Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish.

Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding ß-catenin. HCC-associated CTNNB1 mutations stabilize the ß-catenin protein, leading to nuclear and/or cytoplasmic localization of ß-catenin and downstream activation of Wnt target genes. In patient HCC samples, ß-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in ß-catenin activation are not well understood. To define mechanisms of ß-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated ß-catenin in (1) a small number of hepatocytes in early development; or (2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated ß-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/ß-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish ß-catenin-driven HCC. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish ß-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous ß-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.

Estrogen receptor ß expression induces changes in the microRNA pool in human colon cancer cells.

There is epidemiological, animal and in vitro evidence that estrogen receptor ß (ERß) can mediate protective effects against colon cancer, but the mechanism is not completely understood. Previous research has indicated critical pathways whereby ERß acts in an antitumorigenic fashion. In this study, we investigate ERß's impact on the microRNA (miRNA) pool in colon cancer cells using large-scale genomic approaches, bioinformatics and focused functional studies. We detect and confirm 27 miRNAs to be significantly changed following ERß expression in SW480 colon cancer cells. Among these, the oncogenic miR-17-92 cluster and miR-200a/b are strongly downregulated. Using target prediction and anticorrelation to gene expression data followed by focused mechanistic studies, we demonstrate that repression of miR-17 is a secondary event following ERß's downregulatory effect on MYC. We show that re-introduction of miR-17 can reverse the antiproliferative effects of ERß. The repression of miR-17 also influences cell death upon DNA damage and mediates regulation of NCOA3 (SRC-3) and CLU in colon cancer cells. We further determine that the downregulation of miR-200a/b mediates increased ZEB1 while decreasing E-cadherin levels in ERß-expressing colon cancer cells. Changes in these genes correspond to significant alterations in morphology and migration. Our work contributes novel data of ERß and miRNA in the colon. Elucidating the mechanism of ERß and biomarkers of its activity has significant potential to impact colon cancer prevention and treatment.