MicroRNA-100/99a, deregulated in acute lymphoblastic leukaemia, suppress proliferation and promote apoptosis by regulating the FKBP51 and IGF1R/mTOR signalling pathways

Abstract

Background:MicroRNAs alter multiple cell processes and thus influence tumour carcinogenesis and progression. MiR-100 and miR-99a have been reported to be aberrantly expressed in acute leukaemia. In this study, we focused on their functions in acute lymphoblastic leukaemia (ALL) and the molecular networks in which they are involved.Methods:MiR-100 and miR-99a expression levels were measured in acute leukaemia patients by qRT–PCR. Kaplan−Meier analysis and log-rank tests were used to calculate the survival rate. Three human ALL cell lines were studied. Apoptosis and proliferation were analysed using siRNA transfection, western blot and flow cytometry.Results:In vivo, miR-100 and miR-99a were down-regulated in 111 ALL patients, especially in high-risk groups; their expression levels were correlated with the patient's 5-year survival. In vitro, the restoration of miR-100 and miR-99a in ALL cells suppressed cell proliferation and increased dexamethasone-induced cell apoptosis. Ectopic expression of miR-100 and miR-99a targeted FK506-binding protein 51 (FKBP51) and, in turn, influenced glucocorticoid receptor (GR) activity. Meanwhile, miR-100 and miR-99a overexpression inhibited the expression of IGF1R and mTOR and their downstream oncogene MCL1.Conclusion:MiR-100 and miR-99a have critical roles in altering cellular processes by targeting both the FKBP51 and IGF1R/mTOR signalling pathways in vitro and might represent a potential novel strategy for ALL treatment.

Multiple Roles of MicroRNA-100 in Human Cancer and its Therapeutic Potential

“…Previously, Zheng and his colleague reported that miR-100 was up-regulated in childhood AML and overexpression of miR-100 inhibited the differentiation of granulocyte and monocyte cells and promoted cell survival [94]. On the contrary, they found that miR-100 was down-regulated in childhood ALL and ectopic expression of miR-100 inhibited cell proliferation and enhanced dexamethasone-induced cell apoptosis [80]. Also, Leite's study showed that the expression of miR-100 was reduced during the transition from high grade localized prostate cancer to metastasis [68].…”

Identification of highly expressed host microRNAs that respond to white spot syndrome virus infection in the Pacific white shrimp Litopenaeus vannamei (Penaeidae)

“…Interestingly, the most highly expressed miRNA, lvamiR-100, exhibited a particularly high expression level. lva-miR-100 belongs to the miR-99 family, and it has been demonstrated that miR-99 family members regulate cell proliferation, cell migration, and AKT/m TOR signaling (Jin et al, 2013;Li et al, 2013). Considering the particularly high expression of lva-miR-100 in L. vannamei, we suggest that miR-99 family members may have important biological functions in shrimp.…”

A novel small-molecule compound diaporine A inhibits non-small cell lung cancer growth by regulating miR-99a/mTOR signaling

“…MiR-99a is downregulated in several cancer cell lines and solid tumors including acute lymphoblastic leukemia, 34 hepatocellular carcinoma, 33 prostate cancer, 35 endometrioid endometrial cancer, 32 and lung cancer, 12 but the mechanisms responsible for its downregulation in tumors are still unknown. By overexpression or inhibition, researchers found that miR-99a could suppress cell proliferation, 35 induce G 1 -phase cell cycle arrest, 36 and promote apoptosis.…”

“…By overexpression or inhibition, researchers found that miR-99a could suppress cell proliferation, 35 induce G 1 -phase cell cycle arrest, 36 and promote apoptosis. 34 The biological targets of miR-99a have been partially identified as FGFR3, 37 FKBP51, and IGF1R/mTOR signaling pathways. 34,38 However, little is known about the upstream of miR-99a or what can regulate miR-99a expression.…”

“…34 The biological targets of miR-99a have been partially identified as FGFR3, 37 FKBP51, and IGF1R/mTOR signaling pathways. 34,38 However, little is known about the upstream of miR-99a or what can regulate miR-99a expression. To our knowledge, D261 is the first natural agent that can alter miR-99a expression in NSCLC cells.…”