Gene silencing of beta-catenin in adrenocortical cancer cells causes growth inhibition and reversal of epithelial-to-mesenchymal transition.

A. Salomona (Mme), M. Keramidasa (Mme), C. Maisina (Mlle), M. Thomas*a (Dr)

a Inserm U1036, CEA, iRTSV, Biology of Cancer and Infection, Grenoble, FRANCE

* michael.thomas@cea.fr

Adrenal carcinoma (ACC) is a rare endocrine neoplasm, notorious for its aggressive behavior. Aberrant expression of β-catenin have been found in a third of ACC. Here we studied its effects on the growth of the human ACC cell line H295R. The cells were infected with short hairpin RNA (shRNA)-mediated silencing b-catenin. Two shRNAs used induced down-regulation of b-catenin protein levels. The expression of these shRNAs decreased cell growth and increased H295R cells in S and G2/M phases. This cytostatic effect is due in part to a decrease of phosphorylated MAPK and to an up-regulation expression of the cyclin-dependent kinase inhibitors p57KIP2, p21WAF1/CIP1 and p27KIP1. In addition, the knockdown of β-catenin decreased phosphorylated Akt level and increased apoptosis. Finally, loss of β-catenin was sufficient to induce the reversal of the epithelial-to-mesenchymal transition. We then transplanted these genetically modified H295R cells in Scid mice. The animals were sacrificed 46 days following transplantation. Tumor growth suppression was achieved by the two shRNAs showing in vitro efficacy. Proliferation was not significantly reduced in silenced tumors compared to control ones. In contrast, p57, p27 and p21 proteins were found expressed at high levels in silenced tumors which might modulate cell cycle progression. Moreover, the depletion of b-catenin induced an increase in apoptotic cells.

Taken together, these findings indicate that the blockade of b-catenin inhibits tumor growth of b-catenin-activated tumor cells and finally, shRNA technology may have potential therapeutic use in ACC.

L’auteur n’a pas transmis de déclaration de conflit d’intérêt.

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