Caspase 8 and menin expressions are not correlated in human parathyroid tumors.
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.
Yu
Dong
D
Tumor Endocrinology Project, National Cancer Center Research Institute, Tokyo, Japan.
Nagamura
Yuko
Y
Shimazu
Satoko
S
Naito
Junko
J
Kaji
Hiroshi
H
Wada
Seiki
S
Honda
Munehiro
M
Xue
Lian
L
Tsukada
Toshihiko
T
D053181:Caspase 8 / Q000096:biosynthesis*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D057809:HEK293 Cells; D006801:Humans; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics / Q000378:metabolism*; D010282:Parathyroid Neoplasms / Q000503:physiopathology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics
D050762:Cyclin-Dependent Kinase Inhibitor p15; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D053181:Caspase 8