Overexpression of RKIP Inhibits Cell Invasion in Glioma Cell Lines through Upregulation of miR-98

Abstract

Raf-1 kinase inhibitor protein (RKIP) is a tumor and metastasis suppressor in cancer cells. MicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis-related genes, providing potential therapeutic targets on antimetastasis strategy. In this study, we found that the expression of RKIP and miR-98 in glioma tissues were significantly lower than that in normal brain tissues. Overexpression of RKIP upregulated miR-98 expression and inhibited glioma cell invasion and miR-98 target gene HMGA2 but had no effect in glioma cell proliferation. Moreover, forced expression of miR-98 accelerated the inhibition of glioma cell invasion and the expression of HMGA2 also had no effect in glioma cell proliferation. Our findings newly described RKIP/miR-98 to HMGA2 link and provided a potential mechanism for glioma cell invasion. RKIP and miR-98 may illustrate the potential therapeutic utility of signaling pathway signatures.

Raf Kinase Inhibitory Protein (RKIP): Functional Pleiotropy in the Mammalian Brain

“…79 Evidence from in vitro experiments using human glioma cell lines is consistent with a role of RKIP as a metastasis suppressor, since RKIP inhibition promotes cell migration, whereas its overexpression suppresses glioma cell invasion. 77,79 On the other hand, an in vivo assay using cultured human glioma cells implanted into chick chorioallantoic membrane did not find evidence for an effect of RKIP suppression on cellular proliferation and angiogenesis. 79 The cumulative evidence from this handful of studies supports a potential involvement of RKIP in human gliomas.…”

“…76 An independent clinical study corroborated these findings in primary glioma tissues compared to adjacent normal glial tissues, and human glioma cell lines versus control human glial cells. 77 A third clinical study showed that overall survival was best for high-grade gliomas that are positive for RKIP and negative for STAT3 (signal transducer and activator of transcription 3) expression. 78 However, in another report, Martinho et al found that only a small proportion (i.e., approximately 10%) of gliomas from human patients are associated with loss of RKIP expression.…”

High Mobility Group A (HMGA): Chromatin Nodes Controlled by a Knotty miRNA Network

“…hsa-miR-98-5p belongs to the let-7 gene family and it is located at the Xp11.22 genomic locus (miRbase, HGNC site) [225]. Several studies have reported that miR-98 binds the 3 UTR of HMGA2 mRNA, regulating its expression [107][108][109][110][111][112]. A correlation between miR-98 and chemoresistance that is associated with the downregulation of HMGA2 was found in head and neck squamous cell carcinoma, providing the first link between miR-98 levels and HMGA2 expression [227].…”

Understanding perspectives of signalling mechanisms regulating PEBP1 function

“…These studies gave a possible link between PEBP1/miR-98 and HMGA2 and revealed that upregulated PEBP1 in glioma cells leads to decreased tumour invasion without decrease in the cell proliferation rate. 38 PEBP1 also inhibits cell invasion mechanisms through induction of miR-200b, which in turn inhibits the expression of lysyl oxidase and Syndecan-2 in tumours, thereby inducing apoptosis in such cells and abrogating metastasis. 39 Hence, it is possible that PEBP1 plays a major role in cell invasion and metastasis by exerting its effects on the regulation of miRNAs in the human cells.…”