Oncogene database

442918

MIR373

microRNA 373;MIR373;microRNA 373

-

19q13.42

ncRNA

Endogenous small RNAs (miRNAs) regulate gene expression by mechanisms conserved across metazoans. While the number of verified human miRNAs is still expanding, only few have been functionally annotated. To perform genetic screens for novel functions of miRNAs, we developed a library of vectors expressing the majority of cloned human miRNAs and created corresponding DNA barcode arrays. In a screen for miRNAs that cooperate with oncogenes in cellular transformation, we identified miR-372 and miR-373, each permitting proliferation and tumorigenesis of primary human cells that harbor both oncogenic RAS and active wild-type p53. These miRNAs neutralize p53-mediated CDK inhibition, possibly through direct inhibition of the expression of the tumorsuppressor LATS2. We provide evidence that these miRNAs are potential novel oncogenes participating in the development of human testicular germ cell tumors by numbing the p53 pathway, thus allowing tumorigenic growth in the presence of wild-type p53.

MicroRNAs (miRNAs) are single-stranded, noncoding RNAs that are important in many biological processes. Although the oncogenic and tumour-suppressive functions of several miRNAs have been characterized, the role of miRNAs in mediating tumour metastasis was addressed only recently and still remains largely unexplored. To identify potential metastasis-promoting miRNAs, we set up a genetic screen using a non-metastatic, human breast tumour cell line that was transduced with a miRNA-expression library and subjected to a trans-well migration assay. We found that human miR-373 and miR-520c stimulated cancer cell migration and invasion in vitro and in vivo, and that certain cancer cell lines depend on endogenous miR-373 activity to migrate efficiently. Mechanistically, the migration phenotype of miR-373 and miR-520c can be explained by suppression of CD44. We found significant upregulation of miR-373 in clinical breast cancer metastasis samples that correlated inversely with CD44 expression. Taken together, our findings indicate that miRNAs are involved in tumour migration and invasion, and implicate miR-373 and miR-520c as metastasis-promoting miRNAs.

LATS2 is a member of the LATS tumor suppressor family. It has been implicated in regulation of the cell cycle and apoptosis. Frequent loss of heterozygosity (LOH) of LATS2 has been reported in human esophageal cancer. But, the LATS2 gene expression and its regulatory mechanism in esophageal cancer remain unclear. The present study has shown that LATS2 protein expression was mediated by miR-373 at the post-transcriptional level and inversely correlated with miR-373 amounts in esophageal cancer cell lines. Furthermore, we demonstrated that the direct inhibition of LATS2 protein was mediated by miR-373 and manipulated the expression of miR-373 to affect esophageal cancer cells growth. Moreover, this correlation was supported by data collected ex vivo, in which esophageal cancer tissues from esophageal squamous cell carcinoma (ESCC) patients were analyzed. Finally, by miRNA microarray analysis, four miRNAs including miR-373 were over-expressed in ESCC samples. Our findings reveal that miR-373 would be a potential oncogene and it participates in the carcinogenesis of human esophageal cancer by suppressing LATS2 expression.

MicroRNAs are a class of small noncoding RNAs that function as key regulators of gene expression at the post-transcriptional level. Recently, microRNA-373 (miR-373) has been found to function as an oncogene in testicular germ cell tumors. In our study, we found that miR-373 is upregulated in human hepatocellular carcinoma (HCC) tissues as compared with adjacent normal tissues, and promotes the proliferation of the HCC cell lines HepG2 and QGY-7703 by regulating the transition between G(1)-phase and S-phase. The gene encoding the protein phosphatase 6 catalytic subunit (PPP6C ), a negative cell cycle regulator, was identified as a direct target gene of miR-373 by use of a fluorescent reporter assay. The mRNA and protein levels of PPP6C were both inversely correlated with the miR-373 expression level. Overexpression of PPP6C abolished the regulation of cell cycle and cell growth exercised by miR-373 in HepG2 cells. These results indicate that miR-373 plays an important role in the pathogenesis of HCC, and may be a new biomarker in HCC. Our results demonstrate that miR-373 can regulate cell cycle progression by targeting PPP6C transcripts and promotes the growth activity of HCC cells in vitro. The downregulation of PPP6C by miR-373 may explain why the expression of miR-373 can promote HCC cell proliferation.

miR-373 was reported to be elevated in several tumors; however, the role of miR-373 in cervical cancer has not been investigated. In this study we aimed to investigate the role of miR-373 in tumorigenicity of cervical cancer cells in vivo and in vitro. The expression of miR-373 was investigated using real-time reverse transcription-polymerase chain reaction assay in 45 cervical specimens and cervical cancer cell lines. The role of miR-373 in tumorigenicity of cervical cancer cells was assessed by cell proliferation, colony formation in vitro as well as tumor growth assays in vivo with the overexpression of miR-373 or gene silencing. The functional target gene of miR-373 in cervical cancer cells was identified using integrated bioinformatics analysis, gene expression arrays, and luciferase assay. We founded that the expression of miR-373 is upregulated in human cervical cancer tissues and cervical carcinoma cell lines when compared to the corresponding noncancerous tissues. Ectopic overexpression of miR-373 in human cervical cancer cells promoted cell growth in vitro and tumorigenicity in vivo, whereas silencing the expression of miR-373 decreased the rate of cell growth. YOD1 was identified as a direct and functional target of miR-373 in cervical cancer cells. expression levels of miR-373 were inversely correlated with YOD1 levels in human cervical cancer tissues. RNAi-mediated knockdown of YOD1 phenocopied the proliferation-promoting effect of miR-373. Moreover, overexpression of YOD1 abrogated miR-373-induced proliferation of cervical cancer cells. These results demonstrate that miR-373 increases proliferation by directly targeting YOD1, a new potential therapeutic target in cervical cancer.