Retrospective Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Nov 27, 2020; 12(11): 1031-1045
Published online Nov 27, 2020. doi: 10.4254/wjh.v12.i11.1031
Circulating miR-21-5p level has limited prognostic value in patients with hepatocellular carcinoma and is influenced by renal function
Martin Franck, Cosima Thon, Kerstin Schütte, Peter Malfertheiner, Alexander Link
Martin Franck, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany
Martin Franck, Cosima Thon, Kerstin Schütte, Peter Malfertheiner, Alexander Link, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany
Kerstin Schütte, Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken Marienhospital, Osnabrück 49074, Germany
Author contributions: Franck M performed the experiments; Schütte K and Malfertheiner P provided the clinical material; Franck M, Thon C, and Link A carried out the analysis and interpretation of the data and drafting of the manuscript; Link A created the study concept and design and is the guarantor of the study; All authors edited and approved the final version of the manuscript.
Institutional review board statement: The study was reviewed and approved by the ethical board of the Otto-von-Guericke University (Study number 99/10).
Informed consent statement: The study was performed according to the principle of the Declaration of Helsinki. The study was approved by Institutional Review Board of Otto-von-Guericke University Magdeburg No. 99/10. All patients provided written informed consent.
Conflict-of-interest statement: Authors declare that they have no potential conflicts of interest.
Data sharing statement: Technical appendix and dataset available from the corresponding author: alexander.link@med.ovgu.de. Participants gave informed consent for data analysis and publication. Certain restriction may apply in accordance to patient´s consent.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Alexander Link, MD, PhD, Academic Research, Associate Professor, Doctor, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Street 44, Magdeburg 39120, Germany. alexander.link@med.ovgu.de
Received: June 11, 2020
Peer-review started: June 12, 2020
First decision: July 30, 2020
Revised: August 15, 2020
Accepted: September 18, 2020
Article in press: September 18, 2020
Published online: November 27, 2020
Processing time: 165 Days and 3.8 Hours
Abstract
BACKGROUND

MicroRNAs (miRNAs) have been suggested as biomarkers for malignant diseases including hepatocellular carcinoma (HCC). Specifically, hsa-miR-21-5p (miR-21) is among the most frequently deregulated miRNA in cancer. The diagnostic and prognostic value of miR-21 has been demonstrated in HCC tissue, mostly in the Asian population. Although the impact of various factors has been recently reported for circulating hsa-miR-122-5p (miR-122), at present only limited knowledge is available for miR-21.

AIM

To evaluate the value of miR-21 for the assessment of prognosis in HCC patients and to delineate the influence of clinical and preanalytical factors on miR-21 level in sera.

METHODS

Patients with confirmed HCC from our European cohort with predominantly alcohol-associated liver damage were included in the study. All subjects were characterized according to their clinical and laboratory work-up and overall survival data were obtained. Quantitative real-time polymerase chain reaction was performed for miR-21 and spiked-in cel-miR-39-3p. The results were compared to previously reported miR-122 data.

RESULTS

Survival of HCC patients was comparable between patients with low and high serum miR-21 concentration. No association was observed between miR-21 level in sera and Child-Pugh score, Barcelona Clinic Liver Cancer staging system, or etiology of HCC/liver disease. Age, gender, or pretreatment had no association with miR-21 level. A positive correlation was observed between miR-21 and aspartate aminotransferase (r = 0.2854, P = 0.0061), serum miR-122 (r = 0.2624, P = 0.0120), and the International Normalized Ratio (r = 0.2065, P = 0.0496). Negative correlation of miR-21 with serum creatinine (r = -0.2215, P = 0.0348) suggests renal function as a potential influencing factor in miR-21 biogenesis in blood.

CONCLUSION

The results from this work do not support clinically relevant prognostic value of circulating miR-21 in HCC patients in real-life settings. Following systematic evaluation, we identified renal function and aspartate aminotransferase as potential factors that may affect miR-21 concentration in blood. This knowledge should be considered in future miRNA-based biomarker studies not only for HCC but also for other diseases.

Keywords: Hepatocellular cancer; Hepatocellular carcinoma; MicroRNA; Prognosis; miR-21-5p; Renal function

Core Tip: In our previous work, we identified renal function, hemoglobin, and liver injury as potential factors that may impact circulating microRNA expression. miR-21-5p is the most frequently deregulated miRNA in various types of cancer. Several reports have proposed miR-21-5p as a prognostic biomarker in hepatocellular carcinoma. In this study, serum miR-21-5p values were not associated with prognosis of hepatocellular carcinoma in a European cohort of patients with predominantly alcohol-related liver injury. In a similar fashion as previously reported for miR-122-5p, changes in circulating miR-21-5p level correlated with renal function and liver injury. This observation shows that caution should be taken in interpreting circulating miR-21-5p level and its biomarker potential.