenic role of MAGI2-AS3 in acute myeloid leukemia has been identified[12]. According to our data, MAGI2-AS3 was strikingly lowly expressed in ALL clinical samples and cells. Furthermore, enforced expression of MAGI2-AS3 suppressed proliferation and apoptosis inhibition of ALL cells. Thus, our study was the first to reveal that MAGI2-AS3 functioned as a tumor suppressor lncRNA during ALL development.
Glucose metabolic reprogramming has been considered as a striking hallmark of tumors[25]. Being different from healthy cells, tumor cells are prone to metabolize glucose by glycolysis, leading to enhanced glucose uptake and lactate production[26]. Glycolysis confers the malignant phenotypes as well as drug resistance of ALL cells[27]. HK2 has been recognized as a specific enzyme catalyzing glycolysis process[28]. In this study, we demonstrated that MAGI2-AS3 overexpression restrained glucose uptake, lactate production, ATP level, as well as reduced HK2 expression in ALL cells. Therefore, repression of glycolysis was involved in the anti-cancer effect of MAGI2-AS3 in ALL.
To further probe the regulatory mechanisms of MAGI2-AS3 in ALL, we focused on the ceRNA hypothesis that cytoplasmic lncRNA adsorbs miRNA to release the expression of miRNA target gene. miR-452-5p is a crucial member of miRNA, and its involvement in cancers has been reported. The interaction between miR-452-5p and lncRNAs has been identified by various studies. Song et al showed that lncRNA SOX2-OT facilitated the tumorigenesis of prostate cancer by suppressing miR-452-5p expression[29]. Zhu et al indicated that LINC00052 reversed the malignant behavior of hepatocellular carcinoma cells via sponging miR-452-5p[30]. Our data showed that miR-452-5p was aberrantly highly expressed in ALL, which was negatively correlated with MAGI2-AS3 level. Moreover, the direct binding relationship between MAGI2-AS3 and miR-452-5p was validated. These data indicated that MAGI2-AS3 down-regulation resulted in abnormal higher miR-452-5p expression, which contributed to ALL progression.
As comprehensively reported by previous researches, FOXN3 can function as a tumor suppressor gene in multiple tumors. FOXN3 could repress the growth and metastasis of colon cancer cells via inactivating β-catenin/TCF pathway[31]. More importantly, a decreased transcript level of FOXN3 was verified in ALL cells[19]. Consistent with previous observations, we demonstrated that FOXN3 down-regulated in ALL patients and cells. In addition, FOXN3 was validated to be a target of miR-452-5p. FOXN3 level could be enhanced by MAGI2-AS3, while reduced by miR-452-5p. The inhibition of MAGI2-AS3 in ALL cell growth, apoptosis suppression and glycolysis could be reversed by silencing of FOXN3. Collectively, MAGI2-AS3/miR-452-5p/FOXN3 axis was implicated in the pathogenesis of ALL.