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Research at Mass General
The Neuroendocrine Research Laboratory is dedicated to the investigation of the molecular mechanisms of human pituitary tumor pathogenesis.
Among the major tumor types, clinically non-functioning pituitary tumors account for up to 40% of all human pituitary tumors diagnosed. Derived mainly from gonadotroph cells, these tumors cause clinical symptoms due to the mass effect; and there is no approved medical therapy for such tumors.
We have discovered that an imprinted gene, Maternal Expressed Gene 3 (MEG3), is specifically associated with this type of tumor. Transcribed only from the maternal allele of the chromosome, MEG3 is highly expressed in the pituitary, including gonadotrophs, and other neuroendocrine tissues; however, loss of its expression has been found in most human tumors (Zhang et al, J Clin Endocrinol Metab, 88:5115, 2003). Among human pituitary tumors, loss of MEG3 expression is only observed in clinically non-functioning pituitary tumors, caused by specific hypermethylation in the promoter and enhancer region of the MEG3 gene in tumor cells (Zhao et al, J Clin Endocrinol Metab, 90:2179, 2005; Gejman et al, J Clin Endocrinol Metab, 93:4119, 2008). Functionally, MEG3 is capable of suppressing in vitro tumor cell proliferation and in vivo tumor growth; stimulating p53-mediated transcriptional activation, and selectively activating a number of p53 downstream target genes (Zhou et al, J Biol Chem, 282:24731, 2007).
Importantly, MEG3 does not encode a protein product. It represents the very first large non-coding RNA gene with major biological functions including tumor suppression and p53 activation which may play a role in human pituitary tumor development. Currently, our laboratory is using several approaches to investigate the novel mechanisms of MEG3 gene function, including the development of knockout and transgenic mouse models; the molecular mapping of functional MEG3 RNA domains and studies of structure-function relationship; the use of microarray analysis to identify global change caused by MEG3 expression and its targets; and the potential molecular interaction between MEG3 RNA and other proteins.
Another major research interest is to identify novel compounds with potential clinical use in pituitary tumor treatment and to investigate their mechanisms. One example is somatostatin, a naturally occurring short peptide with functions of hormone reduction and growth suppression via specific binding to its receptors, thus triggering a series of signal transductions. Several somatostatin analogues have been developed to treat different types of pituitary tumors (Danila et al, J Clin Endocrinol Metab, 86:2976, 2001; Batista et al, J Clin Endocrinol Metab, 91:4482, 2007). Other compounds, including rapamycin and a chimera compound targeting both somatostatin receptors and dopamine receptors, are currently under investigation.
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