4804

NGFR

CD271|Gp80-LNGFR|TNFRSF16|p75(NTR)|p75NTR;nerve growth factor receptor;NGFR;nerve growth factor receptor

NGF receptor|TNFR superfamily, member 16|low affinity nerve growth factor receptor|low affinity neurotrophin receptor p75NTR|low-affinity nerve growth factor receptor|p75 ICD|tumor necrosis factor receptor superfamily member 16

17q21-q22

protein-coding

Count: 2; Pubmed_search,Generif

p75 neurotrophin receptor (p75NTR), a member of the TNF receptor superfamily, is a focus for study at present. Up to now, its role and functions in hepatocellular carcinoma were not fully elucidated. In this study, we investigated the expression of p75NTR in hepatocellular carcinoma and the impact of its alteration on tumor growth. We found that the expression of p75NTR was decreased significantly in 158 cases of hepatocellular carcinoma tissues as compared with their adjacent noncancerous counterparts, and its expression was also significantly decreased in various human hepatocellular carcinoma cell lines. Down-regulating p75NTR by specific siRNA promoted the growth of normal liver cell lines, whereas up-regulating p75NTR inhibited the growth of hepatocellular carcinoma cell lines in vitro and caused dramatic attenuation of tumor growth in vivo by induction of cell cycle arrest. Furthermore, we found that up-regulating p75NTR could down-regulate the expression of cyclin A, cyclin D1, cyclin E, cdk2, p-Rb and PCNA, but up-regulate the expression of Rb. Conversely, the results were inverse when p75NTR was down-regulated by specific siRNA. Therefore, we provided the evidence that p75NTR was a potential tumor suppressor and might be used as a therapeutic target for hepatocellular carcinoma.

The transition from the benign retinal tumor retinoma to its malignant counterpart retinoblastoma is accompanied by the loss of expression of the p75(NTR) neurotrophin receptor. This change in expression is mimicked in the TAg-RB murine model of retinoblastoma, where early tumors retain expression of p75(NTR) and advanced tumors lack it. We sought to determine the functional effect on tumor development of absence of p75(NTR) from the onset of TAg-RB tumor initiation. TAg-RB mice were crossed with either p75(NTR) exon 3 (E3KO) or exon 4 knockout (E4KO) mice to produce TAg-RB offspring that lacked one or both normal p75(NTR) alleles. The average tumor area per eye as a percentage of retinal area was measured. TAg-RB/E3KO (TAg-RB(E3KO)) and heterozygous mice showed no significant difference in tumor area compared to the TAg-RB control mice at any time point studied. However, TAg-RB/E4KO (TAg-RB(E4KO)) and heterozygous mice displayed a significantly larger tumor area than the TAg-RB control mice. Furthermore, adenoviral-mediated expression of p75(NTR) in a p75(NTR)-deficient human retinoblastoma cell line resulted in increased apoptosis. Our results confirm that p75(NTR) suppresses progression of both human and TAg-RB murine retinoblastoma, and holds promise as a target for future therapy of the disease.CI - (c) 2008 Wiley-Liss, Inc.

The p75 neurotrophin receptor (p75(NTR)) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75(NTR) retarded cell cycle progression by induced accumulation of cells in G0/G1 and a reduction in the S phase of the cell cycle. The rescue of tumor cells from cell cycle progression by a death domain deleted (DeltaDD) dominant-negative antagonist of p75(NTR) showed that the death domain transduced anti-proliferative activity in a ligand-independent manner. Conversely, addition of NGF ligand rescued retardation of cell cycle progression with commensurate changes in components of the cyclin/cdk holoenzyme complex. In the absence of ligand, p75(NTR)-dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75(NTR) expressing cells occurred via the intrinsic mitochondrial pathway leading to a sequential caspase-9 and -7 cascade. Since the death domain deleted dominant-negative antagonist of p75(NTR) rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75(NTR) was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75(NTR)-dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75(NTR) expressing prostate cancer cells.

p75(NTR) was identified as a tumor and metastasis suppressor that functions in part via induction of apoptosis in tumor cells. To examine p75(NTR)-dependent apoptosis in tumor cells, we demonstrated that a dose-dependent increase in p75(NTR) expression was associated with a concomitant increase in the mitochondrial proapoptotic effector proteins Bad, Bax and Bik and a decrease in the mitochondrial prosurvival effector proteins phospho-Bad, Bcl-2 and Bcl-x(L). Significantly, p75(NTR)-dependent induction of cytochrome c release from the mitochondria occurred during CHX potentiation of apoptosis. Furthermore, p75(NTR) expression largely suppressed expression of IAP-1 and induced cleavage of procaspase-9 and procaspase-7 but not of procaspases 2, 3, 6, 8 and 10. A specific peptide inhibitor of procaspase-9 cleavage also inhibited cleavage of procaspase-7, indicating that caspase-7 is downstream of caspase-9. As end points of apoptosis, we observed p75(NTR)-dependent annexin V binding to the plasma membrane, an indicator of early apoptotic events, and Hoechst staining of DNA nuclear fragmentation, an indicator of late apoptotic events, whereas control tumor cells that lack expression of the p75(NTR) protein did not exhibit either of these apoptotic markers. Together, these results delineate the mitochondria-mediated apoptotic pathway of the p75(NTR) tumor-suppressor gene product.CI - Copyright 2003 Wiley-Liss, Inc.