Abstract
BackgroundThe secretory basic amino acid-specific proprotein convertases (PCs) have often been associated with cancer/metastasis. By controlling the cleavage of cancer-associated proteins, PCs play key roles in multiple steps of cancer development. Most analyses of the implication of PCs in cancer/metastasis relied on the use of in vitro overexpression systems or inhibitors that can affect more than one PC. Aside from the role of furin in salivary gland tumorigenesis, no other in vivo genetic model of PC-knockout was reported in relation to cancer development.ResultsSince PC5/6 is highly expressed in the small intestine, the present study examined its in vivo role in intestinal tumorigenesis. Analysis of human intestinal tumors at various stages showed a systematic down-regulation of PC5/6 expression. Since gene inactivation of PC5/6 leads to lethality at birth, we generated mice lacking PC5/6 in enterocytes and analyzed the impact of the presence or absence of this PC in the mouse ApcMin/+ model that develops numerous adenocarcinomas along the intestinal tract. This resulted in viable mice with almost no expression of PC5/6 in small intestine, but with no overt phenotype. The data showed that by themselves ApcMin/+ tumors express lower levels of PC5/6 mRNA, and that the lack of PC5/6 in enterocytes results in a significantly higher tumor number in the duodenum, with a similar trend in other intestinal segments. Finally, the absence of PC5/6 is also associated with a premature mortality of ApcMin/+ mice.ConclusionOverall, these data suggest that intestinal PC5/6 is protective towards tumorigenesis, especially in mouse duodenum, and possibly in human colon.
Highlights
The secretory basic amino acid-specific proprotein convertases (PCs) have often been associated with cancer/metastasis
Since PC5/6 expression is highest in the adult small intestine [29,31], and as no data were available for intestinal cancers, PC5/ 6 mRNA levels were analyzed by quantitative PCR (QPCR) in 22 human colon tumors at stages I, II, III or IV and compared to those of their match-paired normal adjacent tissue (Figure 1A)
ApcMin/+-induced tumors in the mouse small intestine constitute a good model for colonic tumorigenesis in human
Summary
The secretory basic amino acid-specific proprotein convertases (PCs) have often been associated with cancer/metastasis. By controlling the cleavage of cancer-associated proteins, PCs play key roles in multiple steps of cancer development. The first 7 convertases cleave secretory precursor proteins at single or paired basic residues [2], whereas SKI-1/S1P [3] and PCSK9 [4] do not require a basic residue at the cleavage site. The basic amino acid (aa)-specific convertases process precursors of growth factors, receptors, polypeptide hormones, adhesion molecules, proteases, as well as cell surface proteins of infectious viruses and bacteria [2]. Evidence for in vivo redundancy was provided by furin inactivation in the liver, which revealed that most of the precursors analyzed were still processed, to a lesser extent, in the absence of this ubiquitous convertase [13]. In vivo studies demonstrated that in a spatio-temporal manner furin can uniquely process the Ac45 subunit of the vacuolar type H+-ATPase in pancreatic β-cells [14] and PC5/6 the TGFβ-like growth and differentiation factor Gdf in the developing embryo [15,16]
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