FCF Funded Projects

Micro RNAs and long non-coding RNAs role in fibrolamellar and evaluation of RNA-based therapeutics

Status: Completed

Timeframe: 2017 – 2020

Goal: Investigate the role of microRNAs and long non-coding RNAs in fibrolamellar carcinoma and evaluate RNA-based therapeutics

Principal Investigator: Praveen Sethupathy, PhD

Study overview: This study aimed to leverage genome-scale approaches to discover the molecular factors most critical to FLC tumor formation, metastasis, and drug resistance. MicroRNAs and long non-coding RNAs are RNA species that do not contain instructions for protein formation yet are vital to numerous biological processes including tumor formation.

Specific study efforts included:

  • Identifying microRNAs and long non-coding RNAs that facilitate FLC tumor formation/invasion
  • Evaluating the potential of RNA-based therapeutics to inhibit their activity
  • Integration of these results with multiple large-scale genomic and metabolomic datasets to identify critical druggable pathways.

Key Findings: This investigation identified miR-375 as the most dysregulated miRNA in primary FLC tumors based on an analysis of the small RNA sequencing data from The Cancer Genome Atlas. It also demonstrated that miR-375 expression was decreased significantly in a FLC patient-derived xenograft model compared to 4 different cell populations of the liver. In addition, it showed that the introduction of DNAJB1-PRKACA in mice (by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 engineering and transposon-mediated somatic gene transfer) was sufficient to induce significant loss of miR-375 expression. Furthermore, the study found that overexpression of miR-375 in FLC cells inhibited several well characterized growth regulatory pathways and suppressed cell proliferation and migration.

These results suggest that miR-375 could be a good candidate for therapeutic investigations. The study team also identified miR-10b, another aberrantly elevated pro-proliferation miRNA in FLC, which is responsive to DNAJB1-PRKACA over-expression, but only in human cell models (HepG2, HEK293 cell lines) and not in mouse models (AML-12 cell line, TIB-75 cell lines), thus highlighting the importance of using human cell lines for FLC studies. Inhibition of miR-10b led to reduced proliferation in human cell lines, however the effect was modest. The team concluded that miR10-b may be a good candidate for some type of combination therapy.

Results of this study were published by Cellular and Molecular Gastroenterology and Hepatology in February 2019 and the Journal of Clinical Investigation in April 2022. The full texts of each of those articles can be accessed via the following links:

An article in the Cornell Chronicle available here further describes the February 2019 publication.

Implications: The study’s findings open a potentially new molecular therapeutic approach to FLC. Further studies are necessary to determine whether miR-375 has additional important targets in FLC and exactly how DNAJB1-PRKACA suppresses miR-375 expression.