Transgenic overexpression of the oncofetal RNA binding protein KOC leads to remodeling of the exocrine pancreas.
OBJECTIVE
To elucidate the function of the oncofetal RNA-binding protein, K-homologous (KH) domain containing protein overexpressed in cancer (KOC), we studied the effect of a constitutive reexpression of KOC in transgenic mice.


METHODS
Transgenic mouse lines expressing KOC under the control of the mouse metallothionein promoter were generated and were shown to express the 69-kilodalton protein. Two mouse lines with moderate to strong gene expression of the transgene were further analyzed.


RESULTS
The pancreas of KOC-transgenic mice showed progressive morphologic alterations, including an increased proliferation of acinar cells, acinar-ductal metaplasia, net loss of acinar tissue, and the appearance of numerous interstitial cells. Acinar-ductal metaplasia led to the development of duct-like structures exhibiting the characteristics of normal intralobular ducts. Interstitial cells expressed markers of endocrine or ductal differentiation. Nerve growth factor alpha (NGF-alpha) and the GTPase kir/Gem were identified as potential targets of KOC by expression profiling analyses.


CONCLUSIONS
Reexpression of KOC in the transgenic model is apparently incompatible with the maintenance of a fully differentiated, adult acinar phenotype and may lead to a more fetal ductal phenotype via acinar-ductal metaplasia. This and the appearance of interstitial cells with a ductal and endocrine differentiation capacity suggest that transgenic reexpression of the oncofetal gene KOC may recapitulate a developmental program active during embryogenesis.
Wagner
Martin
M
Department of Internal Medicine I, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany.
Kunsch
Steffen
S
Duerschmied
Daniel
D
Beil
Michael
M
Adler
Guido
G
Mueller
Friederike
F
Gress
Thomas M
TM
D000818:Animals; D017209:Apoptosis; D024042:Collagen Type I / Q000032:analysis; D005353:Fibronectins / Q000032:analysis; D007150:Immunohistochemistry; D020783:Matrix Metalloproteinase 7 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000196:embryology* / Q000473:pathology*; D016601:RNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000032:analysis
D024042:Collagen Type I; D005353:Fibronectins; C498777:Igf2bp3 protein, mouse; D016601:RNA-Binding Proteins; D016211:Transforming Growth Factor alpha; D020783:Matrix Metalloproteinase 7