A Pituitary-Derived MEG3 Isoform Functions as a Growth Suppressor in Tumor Cells

Abstract

Human pituitary adenomas are the most common intracranial neoplasm. Typically monoclonal in origin, a somatic mutation is a prerequisite event in tumor development. To identify underlying pathogenetic mechanisms in tumor formation, we compared the difference in gene expression between normal human pituitary tissue and clinically nonfunctioning pituitary adenomas by cDNA-representational difference analysis. We cloned a cDNA, the expression of which was absent in these tumors, that represents a novel transcript from the previously described MEG3, a maternal imprinting gene with unknown function. It was expressed in normal human gonadotrophs, from which clinically nonfunctioning pituitary adenomas are derived. Additional investigation by Northern blot and RT-PCR demonstrated that this gene was also not expressed in functioning pituitary tumors as well as many human cancer cell lines. Moreover, ectopic expression of this gene inhibits growth in human cancer cells including HeLa, MCF-7, and H4. Genomic analysis revealed that MEG3 is located on chromosome 14q32.3, a site that has been predicted to contain a tumor suppressor gene involved in the pathogenesis of meningiomas. Taken together, our data suggest that MEG3 may represent a novel growth suppressor, which may play an important role in the development of human pituitary adenomas.

Microarray expression profiling of long non-coding RNAs in epithelial ovarian cancer

“…The MEG3 gene is located in chromosome 14q32 (25), and is expressed in numerous normal tissues, but its expression level has been reported by various previous studies to be either downregulated or absent in a variety of tumor tissues, including ovarian cancer cells and epithelial ovarian cancer tissues (26)(27)(28). In the present study, HOTAIR was upregulated and MEG3 was downregulated in epithelial ovarian cancer vs. normal tissues.…”

Silencing of the Imprinted DLK1-MEG3 Locus in Human Clinically Nonfunctioning Pituitary Adenomas

“…6,7 Loss of MEG3 expression has also been found in certain brain tumors and in many human cancer cell lines. 8,9 Furthermore, MEG3 activates p53, selectively stimulates expression of p53 target genes, and inhibits cell proliferation in vitro. 10 In mice, deletion of Gtl2, the murine ortholog of MEG3, causes enhanced embryonic brain angiogenesis and perinatal death.…”

Relevance of long non-coding RNAs in tumour biology

“…A H19-hez hasonlóan a MEG3 is apai imprinting alatt áll, azaz csak az anyai allélról fejeződik ki [28]. Szintén analógiaként értelmez-hető a H19-cel, hogy a MEG3 is kódol egy mikroRNS-t, a miR-770-et, amelynek génje azonban az RNS 3´ végén egy intronban található [29].…”

“…Szintén analógiaként értelmez-hető a H19-cel, hogy a MEG3 is kódol egy mikroRNS-t, a miR-770-et, amelynek génje azonban az RNS 3´ végén egy intronban található [29]. A MEG3 az agyalapi mirigyben és az agyszövetben fejeződik ki legnagyobb mértékben, és hypophysisadenomákban csökkent kifejeződését a MEG3 kifejeződését szabályozó régió fokozott metilációjával hozták összefüggésbe [28]. A MEG3 tumorszuppresszor hatásában a p53-útvonalak aktivá-lása tűnik elsődlegesnek.…”