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Caspase 8 and menin expressions are not correlated in human parathyroid tumors
Dong Yu1, Yuko Nagamura, Satoko Shimazu
1Tumor Endocrinology Project, National Cancer Center Research Institute, Tokyo, Japan.
Abstract:
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.
Insights
Loss of menin in endocrine tumors doesn't always lower caspase 8, suggesting these tumors may not be resistant to apoptosis-inducing therapies targeting caspase 8.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant syndrome causing parathyroid, pituitary, and enteropancreatic tumors.
- Loss of menin protein is linked to reduced caspase 8 expression and apoptosis resistance in preclinical models.
- Menin's role in regulating caspase 8 in human endocrine tumors requires further investigation.
Purpose of the Study:
- To investigate the relationship between menin expression and caspase 8 levels in human endocrine tumors.
- To determine if menin loss in human tumors correlates with apoptosis resistance.
- To assess the clinical implications for apoptosis-inducing therapies in MEN1-associated and sporadic endocrine tumors.
Main Methods:
- Menin knockdown using siRNA in human cell cultures to assess caspase 8 regulation.
- Western blotting to analyze menin, caspase 8, p27(Kip1), and p15(Ink4b) protein expression.
- Analysis of tumor samples from patients with MEN1 and sporadic primary hyperparathyroidism, with DNA analysis for mutation status.
Main Results:
- Menin knockdown confirmed menin's necessity for caspase 8 expression in human cells; overexpression did not increase basal levels.
- Menin and p27(Kip1) levels correlated with MEN1 mutation status.
- Caspase 8 and p15(Ink4b) levels varied and did not correlate with menin levels in human tumors.
Conclusions:
- Human endocrine tumors lacking menin do not consistently show reduced caspase 8 expression.
- The findings challenge the assumption of universal apoptosis resistance in menin-deficient tumors.
- This suggests that apoptosis-inducing therapies may still be effective in a subset of menin-deficient endocrine tumors.
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