Identifying Differentially Expressed MicroRNAs Between Cirrhotic and Non-Cirrhotic Hepatocellular Carcinoma and Exploring Their Functions Using Bioinformatic Analysis

Abstract

Background/Aims: Few studies have been designed to directly investigate the exact mechanisms underlying the different phenotypes between cirrhotic and non-cirrhotic hepatocellular carcinoma (HCC). This study aimed to illuminate the incidence and developmental mechanisms for both types of HCC through differentially expressed microRNAs (miRNAs) using bioinformatic analysis. Methods: The miRNA-seq data and clinical data of patients (from The Cancer Genome Atlas (TCGA) database) were utilized to determine differentially expressed miRNAs between cirrhotic and non-cirrhotic HCC. Afterwards, the function of the selected miRNAs was predicted with online tools. Furthermore, the miRNA expression and clinical significance were validated by external datasets and our experiment. Results: The present study included 135 non-cirrhotic and 80 cirrhotic patients to find differentially expressed miRNAs. Among them, four miRNAs (mir-1296, mir-23c, mir-149, and mir-95) were finally selected for further validation and analysis. Correlation analysis found that two miRNAs are greatly associated with the non-cirrhotic HCC patients’ clinical traits, such as the T, M, and N tumor stages. However, only mir-23c was associated with the cirrhotic HCC patients’ tumor T and N stages. Furthermore, survival analysis revealed that increased mir-149 in non-cirrhotic HCC, patients’ age and the existence of vessels in the tumor in cirrhotic HCC were independent risk factors for the patients’ postoperative overall survival. Functional and interaction analyses also supported the notion that these miRNAs function through some pathways that influence the behavior of the HCC. These results are strongly supported by analysis of extra datasets and our experiment. Conclusions: The cirrhotic and non-cirrhotic HCC types involve differentially expressed miRNAs, which are correlated with distinctive pathological traits. To some extent, non-cirrhotic HCC seems more dependent on miRNA network regulation, but additional studies are needed to confirm this conclusion.

Risk Scoring System based on lncRNA Expression for Predicting Survival in Hepatocellular Carcinoma with Cirrhosis

“…This may help explain why none of the lncRNAs in our risk scoring systems occurs in the previously published risk scoring systems for HCC prognosis. The importance of developing prognostic tools for HCC with cirrhosis is underscored by the observation of several microRNAs differentially expressed between patients with or without cirrhosis, particularly mir-149 (Mei et al, 2018), miR-24 and miR-27a (Salvi et al, 2013). These differences may help explain the different prognosis in the two types of HCC.…”

Dysregulated microRNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Potential as Biomarkers and Therapeutic Targets

“…Since most miRNA have a moderate (<3-fold) difference between cases and controls and both large intra-individual and inter-individual variation, large sample sizes are required for sufficient power to minimize type 1 and II errors. Replication using public datasets [e.g., the Cancer Genome Atlas (TCGA) database] may provide additional supporting evidence (145,146). (2) Validation for circulating miRNAs: To develop liquid biopsies for detection, diagnosis, and prognosis, miRNAs identified from serum/plasma should be validated to miRNAs obtained from tumor tissue before clinical evaluation as biomarkers.…”

“…Since most miRNA have a moderate (<3-fold) difference between cases and controls and both large intra-individual and inter-individual variation, large sample sizes are required for sufficient power to minimize type 1 and II errors. Replication using public datasets [e.g., the Cancer Genome Atlas (TCGA) database] may provide additional supporting evidence ( 145 , 146 ).…”

New and old biomarkers of hepatocellular carcinoma

“…As a prognostic factor, low level and down-regulation of miRNA-542 and miRNA-139 are associated with poor prognosis as vascular invasion, larger tumor size and metastatic disease [79,80] . Expression of miRNA profile in the histopathological analysis after HCC resection can predict the risk of HCC recurrence within the Milan criteria [81] , HCC miRNAs expression varies between cirrhotic and non-cirrhotic HCC [82] . Remarkably, miRNAs like miR503HG suppress metastasis and inhibit malignant cell migration.…”