H. Shen

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome caused by mutations in the MEN1 tumor suppressor gene. Loss of the functional second copy of the MEN1 gene causes individuals to develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and pancreas. While it is clear that the protein encoded by MEN1, menin, suppresses endocrine tumors, its biochemical functions and direct downstream targets remain unclear. Recent studies have suggested that menin may act as a scaffold protein to coordinate gene transcription, and that menin is an oncogenic cofactor for homeobox (HOX) gene expression in hematopoietic cancer. The role of HOX genes in adult cell differentiation is still obscure, but growing evidence suggests that they may play important roles in the development of cancer. Therefore, we hypothesized that specific HOX genes were regulated by menin in parathyroid tumor development. Utilizing quantitative TaqMan RT-PCR, we compared expression profiles of the 39 HOX genes in human familial MEN1 (fMEN1) parathyroid tumors and sporadic parathyroid adenomas with normal samples. We identified a large set of 23 HOX genes whose deregulation is specific for fMEN1 parathyroid tumors, and only 5 HOX genes whose misexpression are specific for sporadic parathyroid tumor development. These findings provide the first evidence that loss of the MEN1 tumor suppressor gene is associated with deregulation of specific HOX gene expression in the development of familial human parathyroid tumors. Our results strongly reinforce the idea that abnormal expression of developmental HOX genes can be critical in human cancer progression.

Aims: Hepatic progenitor cells (HPCs) are crucial in hepatic regeneration and liver remodelling. A correlation of HPC activation during periportal fibrosis in HCV- and NASH-associated liver diseases suggests a role in fibrogenesis. IFN-γ is well recognized as fibrotic inhibitor and also may participate in regulation of HPC activation, although current results are controversial. To get further insight, we studied HPC activation in HBV infected patients and 3,5-diethoxycarbonyl–1,4-dihydrocollidine (DDC) treated mice. Methods: Human HPCs and mouse oval cells (HPCs in rodents) were quantified by cytokeratin–19 (CK19) immunostaining in chronic HBV infected patients and DDC treated wild-type and four kinds of IFN-γ-signaling associated knockout mice (IFN-γ-, IFN-γ receptor-, STAT- and interferon regulator factor (IRF)–1). Results: The CK19 staining score significantly correlates with inflammatory grade (r=0.61, P<0.001) and fibrotic stage (r=0.61, P<0.001) in 110 patients with chronic HBV infection. Nine months IFN-γ treatment decreased HPC numbers concomitant with reduced inflammation and fibrosis in 13/18 such HBV patients. Similarly, 2 weeks IFN-γ treatment remarkably decreased oval cell activation in DDC treated mice, whereas their number was significantly increased in all four knock out models with disrupted IFN-γ signaling. Co-staining for CK19 and BrdU revealed significant increased oval cell proliferation in STAT1- and IRF–1 knockout mice compared with wild-type mice. In vitro, IFN-γ incubation decreased BrdU marked proliferation of wild-type mouse primary oval cells, however, IFN- γ loss this effect in oval cells isolated from STAT1- or IRF–1 knockout mice. In parallel with upregulated oval cell expansion, DDC-mediated inflammatory and fibrotic reactions were remarkably enhanced in all mice with disrupted IFN-γ signaling. Conclusions: Besides its anti-fibrotic role, IFN-γ negatively regulates HPC/oval cell activation in chronic liver damage.