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Transcriptomic profiling of liver of Ctnnb1-KO and WT mice after 12 weeks exposure to Phenobarbital (mRNA)

ABSTRACT: Signaling through the Wnt/b-catenin pathway is a crucial determinant of hepatic zonal gene expression, liver development, regeneration, and tumorigenesis. The gene encoding b-catenin is called Ctnnb1. We have previously shown, that liver tumour promotion mediated by the model tumour promoter phenobarbital (PB) is completely lost in mice, where Ctnnb1 has been conditionally knocked out in hepatocytes (CTNNB1KO mice; Rignall et al., Carcinogenesis 32, 52-57, 2010). In the present study, the effect of a 12 weeks PB exposure on the liver miRNA expression pattern was investigated, in order to potentially get information on the nature of the loss of promotional activity in the CTNNB1KO mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE68779 | GEO | 2018/05/11

REPOSITORIES: GEO

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Project description:Stable activation of the WNT signaling effector beta-catenin (CTNNB1(ex3) in ovarian granulosa cells results in the formation of premalignant lesions that develop into granulosa cell tumors (GCTs) spontaneously later in life. Loss of the tumor suppressor gene Pten accelerates GCT formation in the CTNNB1 strain. Conversely, expression of oncogenic KRASG12D causes the dramatic arrest of proliferation, differentiation and apoptosis in granulosa cells, and consequently, small abnormal follicle-like structures devoid of oocytes accumulate in the ovary. Because of the potent anti-proliferative effects of KRASG12D in granulosa cells, we sought to determine if KRASG12D would block precancerous lesion and tumor formation in follicles of the CTNNB1 mutant mice. Unexpectedly, transgenic Ctnnb1;Kras mutant mice developed early-onset GCTs leading to premature death in a manner similar to theCtnnb1;Pten mutant mice. Moreover, the GCTs in the Ctnnb1;Kras mutant mice exhibited increased GC proliferation, decreased apoptosis and impaired differentiation. Microarray and RT-PCR analyses revealed that ovaries from mice expressing dominant-stable CTNNB1 with either Pten loss or KRAS activation were unpredictably similar. Specifically, gene regulatory processes induced by CTNNB1 were mostly enhanced by either KRAS activation or Pten loss in remarkably similar patterns and degree. Furthermore, the concomitant activation of CTNNB1 and KRAS in Sertoli cells resulted in the development of granulosa cell tumors of the testis. RT-PCR studies showed a partial overlap in gene regulatory processes associated with tumor development in the ovary and testis. Together, these results suggest that KRAS activation and Pten loss induce GCT development from premalignant lesions via highly similar molecular mechanisms. four samples: average of two wild type samples (previously submitted as GSM403220 and GSM403221), beta-Catenin constitutively active mutant, beta-Catenin;Pten double mutant, and beta-Catenin;Kras(G12D) double mutant

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Transcriptomic profiling of liver of Ctnnb1-KO and WT mice after 12 weeks exposure to Phenobarbital (mRNA)

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