Expression of PACE4 in chemically induced carcinomas is associated with spindle cell tumor conversion and increased invasive ability.
Gene expression changes associated with the conversion of squamous cell carcinoma (SCC) to a more advanced malignant spindle cell carcinoma (SPCC) were determined by differential display. Using an animal model of human SCC progression, we provide evidence of increased PACE4 expression in SPCC cell lines and primary tumors induced by chemical carcinogenesis protocols, thus implicating this proprotein convertase in the process of tumor progression. Exogenous overexpression of PACE4 cDNA in mouse SCC cells of low invasive ability resulted in enhanced tumor cell invasiveness that was absent in parental or mock-transfected SCC cells. In addition, the PACE4-transfected cells acquired the ability to process prostromelysin 3 into its active enzyme form. Taken together, these results show that up-regulation of PACE4 expression is associated with SCC conversion to SPCC and suggests that activation of essential PACE4 substrates, such as the metalloproteinase stromelysin 3, is required for tumor cell invasion.
Hubbard
F C
FC
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Goodrow
T L
TL
Liu
S C
SC
Brilliant
M H
MH
Basset
P
P
Mains
R E
RE
Klein-Szanto
A J
AJ
D000818:Animals; D002273:Carcinogens; D002277:Carcinoma / Q000201:enzymology / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D018450:Disease Progression; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D043484:Proprotein Convertases; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D004792:Enzyme Precursors; D007527:Isoenzymes; D011994:Recombinant Proteins; C080654:PCSK6 protein, human; C513086:Pcsk6 protein, mouse; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases