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Reciprocal interaction of Wnt and RXR-α pathways in hepatocyte development and hepatocellular carcinoma

ABSTRACT: Genomic analysis of human hepatocellular carcinoma (HCC) is potentially confounded by the differentiation state of the hepatic cell-of-origin. Here we integrated genomic analysis of mouse HCC (with defined cell-of-origin) along with normal liver development. We found a major shift in expression of Wnt and RXR-α pathway genes (up and down, respectively) coincident with the transition from hepatoblasts to hepatocytes. A combined Wnt and RXR-α gene signature categorized HCCs into two subtypes (high Wnt, low RXR-α and low Wnt, high RXR-α), which matched cell-of-origin in mouse models and the differentiation state of human HCC. Suppression of RXR-α levels in hepatocytes increased Wnt signaling and enhanced tumorigenicity, whereas ligand activation of RXR-α achieved the opposite. These results corroborate that there are two main HCC subtypes that correspond to the degree of hepatocyte differentation and that RXR-α, in part via Wnt signaling, plays a key functional role in the hepatocyte-like subtype and potentially could serve as a selective therapeutic target.

ORGANISM(S): Mus musculus

PROVIDER: GSE65063 | GEO | 2015/01/17

SECONDARY ACCESSION(S): PRJNA272817

REPOSITORIES: GEO

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Project description:Genomic analysis of human hepatocellular carcinoma (HCC) is potentially confounded by the differentiation state of the hepatic cell-of-origin. Here we integrated genomic analysis of mouse HCC (with defined cell-of-origin) along with normal liver development. We found a major shift in expression of Wnt and RXR-Î± pathway genes (up and down, respectively) coincident with the transition from hepatoblasts to hepatocytes. A combined Wnt and RXR-Î± gene signature categorized HCCs into two subtypes (high Wnt, low RXR-Î± and low Wnt, high RXR-Î±), which matched cell-of-origin in mouse models and the differentiation state of human HCC. Suppression of RXR-Î± levels in hepatocytes increased Wnt signaling and enhanced tumorigenicity, whereas ligand activation of RXR-Î± achieved the opposite. These results corroborate that there are two main HCC subtypes that correspond to the degree of hepatocyte differentation and that RXR-Î±, in part via Wnt signaling, plays a key functional role in the hepatocyte-like subtype and potentially could serve as a selective therapeutic target. Total RNA from whole livers taken at different developmental timepoints (embryonic day 14, embryonic day 18, post-natal day 5 and post-natal day 56) along with hepatoblasts isolated from E14 livers and immature hepatocytes isolated from E18 livers was extracted and purified using the Qiagen RNeasy Mini Kit. RNA purity and integrity were assayed by the Bioanalyser 2100 (Agilent Technologies). For each sample, 2 Âµg of total RNA was reverse transcribed and amplified by using an RNA amplification kit from Ambion. Fifteen micrograms of amplified RNA were labeled by direct chemical coupling to the Cy5 NHS ester (Amersham Biosciences). Normal adult mouse liver (Agilent) was used as control and Cy3 labeled. Labeled RNAs were purified, fragmented, and used as probes to hybridize microarrays. Gene expression profiling was done with the 4x44k mouse Agilent platform. Expression profiling of the 23 human HCC samples was previously described

Project description:An integrative transcriptomics analysis was performed to evaluate the clinical relevance of genes associated with hepatocyte differentiation in human hepatocellular carcinoma (HCC). The well-established HepaRG cell line model was used to define a gene expression signature reflecting the status of tumor hepatocyte differentiation. This signature was able to stratify HCC patients into clinically relevant molecular subtypes. Then, a minimal subset of 7 differentiation-associated genes was identified to predict a poor prognosis in several cancer datasets. Hepatocellular carcinoma (HCC) is a deadly cancer worldwide as a result of a frequent late diagnosis which limits the therapeutic options. Tumor progression is correlated with a dedifferentiation of hepatocytes, the main parenchymal cells in the liver. Here, we hypothesized that the level of expression of genes reflecting the differentiation status of tumor hepatocytes could be clinically relevant in defining subsets of patients with variable clinical outcomes. To test this hypothesis, an integrative transcriptomic approach was used to stratify a cohort of 139 HCC patients based on a gene expression signature established using a well-controlled in vitro model of tumor hepatocyte differentiation in HepaRG cell line. First, we validated the HepaRG model by identifying a robust gene expression signature associated with hepatocyte differentiation and liver metabolism. This signature was able to distinguish specific developmental stages in mice. More importantly, the signature identified a subset of human HCC associated with a poor prognosis and cancer stem cell features. By using an independent HCC dataset (TCGA), a minimal subset of 7 differentiation-related genes was shown to predict a reduced overall survival, not only in patients with HCC but also in other types of cancers (e.g. kidney, pancreas, skin). In conclusion, the study demonstrates that genes reflecting the differentiation status of tumor hepatocytes are clinically relevant for predicting the prognosis of HCC patients.

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Reciprocal interaction of Wnt and RXR-α pathways in hepatocyte development and hepatocellular carcinoma

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