Genomic Loss ofmiR-486Regulates Tumor Progression and theOLFM4Antiapoptotic Factor in Gastric Cancer

Abstract

Purpose: MicroRNAs (miRNA) play pivotal oncogenic and tumor-suppressor roles in several human cancers. We sought to discover novel tumor-suppressor miRNAs in gastric cancer (GC).Experimental Design: Using Agilent miRNA microarrays, we compared miRNA expression profiles of 40 primary gastric tumors and 40 gastric normal tissues, identifying miRNAs significantly downregulated in gastric tumors.Results: Among the top 80 miRNAs differentially expressed between gastric tumors and normals (false discovery rate < 0.01), we identified hsa-miR-486 (miR-486) as a significantly downregulated miRNA in primary GCs and GC cell lines. Restoration of miR-486 expression in GC cell lines (YCC3, SCH and AGS) caused suppression of several pro-oncogenic traits, whereas conversely inhibiting miR-486 expression in YCC6 GC cells enhanced cellular proliferation. Array-CGH analysis of 106 primary GCs revealed genomic loss of the miR-486 locus in approximately 25% to 30% of GCs, including two tumors with focal genomic losses specifically deleting miR-486, consistent with miR-486 playing a tumor-suppressive role. Bioinformatic analysis identified the secreted antiapoptotic glycoprotein OLFM4 as a potential miR-486 target.Restoring miR-486 expression in GC cells decreased endogenous OLFM4 transcript and protein levels, and also inhibited expression of luciferase reporters containing an OLFM4 3 0 untranslated region with predicted miR-486 binding sites. Supporting the biological relevance of OLFM4 as a miR-486 target, proliferation in GC cells was also significantly reduced by OLFM4 silencing.Conclusions: miR-486 may function as a novel tumor-suppressor miRNA in GC. Its antioncogenic activity may involve the direct targeting and inhibition of OLFM4. Clin Cancer Res; 17(9); 2657-67. Ó2011 AACR.

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

“…Thus, our results together with previous studies suggest that miR-486 plays important roles in the progression of gliomas and that miR-486 expression may be useful for evaluating responses to therapy and surveillance of cancer outcomes. Interestingly, Oh et al [46] found that miR-486 is downregulated in gastric cancer and functions as a tumor suppressor. It has been proposed that a single miRNA may have several distinct functions in different cell types, which likely depends on the availability of specific targets or downstream effectors [47,48].…”

The combined use of miRNAs and mRNAs as biomarkers for the diagnosis of papillary thyroid carcinoma

“…A number of studies have demonstrated that miRNA expression is associated with cell proliferation, metastasis, invasion and and response to therapy (14)(15)(16)(17)(18)(19)(20). miRNA expression differs between cancer tissues and adjacent normal tissues in patients (21)(22)(23). These data indicate that miRNAs may be used as potential biomarkers for the diagnosis and prognosis of patients with cancer.…”

MicroRNA-486-5p enhances hepatocellular carcinoma tumor suppression through repression of IGF-1R and its downstream mTOR, STAT3 and c-Myc

“…It is important to note that miR-486-5p has also been found to be downregulated in numerous other cancer types, including pancreatic cancer (34), gastric cancer (29), osteosarcoma (35), and lung cancer (23), however, the mechanism of miR-486-5p downregulation in those types of cancer, including HCC, is largely unknown. According to previous studies, miR-486-5p downregulation in HCC tissues could be highly accredited to its chromosomal location (8p11.21), which is one of the most typically occurring genomic deletion regions, containing potential tumor suppressor genes (29).…”

“…According to previous studies, miR-486-5p downregulation in HCC tissues could be highly accredited to its chromosomal location (8p11.21), which is one of the most typically occurring genomic deletion regions, containing potential tumor suppressor genes (29). Epigenetic silencing …”

“…Due to the fact that miR-486-5p was found to have a dual action and can function as a cancer-specific tumor suppressor, as in gastric cancer (29) and non-small cell lung cancer (23,30), or as an aggressive oncomiR as in case of colorectal cancer (41) and glioblastoma (42), it was tempting to mechanistically investigate the role for miR-486-5p as either a tumor suppressor miRNA or an oncomiR in HCC. In the current study, miR-486-5p was shown to act as a tumor suppressor miRNA in HCC as it markedly reduced the Huh-7 cell viability, proliferation, migration and clonogenicity in a similar pattern to that exhibited by IGF-1R siRNAs (Figs.…”