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FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis

ABSTRACT: Fibroblast growth factor 19 (FGF19) gene amplification is a common event in human hepatocellular carcinoma (HCC). The protein it encodes acts as a hormone with multiple metabolic functions beneficial for the liver, which has led to the development of analogues for the treatment of metabolic disorders such as Nonalcoholic Steatohepatitis (NASH). The most studied analogue is Aldafermin (NGM282), with previous reports showing the absence of oncogenic properties when given alone. However, potential oncogenic cooperation with frequent disrupted pathways in HCC have not been studied. Here, we used hydrodynamic gene transfer and recombinant protein injection to study oncogenic cooperation between FGF19 and its rodent orthologue FGF15, FGF19 analogue Aldafermin and common HCC events. We found a strong cooperation between FGF15/19 or Aldafermin and hepatocyte overexpression of Myc. The resulting tumours appeared in a short frame (2 to 4 weeks), were well differentiated, and expressed typical HCC markers (alpha foetoprotein and glypican 3). Transcriptomic and pathological analyses showed that Myc/FGF19 and Myc/Aldafermin tumours were almost identical. Our findings could be clinically relevant since clinical studies are currently ongoing in patients with cirrhosis, a condition associated with high susceptibility to HCC development.

ORGANISM(S): Mus musculus

PROVIDER: GSE242953 | GEO | 2023/12/18

REPOSITORIES: GEO

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Project description:Global transcriptomic alterations of both coding and non-coding RNA species are a ubiquitous feature associated with human cancers including hepatocellular carcinoma (HCC). Dysregulation of RNA-binding proteins (RBPs), the key regulators of RNA processing, is one mechanism in which cancer cells select to promote tumorigenesis. We analyzed genomic alterations amongst a family of more than 800 mRNA RBPs (mRBPs) in 1,225 clinical specimens from HCC patients and found that RBPs are significantly activated through gene amplification in a subset of tumors with poor prognosis, suggesting their potential oncogenic roles in HCC progression. Amongst the top candidates, RD binding protein (RDBP) was further characterized for its oncogenic role and effects on the HCC transcriptome. While the activation of RDBP induced an oncogenic phenotype, the abrogation of RDBP in HCC cells significantly decreased cancer associated phenotypes such as cell proliferation, migration/invasion and tumorigenicity in vivo. Further microarray analyses revealed that RDBP-dependent genes were tumor-related with a significant enrichment for c-Myc targets, suggesting interplay between RDBP and c-Myc signaling. Similar data were also found in HCC clinical specimens where c-Myc amplification was uncommon. Consistently, the RDBP-dependent c-Myc target gene signature was able to predict HCC patient survival in two independent cohorts of more than 400 patients. Taken together, our results suggest that oncogenic activation of RDBP is a novel mechanism that contributes to global transcriptome imbalance that is selective for the activation of c-Myc oncogenic signaling in HCC. We used microarray analysis to determine the affects of siRNA mediated RDBP knockdown in HCC transcriptome in cell lines. Hep3b and Huh1 cells were transfected with RDBP or scramble control siRNA for 48 hours in quadruplicates. Quality control using Spearman or Pearson correlation removes outliers resulting in triplicates for each group

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FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis

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