The role of microRNAs in the different phases of liver regeneration

ABSTRACT

Introduction

Since the first discovery of microRNAs (miRs) extensive evidence reveals their indispensable role in different patho-physiological processes. They are recognized as critical regulators of hepatic regeneration, as they modulate multiple complex signaling pathways affecting liver regeneration. MiR-related translational suppression and degradation of target mRNAs and proteins are not limited to one specific gene, but act on multiple targets.

Areas covered

In this review, we are going to explore the role of miRs in the context of liver regeneration and discuss the regulatory effects attributed to specific miRs. Moreover, specific pathways crucial for liver regeneration will be discussed, with a particular emphasis on the involvement of miRs within the respective signaling cascades.

Expert opinion

The considerable amount of studies exploring miR functions in a variety of diseases paved the way for the development of miR-directed therapeutics. Clinical implementation has already shown promising results, but additional research is warranted to assure safe and efficient delivery. Nevertheless, given the broad functional properties of miRs and their critical involvement during hepatic regeneration, they represent an attractive treatment target to promote liver recovery after hepatic resection.

KEYWORDS:

• MicroRNA
• liver regeneration
• liver surgery
• priming phase
• proliferation phase

Article highlights

• This review discusses current evidence on the involvement of microRNAs (miRs) in liver regeneration in the context of partial hepatectomy.

• MiRs are small non-coding RNAs that regulate the expression of specific target genes and their crucial function in development and disease has been extensively studied.

• Several studies have investigated expression patterns and functions of miRs during hepatic regeneration in different partial hepatectomy models, which we have aimed to categorize into the different phases and respective pathways.

• MiRs are critically involved in inflammatory signaling and cell cycle pathway regulation in the initiation and maintenance of hepatocyte proliferation.

• The careful reviewing of the latest developments in this field has garnered tremendous insights but also highlighted the need for more extensive studies in humans to facilitate translation of these results into the clinical setting.

Abbreviations

miR (microRNA), PHx (partial hepatectomy), LSECs (liver sinusoidal endothelial cells), TNFα (tumor necrosis factor alpha), IL6 (interleukin 6), KCs (Kupffer cells), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells), HGF (hepatocyte growth factor), EGFR (epidermal growth factor receptor), VEGF (vascular endothelial growth factor), mTOR (mammalian target of rapamycin), TGFβ (transforming growth factor beta), JAK1 (Janus kinase 1), MAPK (mitogen-activated protein kinase), PI3K (phosphatidyl inositol 3-kinase), STAT3 (signal transducer and activator of transcription 3), SOCS1 (suppressor of cytokine signaling 1), PRAP1 (proline-rich acidic protein 1), CDC25A (cell division cycle 25A), CCND1 (cyclin D1), CDK (cyclin-dependent kinase), CCNA1 (cyclin A1), CCNB1 (cyclin B1), CCND2 (cyclin D2), CCNE2 (cyclin E2), IκB (inhibitor of κB), HGF-A (HGF-activator), uPA (urokinase-type plasminogen activator), HSCs (hepatic stellate cells), EGF (epidermal growth factor), VEGFR (vascular endothelial growth factor), HCC (hepatocellular carcinoma), BCL2 (B-cell lymphoma 2), CCNA2 (cyclin A2), AKT (Akt serine/threonine kinase), PTEN (phosphatase and tensin homolog), PDK1 (phosphatidyl inositol dependent kinase 1), GSK3β (glycogen synthase kinase 3β), mTORC1 (mTOR complex 1), CTNNB1 (β-catenin), CDC2 (cell division protein 2), YAP (Yes-associated protein), TAZ (transcriptional co-activator with PDZ binding motif), NECD (Notch extracellular domain), NICD (Notch intracellular domain), Hh (Hedgehog), PTCH (Patched receptor), Smo (Smoothened), Gli3 (Gli zinc finger 3), CCNE1 (cyclin E1).

Declaration of interest

Patrick Starlinger and Alice Assinger were involved in the development and commercialization of a microRNA-based PCR kit. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.