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

Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BUL 457B, Boston, Massachusetts 02114. E-mail: aklibanski{at}partners.org.

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.

This work was supported in part by National Institutes of Health Grant R01-DK-40947, American Cancer Society Grant IRG-87-007-13, the Massachusetts General Hospital/Giovanni Armenise Neuro-Oncology and Related Disorder Program, and the Jarislowsky Foundation.

Present address for K.R.M.: Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143.

Abbreviations: EST, Expressed sequence tag; FSH-ß, ß-subunit of FSH; ORF, open reading frame; RDA, representational difference analysis; SSC, standard saline-citrate.

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