MiR-744 functions as a proto-oncogene in nasopharyngeal carcinoma progression and metastasis via transcriptional control of ARHGAP5

Abstract

Nasopharyngeal carcinoma (NPC) is a highly invasive and metastasis-prone epithelial cancer. The paucity of effective treatment strategies for recurrent and metastatic NPC is the major cause for stagnating survival rate of NPC. Therefore, it's urgent to understand the molecular mechanisms underlying NPC progression and identify novel avenues for targeted therapy. It has emerged recently that microRNAs are potential pro-tumorigenic or tumor-suppressive factors that participate in oncogenesis. In this study, we found that miR-744 expression was upregulated in NPC specimens compared to nasopharyngeal epithelium (NPE) tissue, and miR- 744 upregulation was significantly associated with TNM stage, tumorigenesis and metastasis. Functional studies revealed that miR-744 acts as a novel tumor promotor in NPC. Moreover, we determined that miR-744 targets ARHGAP5 (Rho GTPase activating protein 5), a protumorigenic gene, by directly interacting with its promoter and thereby regulating its expression at transcriptional level. Reintroduction of ARHGAP5 resembled the effects of miR-744 and silencing of ARHGAP5 clearly abrogated miR-744-induced enhancement of cell migration and invasion. High level of ARHGAP5 was positively correlated with that of miR-744 and with advanced stages of NPC, as well as with lymph node metastasis. Taken together, these data reveal for the first time that miR-744 exerts its proto-oncogenic function by directly targeting ARHGAP5 promoter. This newly identified miR-744/ARHGAP5 pathway provides further insight into the progression and metastasis of NPC and indicates potential novel therapeutic targets for NPC.

MicroRNA‑744 suppresses cell proliferation and invasion of papillary thyroid cancer by directly targeting NOB1

“…miR-744 upregulation inhibits cell proliferation and promotes cell cycle arrest in hepatocellular carcinoma (31). On the contrary, miR-744 serves oncogenic roles in prostate cancer (28), laryngeal squamous cell carcinoma (29), pancreatic cancer (27) and nasopharyngeal carcinoma (32). These findings indicate that the biological roles of miR-744 exhibit tissue specificity in tumorigenesis and tumour development.…”

“…miRNAs serve crucial roles in the regulation of their target genes (33). Numerous human genes, including Notch1 (17), B-cell lymphoma 2 (18), secreted frizzled-related protein 1 precursor (27), glycogen synthase kinase 3β (27), transducing like enhancer of split 2 (27), naked cuticle homolog 1 (28), programmed cell death 4 (29), phosphatase and tensin homolog (29), c-myc (31) and Rho GTPase activating protein 5 (32), have been identified as direct miR-744 targets. In the present study, NOB1 was predicted as a direct target gene of miR-744 in PTC.…”

miR‐346 promotes migration and invasion of nasopharyngeal carcinoma cells via targeting BRMS1

“…For example, miR‐497 was found to inhibit NPC cell proliferation and migration in vitro and xenograft tumor growth in vivo . miR‐744 shows the ability to promote NPC growth and metastasis . These studies pinpoint the importance of miRNAs in the pathogenesis of NPC.…”

MiR‐744‐3p regulates keratinocyte proliferation and differentiation via targeting KLLN in psoriasis

“…MiR‐744‐3p has been shown to regulate tumor development and growth in cell line by inducing cyclin B1 expression and functioned as a tumor promoter in nasopharyngeal carcinoma . Previous microarray studies have identified that miR‐744‐3p was up‐regulated in psoriasis .…”