Immortalized Human Hepatic Stellate Cells-SV40 (Tet-on)

Hepatocyte‑Derived miR‑887‑3p as a Response Biomarker and Independent Prognostic Factor in PRI‑724 Antifibrotic Therapy

There are currently no antifibrotic therapies for liver cirrhosis. Yoshida et al. previously conducted a phase I trial demonstrating the safety and potential antifibrotic activity of the investigational agent PRI-724. They sought to determine which circulating EV-miRNAs were associated with treatment response and which were associated with treatment efficacy after therapy with PRI-724 as potential biomarkers for antifibrotic therapies.

Three miRNAs were associated with response to PRI-724 (miR-6510-5p, miR-6772-5p, miR-4261), and three were associated with treatment efficacy (miR-939-3p, miR-887-3p, miR-7112-5p). Of these six miRNAs tested in liver tissue, only miR-887-3p had a signal intensity >26 and significantly changed levels after PRI-724 treatment (P=0.045) (Fig. 1A).

ISH demonstrated that miR-887-3p was expressed in hepatocytes similarly to the hepatocyte enriched miR-122-3p. qPCR of EV-miRNAs from immortalized hepatocytes (THLE-3) and hepatic stellate cells (LX-2) revealed miR-887-3p expression only in THLE-3 immortalized hepatocytes suggesting hepatocytes are the primary source of miR-887-3p. Exposure to C-82, the active metabolite of PRI-724 did not significantly change expression of miR-887-3p in THLE-3 cells(Fig. 1B).

Of interest, increased expression of miR-887-3p in HCC tissue was associated with worse prognosis using the TCGA-LIHC dataset (Fig. 1C). Tissue miR-887-3p was also determined to be an independent prognostic factor for HCC through Cox regression. These data suggest inhibition of miR-887-3p may provide cytoprotective effects to the liver.