Biochemical Signatures of Doppel Protein in Human Astrocytomas to Support Prediction in Tumor Malignancy

Abstract

Doppel (Dpl) is a membrane-bound glycoprotein mainly expressed in the testis of adult healthy people. It is generally absent in the central nervous system, but its coding gene sequence is ectopically expressed in astrocytoma specimens and in derived cell lines. In this paper, we investigated the expression and the biochemical features of Dpl in a panel of 49 astrocytoma specimens of different WHO malignancy grades. As a result, Dpl was expressed in the majority of the investigated specimens (86%), also including low grade samples. Importantly, Dpl exhibited different cellular localizations and altered glycan moieties composition, depending on the tumor grade. Most low-grade astrocytomas (83%) showed a membrane-bound Dpl, like human healthy testis tissue, whereas the majority of high-grade astrocytomas (75%) displayed a cytosolic Dpl. Deglycosylation studies with N-glycosidase F and/or neuraminidase highlighted defective glycan moieties and an unexpected loss of sialic acid. To find associations between glial tumor progression and Dpl biochemical features, predictive bioinformatics approaches were produced. In particular, Decision tree and Nomogram analysis showed well-defined Dpl-based criteria that separately clustered low-and high-grade astrocytomas. Taken together, these findings show that in astrocytomas, Dpl undergoes different molecular processes that might constitute additional helpful tools to characterize the glial tumor progression.

Prion proteins (PRNP and PRND) are over‐expressed in osteosarcoma

“…This implies that PrP c may be involved in resistance to apoptosis, proliferation, and metastasis of human cancer cells 5. The resistance to cell death, particularly to apoptotic cell death, is an important aspect of both tumorigenesis and development of resistance to drugs used to treat cancer 5, 6. The expression levels of PRNP (the gene that encodes for PrP c ) may have a prognostic value in colorectal cancer, suggesting a role for the prion protein in colorectal cancer 1.…”

Cellular Prion Protein: From Physiology to Pathology

“…Dpl shows structural homology with the C-terminal globular domain of PrP C , but lacks the N-terminal octarepeats and the hydrophobic core (HC) [61], suggesting that Dpl is not cleaved at the same position as PrP C . As expected, murine Dpl appears as a single band of ~17 KDa after PNGase F treatment [62], although human Dpl from testis additionally possesses an O-bound oligosaccharide [63,64]. Interestingly, Aguzzi’s group produced mice expressing fusion proteins in which the CC and HC regions of PrP C (residues 90-133) (cleavable) were inserted into the middle of Dpl (between 65 and 66), and the chimeric CD-Dpl proteins are cleaved into two fragments [65].…”

PRND (Prion Protein 2 (Dublet))

“…altered glycosilation pattern) different from Doppel as normally expressed in testis (Azzalin et al, 2006;Azzalin et al, 2008;Comincini et al, 2006;Comincini et al, 2004;Comincini et al, 2007;Rognoni et al, 2010;Sbalchiero et al, 2008).…”