MicroRNA-125b promotes tumor growth and suppresses apoptosis by targeting DRAM2 in retinoblastoma

Abstract

Purpose It is known that microRNAs (miRNAs) are a class of small, noncoding RNAs that act as key regulators in various physiological and pathological processes. However, the regulatory mechanisms involving miRNAs in retinoblastoma (RB) remain largely unknown. The miRNA miR-125b is dysregulated in various human cancers such as breast cancer, human hepatocellular carcinoma, ovarian cancer, and colorectal cancer. However, the significance of miR-125b in RB has not been sufficiently investigated. Our objective was to explore the role of the miR-125b in RB. Methods In this study, we measured miR-125b levels using real-time polymerase chain reaction in human RB cell lines, including HXO-Rb44, Y79, SO-RB50, and the normal human retinal pigment epithelial cell line ARPE-19; a total of 38 pairs of primary RB tissues and adjacent noncancerous tissues were also measured. In addition, overexpression of miR-125b in RB cell lines was performed to determine the role of miR-125b in RB. Results We found that miR-125b is significantly upregulated in RB, and closely associated with tumor cell proliferation and apoptosis. In addition, overexpression of miR-125b apparently promotes RB cell proliferation and migration in vitro. Gain-offunction in vitro experiments further showed that the miR-125b mimic significantly suppressed RB cell apoptosis. A subsequent dual-luciferase reporter assay identified the suppressor gene DRAM2 as direct target of miR-125b.Conclusions Our data collectively demonstrate that miR-125b is a suppressor gene miRNA that can promote RB cell proliferation and migration by downregulating the suppressor gene DRAM2, indicating that miR-125b may represent a new potential diagnostic and therapeutic target for RB treatment.

<p>The Emerging Roles of miR-125b in Cancers</p>

“…In RB and GMB, miR is significantly upregulated, and then it apparently suppresses DRAM2, p53, and P38. 15,16,65 DRAM2 is a crucial component of the p53 signaling pathway, and the induction of autophagy by DRAM is a potential mechanism contributing to cell death. DRAM2 encodes a transmembrane lysosomal protein that is thought to play a key role in autophagy initiation, and the autophagy induced by DRAM2 is an underlying mechanism of p53-mediated cell death.…”

“…DRAM2 encodes a transmembrane lysosomal protein that is thought to play a key role in autophagy initiation, and the autophagy induced by DRAM2 is an underlying mechanism of p53-mediated cell death. 15,65 Both p53 and p38MAPK are direct target genes of miR-125b, and p53 is known to activate the apoptotic pathway, while p38MAPK can induce mitochondrial apoptosis. 16, 66 Zheng et al reported that miR-125b expression was significantly higher in poorly differentiated NSCLC cells with high metastatic potential and that it reduced the level of TP53INP1.…”

Expression Profiling Analysis Reveals Key MicroRNA–mRNA Interactions in Early Retinal Degeneration in Retinitis Pigmentosa

“…Given the established role played by miRNAs in retinal development and survival, 1 , 2 as well as in a growing number of distinct diseases, 7 – 10 , 12 , 14 , 15 , 19 , 22 , 39 , 40 we hypothesized that alterations in miRNA expression might contribute to the molecular mechanisms involved in the physiopathology of RP. To provide experimental evidence to support the possible association between miRNA expression and retinal degeneration, miRNA expression profile in retinas from the rd10 RP mouse model 27 – 29 and C57BL/6J wild-type mice were compared by microarray and RT-qPCR analysis in the early stages of retinal degeneration.…”

“…Indeed, there is a growing list of miRNAs that are known to be differentially expressed in retinal disorders in humans and in animal models, including miR-9, miR-34a, miR-125b, and miR-155 in macular degeneration, 18 , 19 miR-146a and miR-195 in diabetic retinopathy, 20 , 21 and miR-125a and miR-17 in retinoblastoma. 22 , 23 In addition, a group of antiapoptotic miRNAs (miR-155, miR-146a, and miR-29b) was found to be differentially expressed during the chronic cell death stage in canine models of retinal degeneration. 24 Furthermore, a common pattern of aberrantly expressed miRNAs was described in four murine models of RP where miR-1, miR-133, and miR-142 were upregulated despite different genes ( Rho and Rds ) and inheritance patterns being involved.…”

Downregulation of microRNA-224-3p Hampers Retinoblastoma Progression via Activation of the Hippo-YAP Signaling Pathway by Increasing LATS2

“…For instance, miR-124 and miR-34a act as tumor suppressors 8,9 while miR-125b functions as a tumor promoter. 10 The carcinogenic role of miR-224-3p has also been identified in human cancer. Although the involvement of miR-224-3p in the progression of retinoblastoma remains unknown, ectopic expression of miR-224-3p has been detected in high-risk human papillomavirus (HPV)-positive cervical cancer cells, and its overexpression has been proven to inhibit autophagy in HPV-infected cells.…”