Abstract
BackgroundInhibin is a tumor-suppressor and activin antagonist. Inhibin-deficient mice develop gonadal tumors and a cachexia wasting syndrome due to enhanced activin signaling. Because activins signal through SMAD2 and SMAD3 in vitro and loss of SMAD3 attenuates ovarian tumor development in inhibin-deficient females, we sought to determine the role of SMAD2 in the development of ovarian tumors originating from the granulosa cell lineage.MethodsUsing an inhibin α null mouse model and a conditional knockout strategy, double conditional knockout mice of Smad2 and inhibin alpha were generated in the current study. The survival rate and development of gonadal tumors and the accompanying cachexia wasting syndrome were monitored.ResultsNearly identical to the controls, the Smad2 and inhibin alpha double knockout mice succumbed to weight loss, aggressive tumor progression, and death. Furthermore, elevated activin levels and activin-induced pathologies in the liver and stomach characteristic of inhibin deficiency were also observed in these mice. Our results indicate that SMAD2 ablation does not protect inhibin-deficient females from the development of ovarian tumors or the cachexia wasting syndrome.ConclusionsSMAD2 is not required for mediating tumorigenic signals of activin in ovarian tumor development caused by loss of inhibin.
Highlights
Inhibin is a tumor-suppressor and activin antagonist
Generation of Smad2flox/-; inhibin α (Inha)-/-; Amhr2cre/+ mice To understand the roles of SMAD2 in ovarian tumor development in inhibin-deficient mice, we took advantage of a conditional knockout strategy to disrupt the Smad2 gene in mouse ovarian granulosa cells
We previously demonstrated that the Smad2 floxed allele can be recombined and deleted in mouse granulosa cells in Smad2 conditional knockout (cKO) mice [38]
Summary
Inhibin-deficient mice develop gonadal tumors and a cachexia wasting syndrome due to enhanced activin signaling. Because activins signal through SMAD2 and SMAD3 in vitro and loss of SMAD3 attenuates ovarian tumor development in inhibin-deficient females, we sought to determine the role of SMAD2 in the development of ovarian tumors originating from the granulosa cell lineage. Inhibin is a tumor suppressor [21], as inhibin α (Inha) null mice develop gonadal sex cordstromal tumors originating from the granulosa/Sertoli cell lineages [21], presumably due to the loss of activin antagonism. The mechanisms of tumorigenesis in Inha null mice are not fully understood, activin, FSH, and estradiol may play pivotal roles in the development of gonadal tumors [25,26,27,28]. We demonstrated that administration of a chimeric ACVR2 ectodomain (ActRII-mFc), a known activin antagonist, delayed gonadal tumorigenesis in inhibin-deficient mice [32]
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