Menin is lost by the sequential inactivation of both MEN1 alleles in subsets of non-hereditary endocrine
tumors as well as those associated with
multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant
hereditary cancer syndrome characterized by multiple
tumors including parathyroid, pituitary and enteropancreatic endocrine
tumors. Loss of menin has been reported to be associated with lowered
caspase 8 expression and resistance to apoptosis in murine fibroblasts and in pancreatic islet
tumors arising in heterozygous MEN1 gene knockout mice, the animal model of the human MEN1 syndrome. We confirmed by menin-knockdown experiments with specific
siRNA that menin is crucial for
caspase 8 expression in human culture cells while overexpression of menin did not increase
caspase 8 protein over basal levels. We then examined expression of menin,
caspase 8 and
cyclin-dependent kinase inhibitors p27(Kip1) and p15(Ink4b) by Western blotting in human parathyroid
tumors surgically resected from patients with MEN1 and those with non-hereditary
primary hyperparathyroidism. The menin and p27(Kip1) expression levels were correlated with MEN1 mutation status that was confirmed by
DNA analysis. The
caspase 8 and p15(
Ink4b) protein levels were variable among
tumors, and were not correlated with menin
protein levels. These findings suggest that human endocrine
tumors lacking menin may not always exhibit lowered
caspase 8 expression and hence may not be resistant to apoptosis-inducing
therapy.