Abstract
Adrenocortical cancer (ACC) is a very aggressive tumor, and genomics studies demonstrate that the most frequent alterations of driver genes in these cancers activate the Wnt/β-catenin signaling pathway. However, the adrenal-specific targets of oncogenic β-catenin-mediating tumorigenesis have not being established. A combined transcriptomic analysis from two series of human tumors and the human ACC cell line H295R harboring a spontaneous β-catenin activating mutation was done to identify the Wnt/β-catenin targets. Seven genes were consistently identified in the three studies. Among these genes, we found that AFF3 mediates the oncogenic effects of β-catenin in ACC. The Wnt response element site located at nucleotide position −1408 of the AFF3 transcriptional start sites (TSS) mediates the regulation by the Wnt/β-catenin signaling pathway. AFF3 silencing decreases cell proliferation and increases apoptosis in the ACC cell line H295R. AFF3 is located in nuclear speckles, which play an important role in RNA splicing. AFF3 overexpression in adrenocortical cells interferes with the organization and/or biogenesis of these nuclear speckles and alters the distribution of CDK9 and cyclin T1 such that they accumulate at the sites of AFF3/speckles. We demonstrate that AFF3 is a new target of Wnt/β-catenin pathway involved in ACC, acting on transcription and RNA splicing.
Highlights
Adrenocortical cancer (ACC) is a very aggressive tumor with a 5-year survival rate below 35% in most series.[1]
Whole-transcript gene expression was analyzed in three stable clones of H295R cells expressing a doxycyclin-inducible small hairpin RNAtargeting CTNNB1 messenger RNA (mRNA).[12]
We show that one of these genes, AFF3, mediates some of the effects of Wnt/β-catenin signaling pathway activation in ACC (Figure 8)
Summary
Adrenocortical cancer (ACC) is a very aggressive tumor with a 5-year survival rate below 35% in most series.[1] There are few effective treatments available.[2] At present, surgery is the only curative therapy available and is only effective if complete tumor removal is possible. Medical therapy is of very limited efficacy. Several studies show the importance of the Wnt/β-catenin signaling pathway in the development and maintenance of numerous organs, and that alterations of the Wnt/β-catenin signaling are involved in a wide range of human diseases, and especially malignancies.[3,4,5,6]. Constitutive activation of the Wnt/β-catenin pathway in the adrenal cortex of transgenic mice leads to the development of adrenocortical tumors with malignant characteristics.[9,10] Inhibition of the Wnt/β-catenin pathway in the adrenocortical cell line H295R by PKF115-584 or a shRNA against β-catenin messenger RNA (mRNA) increases apoptosis[11,12] and is associated with a complete absence of tumor growth in a xenograft model.[12]
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