Non coding RNA analysis in fibrolamellar hepatocellular carcinoma

Abstract

Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary liver cancer found in adolescents and young adults without underlying liver disease. A deletion of ~400 kD has been found in one copy of chromosome 19 in the tumor tissue of all patients tested. This produces a fusion of the genes DNAJB1 and PRKACA which, in turn, produces a chimeric transcript and protein. Transcriptomic analysis of the tumor has shown upregulation of various oncologically relevant pathways, including EGF/ErbB, Aurora Kinase A, pak21 and wnt. To explore other factors that may contribute to oncogenesis, we examined the microRNA (miRNA) and long non-coding RNA (lncRNA) expression in FLC. The non-coding RNA expression profile in tumor tissue samples is distinctly different from the adjacent normal liver and from other liver tumors. Furthermore, miRZip knock down or over expression of certain miRNAs led to changes in the levels of coding genes that recapitulated changes observed in FLC, suggesting mechanistically that the changes in the cellular levels of miRNA are not merely correlative. Thus, in addition to serving as diagnostic tools for FLC, non-coding RNAs may serve as therapeutic targets.

MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma

“…Consistent with our previous results, we observed dramatic loss of miR-375 expression in FLC (Figure 1 E ). As a final validation, we examined recently published smRNA-seq data from FLC tumors 11 and confirmed significant loss of miR-375 expression in this data set (∼20-fold down-regulation in FLC compared with NML, FDR < 2.5 × 10 -12 , DESeq2). Together, these data indicate that miR-375 expression is dramatically suppressed in FLC tumors.…”

“…They have been implicated as drivers and candidate therapeutic targets in numerous diseases including a wide variety of cancers 10 . Recently, 1 group profiled miRNA expression in FLC tumors and identified several dysregulated miRNAs compared with nonmalignant livers (NMLs) 11 . However, it still remains unclear whether dysregulation of these miRNAs is the result of DNAJB1-PRKACA signaling and if any of these miRNAs have important functions in FLC pathogenesis and disease progression.…”

Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1–Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma

“…Furthermore, simply manipulating one of the differentially expressed miRNAs in a hepatocellular carcinoma cell line (Huh-7) was sufficient to alter oncogenic signaling in those cells, leading the authors to suggest that in FLCs, miRNAs and long noncoding RNAs help promote the activity of oncogenic pathways, such as Hippo-Yap. 43 Third, additional evidence supports the functional significance of miRNA-YAP1 interaction in FLC. miR-375, an miRNA that directly binds to and destabilizes YAP1 transcripts, is known to be suppressed by PKA and is one of the most down-regulated miRNAs in human FLC.…”

Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal molecular mechanisms of oncogenesis and intrinsic drug resistance

“…This fusion occurs in at least 80% of patients (Cornella et al, 2014;Honeyman et al, 2014), is specific to FLC (Dinh et al, 2017;Graham et al, 2015;Kastenhuber et al, 2017), and is sufficient to drive liver tumor formation in mice (Engelholm et al, 2017;Kastenhuber et al, 2017). Multiple groups have performed genome-scale analyses to identify dysregulated genes (Cornella et al, 2014;Dinh et al, 2017;Griffith et al, 2016;Malouf et al, 2014;Simon et al, 2015;Sorenson et al, 2017;Xu et al, 2014), long non-coding RNAs (Dinh et al, 2017), and microRNAs (Dinh et al, 2019;Farber et al, 2018) in FLC. Yet, little is known about the causative transcriptional regulatory mechanisms that lead to aberrant gene expression and FLC tumor formation.…”