Transgenic overexpression of the oncofetal RNA binding protein KOC leads to remodeling of the exocrine pancreas

M Wagner, S Kunsch, D Duerschmied, M Beil, G Adler… - Gastroenterology, 2003 - Elsevier
M Wagner, S Kunsch, D Duerschmied, M Beil, G Adler, F Mueller, TM Gress
Gastroenterology, 2003Elsevier
BACKGROUND & AIMS:: 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 …
BACKGROUND & AIMS
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 α (NGF-α) 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 embroygenesis.
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