Abstract
In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.
Highlights
Introduction to miRNABiologyHuman miRNAs are transcribed in the cell nucleus as long primary transcripts containing a characteristic stem-loop structure of internally paired RNA bases (Figure 1)
By unraveling which common miRNAs and related pathways affect the development and progression of these—at first sight—dissimilar cancer types, one can learn that diverse cancer cells take advantage from similar and conserved mechanisms that have evolved in miRNA-biology
We showed that deltarasin—a novel small-molecule KRAS inhibitor—strongly inhibited proliferation and induced apoptosis in hepatocellular carcinoma (HCC) and in melanoma cells, which was associated with the inhibition of the downstream RAF/MAPK- and PI3K/AKT pathway as well as with the down-regulation of anti-apoptotic (BCL-2, BCL-XL) and the up-regulation of pro-apoptotic (BAX, PUMA) molecules [109]
Summary
According to the last version of the human genome (GRCh38/hg38), the length of the human genome contains about 3.2 billion nucleotides but only about 20,000 protein-coding genes [1]. More and more novel miRNAs are identified as crucial diagnostic and prognostic markers in all types of cancer such as oral cancer [23], glioblastoma [24], melanoma [25], liver cancer [26], colon cancer [27], gastric cancer [28], breast cancer [29], bladder cancer [30] and pancreatic cancer [31]. Likewise, they constitute promising therapeutic targets against cancer [32,33,34]. By unraveling which common miRNAs and related pathways affect the development and progression of these—at first sight—dissimilar cancer types, one can learn that diverse cancer cells take advantage from similar and conserved mechanisms that have evolved in miRNA-biology
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