Functional and Clinical Significance of Dysregulated microRNAs in Liver Cancer

Abstract

Liver cancer is the leading cause of cancer-related mortality in the world. This mainly reflects the lack of early diagnosis tools and effective treatment methods. MicroRNAs (miRNAs) are a class of non-transcribed RNAs, some of which play important regulatory roles in liver cancer. Here, we discuss microRNAs with key impacts on liver cancer, such as miR-122, miR-21, miR-214, and miR-199. These microRNAs participate in various physiological regulatory pathways of liver cancer cells, and their modulation can have non-negligible effects in the treatment of liver cancer. We discuss whether these microRNAs can be used for better clinical diagnosis and/or drug development. With the advent of novel technologies, fast, inexpensive, and non-invasive RNA-based biomarker research has become a new mainstream approach. However, the clinical application of microRNA-based markers has been limited by the high sequence similarity among them and the potential for off-target problems. Therefore, researchers particularly value microRNAs that are specific to or have special functions in liver cancer. These include miR-122, which is specifically expressed in the liver, and miR-34, which is necessary for the replication of the hepatitis C virus in liver cancer. Clinical treatment drugs have been developed based on miR-34 and miR-122 (MRX34 and Miravirsen, respectively), but their side effects have not yet been overcome. Future research is needed to address these weaknesses and establish a feasible microRNA-based treatment strategy for liver cancer.

Trials and Tribulations of MicroRNA Therapeutics

“…Miravirsen demonstrated significant efficacy in reducing viremia among HCV patients [168,169,183], leading to several phase II clinical trials (NCT01200420, NCT01872936, NCT02031133, NCT02508090). However, the trial was terminated due to severe side effects [145,184].…”

Evaluation and Application of Drug Resistance by Biomarkers in the Clinical Treatment of Liver Cancer

“…As the number of models designed to identify and predict biomarker genes capable of identifying drug susceptibility continues to grow, a priority for future research should be the development of new therapies targeting specific pathways involved in the pathogenesis of HCC [ 41 , 42 , 43 ]. Among the challenges in the clinical diagnosis of liver cancer is identifying biomarkers that satisfy the criteria of specificity, ease of detection (noninvasiveness), and the ability to reflect different pathological phenomena (tumor stage, size, invasion degree, and patient survival rate) [ 44 ]. Although still in the research stage, many biomarkers are available for use in evaluating the outcome of different treatments for liver cancer.…”

“…A trend in recent years in the selection of biomarkers has been a focus on nucleic acid candidates. Compared with protein biomarkers, nucleic acids offer advantages of high speed, low cost, ease of sampling, and high accuracy [ 44 ]. One such example is the long noncoding RNA, ARSR (lncARSR), which was shown to be significantly upregulated in HCC tissues compared with adjacent noncancerous liver tissues [ 66 ].…”

Prospective therapeutics for intestinal and hepatic fibrosis

“…The application of delivery systems has increased the feasibility of ncRNA manipulation in vivo making ncRNAs feasible therapeutic targets for various diseases 24,25 . miRNAs can be knocked down or complemented through the administration of antisense oligonucleotides or the delivery of miRNA mimics 26,27 . In IBD, various miRNAs are upregulated or downregulated at the intestinal fibrotic site compared to their expression in healthy tissues supporting the use of miRNA‐based therapeutics for intestinal fibrosis.…”

“…24,25 miRNAs can be knocked down or complemented through the administration of antisense oligonucleotides or the delivery of miRNA mimics. 26,27 In IBD, various miRNAs are upregu- Compared to a PBS (phosphate buffered saline)-treated control, miR-200b-MVs reduced the expression of colonic fibronectin and collagen I by 28.08% and 51.65%, respectively, in rats with intestinal fibrosis. 29 lncRNAs are long-chain (>200 nucleotides) ncRNAs that play important roles in gene transcription, mRNA processing, and translation.…”