Oncogene database

406911

MIR125B1

microRNA 125b-1;MIR125B1;microRNA 125b-1

hsa-mir-125b-1

11q24.1

ncRNA

Although prostate cancer (CaP) is the most frequently diagnosed malignant tumor and the second leading cause of cancer deaths in American men, the mechanisms explaining the development and progression of CaP remain largely unknown. Recent studies have shown that some aberrantly expressed microRNAs (miRNAs) are involved in tumorigenesis. Although aberrant expression of certain miRNAs has been discovered in CaP, their function in this disease has not yet been defined. In this study, we found differential expression of miR-125b in androgen-dependent and independent CaP cells, as well as in benign and malignant prostate tissues. Furthermore, androgen signaling was able to up-regulate the expression of miR-125b. In addition, transfection of synthetic miR-125b stimulated androgen-independent growth of CaP cells and down-regulated the expression of Bak1. Our results suggest that miR-125b acts as an oncogene, contributing to the pathogenesis of CaP.

The MUC1 oncoprotein is overexpressed in most human breast cancers by mechanisms that are incompletely understood. The microRNA, miR-125b, is downregulated in breast cancer cells. The present studies demonstrate that the MUC1 3 UTR contains a site for binding of the miR-125b seed region. The results show that the MUC1 3 UTR suppresses luciferase expression and that this effect is abrogated by mutation or deletion of the miR-125b binding site. expression of an anti-sense miR-125b in BT-549 breast cancer cells was associated with induction of MUC1 protein, but not MUC1 mRNA, levels. The anti-sense miR-125b also increased BT-549 cell growth by a MUC1-dependent mechanism. In addition, overexpression of exogenous miR-125b downregulated MUC1 protein, and not MUC1 transcripts, in ZR-75-1 breast cancer cells. Silencing of MUC1 in ZR-75-1 cells with a siRNA has been shown to promote DNA damage-induced apoptosis. In concert with these observations, miR-125b-induced decreases in MUC1 levels increased the apoptotic response of ZR-75-1 cells to cisplatin treatment. These findings indicate that miR-125b suppresses translation of the MUC1 oncoprotein and that miR-125b thereby functions as a tumor suppressor in breast cancer cells.

BACKGROUND: Increasing evidence demonstrates that aberrantly regulated microRNAs (miRNAs) contribute to the initiation and progression of human cancer. We previously have demonstrated that miR-125b stimulated the growth of prostate cancer (CaP) cells. In this study, we further determined the influence of miR-125b on the pathogenesis of CaP. METHODS: To evaluate the effect of miR-125b on xenograft tumor growth, male athymic mice were subcutaneously injected with PC-346C-miR-125b cells that stably overexpressed miR-125b. Potential direct target transcripts of miR-125b were identified using a bioinformatics approach and three miR-125b targeted molecules were confirmed by means of biochemical analyses. RESULTS: Enforced expression of miR-125b promoted tumor growth in both intact and castrated male nude mice. In an effort to define the molecular mechanism(s) mediating its tumor growth properties, we found that miR-125b directly targets eight transcripts, including three key pro-apoptotic genes: p53, Puma, and Bak1. Increasing the abundance of miR-125b resulted in a dramatic decrease in the levels of these three proteins in CaP cells. A direct repressive effect on each of these was supported by the ability of miR-125b to significantly reduce the activity of luciferase reporters containing their 3 -untranslated regions of each gene encompassing the miR-125b-binding sites. Additionally, we found that repression of miR-125b activity was able to sensitize CaP cells to different therapeutic interventions. CONCLUSION: Data obtained in this study demonstrate that miR-125b promotes growth of prostatic xenograft tumors by down-regulating three key pro-apoptotic genes. This suggests that miR-125b is oncogenic and makes it an attractive therapeutic target in CaP.

MicroRNA miR-125b has been implicated in several kinds of leukemia. The chromosomal translocation t(2;11)(p21;q23) found in patients with myelodysplasia and acute myeloid leukemia leads to an overexpression of miR-125b of up to 90-fold normal. Moreover, miR-125b is also up-regulated in patients with B-cell acute lymphoblastic leukemia carrying the t(11;14)(q24;q32) translocation. To decipher the presumed oncogenic mechanism of miR-125b, we used transplantation experiments in mice. ALL mice transplanted with fetal liver cells ectopically expressing miR-125b showed an increase in white blood cell count, in particular in neutrophils and monocytes, associated with a macrocytic anemia. Among these mice, half died of B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, or a myeloproliferative neoplasm, suggesting an important role for miR-125b in early hematopoiesis. Furthermore, coexpression of miR-125b and the BCR-ABL fusion gene in transplanted cells accelerated the development of leukemia in mice, compared with control mice expressing only BCR-ABL, suggesting that miR-125b confers a proliferative advantage to the leukemic cells. Thus, we show that overexpression of miR-125b is sufficient both to shorten the latency of BCR-ABL-induced leukemia and to independently induce leukemia in a mouse model.

The microRNA miR-125b is dysregulated in various human cancers but its underlying mechanisms of action are poorly understood. Here, we report that miR-125b is downregulated in invasive breast cancers where it predicts poor patient survival. Hypermethylation of the miR-125b promoter partially accounted for reduction of miR-125b expression in human breast cancer. Ectopic restoration of miR-125b expression in breast cancer cells suppressed proliferation, induced G(1) cell-cycle arrest in vitro, and inhibited tumorigenesis in vivo. We identified the ETS1 gene as a novel direct target of miR-125b. siRNA-mediated ETS1 knockdown phenocopied the effect of miR-125b in breast cell lines and ETS1 overexpression in invasive breast cancer tissues also correlated with poor patient prognosis. Taken together, our findings point to an important role for miR-125b in the molecular etiology of invasive breast cancer, and they suggest miR-125b as a potential theranostic tool in this disease.

B-cell acute lymphoblastic leukemia (B-ALL) is often associated with chromosomal translocations leading to the deregulation of proto-oncogenes. MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis. The microRNA, miR-125b-1, is overexpressed in B-ALL cases with the t(11;14)(q24;q32) translocation; therefore, we sought to determine the role of this microRNA in B-cell fate. We used murine pre-BI cells alongside murine and human leukemic B-cell lines to show that miR-125b expression enhances proliferation by targeting B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a, an activator of immunoglobulin heavy-chain transcription. Accordingly, this target gene was downregulated in B-ALL patients with the t(11;14)(q24;q32) translocation. Repression of Bright/ARID3a blocked differentiation and conferred a survival advantage to Ba/F3 cells under interleukin-3 starvation. In addition, overexpression of miR-125b protected pre-BI and leukemic B-cell lines from apoptosis by blockade of caspase activation by a mechanism that was independent of p53 and BAK1. In summary, miR-125b can act as an oncogene in B-ALL by targeting ARID3a and mediating its repression, thus leading to a blockage in differentiation, increased proliferation and inhibition of apoptosis.

Dysregulation of microRNA (miRNA) biogenesis is implicated in cancer development and progression. Dicer and Drosha are established regulators of miRNA biogenesis. In this study, we used a miRNA array to evaluate the miRNA expression profiles in nasopharyngeal carcinoma (NPC) samples. The significance analysis of microarrays showed a global downregulation of miRNA expression in NPC samples compared with normal nasopharyngeal epithelial tissues. Notably, miR-18a, a member of the oncogenic miR-17-92 cluster, was upregulated in the NPC samples and cell lines. Clinical parameter studies showed that higher levels of miR-18a correlated with NPC advanced stage, lymph node metastasis, Epstein-Barr virus infection and a higher death rate from NPC, indicating oncogenic roles in NPC development. The expression levels of miR-18a and Dicer1 were inversely related in NPC tissues. Further studies demonstrated that miR-18a negatively regulated Dicer1 by binding to the 3 untranslated regions of Dicer1. In vitro and in vivo biological function assays showed that miR-18a promoted the growth, migration and invasion of NPC cells by regulating Dicer1 expression, which caused the global downregulation of miRNA expression levels including miR-200 family and miR-143. Furthermore, we found that the epithelial mesenchymal transition marker E-cadherin and the oncogene K-Ras were aberrantly expressed after miR-18a transduction, and these alterations were directly induced by downregulation of the miR-200 family and miR-143. Collectively, our findings indicate that miR-18a plays an oncogenic role in the development of NPC by widespread downregulation of the miRNome and could be a potential therapeutic target for NPC.

Emerging evidence has demonstrated that microRNAs (miRNAs) can act as oncogenes or tumor suppressors to participate in cancer development. In this study, we found that miR-429 expression was up-regulated in human colorectal cancer (CRC) tissues, and the high miR-429 expression was significantly associated with tumor size, lymph node metastasis and poor prognosis. Functionally, miR-429 overexpression suppressed cell apoptosis by directly targeting SOX2 in HT-29 cells. Taken together, our data suggest for the first time that miR-429 could play an oncogenic role in the cellular processes of CRC and represent a novel prognostic biomarker for CRC.

MicroRNAs exert regulatory effects on a number of genes, thereby contributing to both physiological and pathological processes. The functions of microRNAs in tumorigenesis are becoming increasingly clear. In the present study, we investigated the role of microRNA-125b (miR125b), previously implicated in prostate and breast cancer, in gastric cancer, particularly regarding proliferation and apoptosis of gastric cancer cells. The expression of miR125b was measured in 50 samples of gastric cancer tissues and corresponding para-cancerous tissues by real-time PCR. The levels of miR125b expression in the gastric cancer tissues were significantly higher compared to the adjacent normal tissues (P<0.05). To begin to understand how the increased expression of miR125b may promote gastric cancer, the miR125b mimic was transfected into the gastric cancer cell line, HGC27, for the determination of proliferation (CCK8) and apoptosis (Annexin V) by flow cytometry. The results demonstrated that the proliferation significantly increased and apoptosis significantly decreased in the HGC27 cells following transfection with the miR125b mimic, compared to the untreated and scrambletreated controls (P<0.05). Thus, miR125b may act as an oncogene in gastric cancer by dysregulating gastric cell proliferation and apoptosis.

MicroRNA-27a (miR27a) is an oncogene that contributes to drug resistance in various types of cancer. However, the involvement of miR27a in gastric cancer has yet to be elucidated. Perifosine is an alkylphospholipid exhibiting antitumor activity as shown in both preclinical studies and clinical trials. The effects of perifosine on gastric cancer have yet to be determined. Therefore, this study was conducted to detect the role of miR27a and perifosine in human gastric cancer. miR27a was found to be expressed in human gastric cancer tissues and cell lines by quantitative reverse-transcription polymerase chain reaction (qRTPCR). The correlation between miR27a expression and clinicopathological characteristics of gastric cancer. We also explored the growth inhibitory effect of perifosine on human gastric cancer cells with or without cotargeting miR27a by sulforhodamine B (SRB) assay. The results showed that miR27a expression was significantly upregulated in gastric cancer tissues, compared with their nontumor adjacent tissues. High expression levels of miR27a were associated with poor tumor histological grade (P=0.037). MiR27a inhibitors suppressed the growth of MGC803 cells. Assay results showed that perifosine exerted its activity selectively on the AGS cell line and the growth inhibitory effect of perifosine was enhanced significantly in combination with miR27a inhibitors in MGC803 cells. In conclusion, our results demonstrated that miR27a may be a therapeutic target and potential prognostic biological marker in gastric cancer. MiR27a inhibitors alone or in combination with perifosine may be a novel therapeutic approach against gastric cancer.

Acute promyelocytic leukemia (APL) is characterized by the t(15;17)-associated PML-RARA fusion gene. We have previously found that MIR125B1 is highly expressed in patients with APL and may be associated with disease pathogenesis; however, the mechanism by which MIR125B1 exerts its oncogenic potential has not been fully elucidated. Here, we demonstrated that MIR125B1 abundance correlates with the PML-RARA status. MIR125B1 overexpression enhanced PML-RARA expression and inhibited the ATRA-induced degradation of the PML-RARA oncoprotein. RNA-seq analysis revealed a direct link between the PML-RARA degradation pathway and MIR125B1-arrested differentiation. We further demonstrated that the MIR125B1-mediated blockade of PML-RARA proteolysis was regulated via an autophagy-lysosomal pathway, contributing to the inhibition of APL differentiation. Furthermore, we identified DRAM2 (DNA-damage regulated autophagy modulator 2), a critical regulator of autophagy, as a novel target that was at least partly responsible for the function of MIR125B1 involved in autophagy. Importantly, the knockdown phenotypes for DRAM2 are similar to the effects of overexpressing MIR125B1 as impairment of PML-RARA degradation, inhibition of autophagy, and myeloid cell differentiation arrest. These effects of MIR125B1 and its target DRAM2 were further confirmed in an APL mouse model. Thus, MIR125B1 dysregulation may interfere with the effectiveness of ATRA-mediated differentiation through an autophagy-dependent pathway, representing a novel potential APL therapeutic target.