Proteolysis-inducing factor is expressed in tumours of patients with gastrointestinal cancers and correlates with weight loss.

Proteolysis-inducing factor (PIF), a novel cachectic factor, is detectable in the urine of cancer patients experiencing weight loss. We report the expression of PIF in gastrointestinal cancers, and a correlation between PIF expression in tumours, its detection in urine and weight-loss. These data provide the first direct evidence that tumours are the source of PIF in humans.

Influence of the human endogenous retrovirus-like element HERV-E.PTN on the expression of growth factor pleiotrophin: a critical role of a retroviral Sp1-binding site.

Germ line insertion of a human endogenous retrovirus-like element (HERV-E.PTN) into the growth factor pleiotrophin (PTN) gene generated a phylogenetically new promoter driving the expression of functional HERV-PTN fusion transcripts. Here we show by in situ hybridization, that HERV-PTN fusion transcripts are expressed in malignant trophoblasts (i.e. choriocarcinoma) and in the proliferative and in the invasive trophoblasts of gestational trophoblastic tissue. Additionally, a 1.9 kb fragment of the HERV-derived PTN promoter was analysed which has strong activity when transiently transfected into choriocarcinoma JEG-3 cells in contrast to HeLa cells. Deletion of the retrovirally-derived promoter portion abolished its activity and an enhancer (+443 to +486) was identified in this region. Electrophoretic mobility shift and supershift experiments identified a Sp1 binding site in this enhancer and site specific mutation of this site abolished its activity in choriocarcinoma cells. Sp1 overexpression in Drosophila SL2 cells showed that the enhancer activity is mediated via Sp1 binding in vivo. Furthermore, mutation of the Sp1 binding site reduced the activity of a promoter test fragment in choriocarcinoma cells by 80%. Our result shows that a retroviral Sp1 binding site in the PTN promoter is important for the expression of growth factor pleiotrophin in human choriocarcinoma cells. Oncogene (2000) 19, 3988 - 3998.

Aberrant cutaneous expression of the angiogenic factor midkine is associated with neurofibromatosis type-1.

Neurofibromatosis type 1 is a common autosomal dominant disorder (incidence 1:3500) characterized by lesions that include neural crest derivatives such as Schwann cells and melanocytes. A critical event in the pathogenesis of neurofibromatosis type 1 is the heterozygous germ-line loss of the tumor suppressor gene NF1. Additional genetic and/or epigenetic events have been posited, including various alterations in growth factor expression. By in situ hybridization and immunohistochemistry, we demonstrate aberrant expression of the angiogenic and tumorigenic growth factor midkine in the skin of patients with neurofibromatosis type 1, but not normal individuals. We demonstrate that midkine expression is independent of the presence of neurofibromas, and thus appears to be associated with mutations in the NF1 gene. Furthermore, midkine-containing culture media is shown to stimulate the growth of human endothelial and neurofibroma-derived cells. In conclusion, we introduce the skin as a source of dysregulated growth factors in neurofibromatosis type 1, and suggest the further study of the angiogenic factor midkine in neurofibromatosis type 1 pathogenesis.