Array-CGH-Plattform
Final Report Abstract
We analyzed hepatocarcinogenesis in different mouse models. We used mouse models of an inducible telomere dysfunction, by overexpression of a dominant negative form of TRF2, on a telomerase-proficient background, telomerase knockout mice with chronic telomere dysfunction (late generation telomerase knockout mice: G3 Terc-/-), and wildtype mice with functional telomeres and telomerase. Enhanced rates of chromosomal aberrations during hepatocarcinogenesis were seen in mice with transient or chronic dysfunctional telomeres, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. Furtheron we could show that the liver-specific deletion of Trp53 by using a AlfpCRE, Trp53 flox/flox mouse, lead to the formation of carcinomas with a bilineal differentiation. These liver tumors showed a distinct pattern of aberrations of the chromosomes 9, 10 and 12. Moreover we analyzed chromosomal aberrations in freshly sorted liver progenitor cells (LPC) and from cultured LPCs. Here, aCGH analysis revealed that a - significantly increased number of freshly isolated progenitor cells (10/28) from non-tumorous livers of Trp53-/- mice carried chromosomal imbalances compared to Trp53-positive and p21-/- LPCs (2/36). Freshly isolated hepatocytes from Trp53 -/- liver represented genomic imbalances similar to Trp53-/- progenitor cells (3/25). An increased rate of chromosomal aberrations was also present in primary colonies derived from single cell sorted, freshly isolated Trp53-/- LPCs (10/20) compared to colonies from Trp53-positive (1/16) and p21-/- mice (1/12). Together, these data demonstrated that loss of p53 function is associated with increased chromosomal instability of LPCs and hepatocytes. The comparison of spontaneous bilineal differentiated liver tumors in AlfpCRE, Trp53 flox/flox mice with chemically induced liver tumors in Trp53 wildtype mice exhibited highly significant but complex alterations in the expression of Rb-checkpoint genes.
Publications
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Nat Cell Biol. 2011 Dec 4;14(1):73-9
Sperka T, Song Z, Morita Y, Nalapareddy K, Guachalla LM, Lechel A, Begus-Nahrmann Y, Burkhalter MD, Mach M, Schlaudraff F, Liss B, Ju Z, Speicher MR, Rudolph KL
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Gastroenterology. 2012 Apr;142(4):907-17
Kleger A, Mahaddalkar PU, Katz SF, Lechel A, Joo JY, Loya K, Lin Q, Hartmann D, Liebau S, Kraus JM, Cantz T, Kestler HA, Zaehres H, Schöler H, Rudolph KL
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Gastroenterology. 2012 May;142(5):1229-1239
Katz SF, Lechel A, Obenauf AC, Begus-Nahrmann Y, Kraus JM, Hoffmann EM, Duda J, Eshraghi P, Hartmann D, Liss B, Schirmacher P, Kestler HA, Speicher MR, Rudolph KL
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J Clin Invest. 2012 May 24
Begus-Nahrmann Y, Hartmann D, Kraus J, Eshraghi P, Scheffold A, Grieb M, Rasche V, Schirmacher P, Lee HW, Kestler HA, Lechel A, Rudolph KL
