MicroRNAs in cancer: from developmental genes in worms to their clinical application in patients

Abstract

Several discoveries have paved the way to personalise cancer medicine and a tremendous gain of knowledge in genomics and molecular mechanisms of cancer progression cumulated over the last years. Big stories in biology commonly start in a simple model system. No wonder microRNAs have been identified as regulators of embryonic development in the nematode Caenorhabditis elegans. From the first identification in worms to the first-in-man microRNA-based clinical trial in humans, almost 20 years passed. In this review we follow the story of understanding microRNA alterations in cancer, describe recent developments in the microRNA field and critically discuss their potential as diagnostic, prognostic and therapeutics factors in cancer medicine. We will explain the rationale behind the use of microRNAs in cancer diagnosis and prognosis prediction, but also discuss the limitations and pitfalls associated with this. Novel developments of combined microRNA/siRNA pharmacological approaches will be discussed and most recently data about MXR34, the first-tested microRNA drug will be described.

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

“…First, the multitargeted action of miRNAs, which might potentate the efficacy of miRNA-based drugs, also carries the risk of off-target effects resulting in frequently occurring and severe adverse events in other organs [193]. Additionally, while miRNA mimicry increases the levels of a miRNA that is lost during disease progression, systemic delivery of such miRNA mimics can also result in uptake by non-target tissues that normally do not express the miRNA of interest, resulting in potential off-target effects [194].…”

MicroRNA‑154/ADAM9 axis inhibits the proliferation, migration and invasion of breast cancer cells

“…The importance of miRNAs in tumor initiation and development has been recognized; the abnormal expression of miRNAs serves a significant role in human cancer, caused by a variety of mechanisms, including deletions, amplifications, epigenetic silencing or mutations in miRNA loci (17). Emerging evidence has demonstrated that miRNAs can function as oncogenes or tumor suppressor genes, depending on the roles of their target genes (18). The inactivation of oncogenic miRNAs (19,20) or restoration of tumor-suppressor miRNAs (21,22) may have potential in cancer treatment.…”

Noncoding RNAs: New Players in Cancers

“…In addition, the intratumoral and intercellular heterogeneity of tumors should be fully considered when evaluating the practical application values of miRNAs [ 157 ].…”

“…The mode of action of miRNA-based drugs depends on either suppressing their gain of function (for oncomiRs) or restoring their loss of function (for tumor-suppressive miRNAs) [ 157 ]. On the one hand, synthetic anti-miRNA oligonucleotides (AMOs) with 20-O-methyl modifi cation have been shown to effectively mediate the inhibition of endogenous oncomiRs in cell culture and xenograft mouse models [ 158 ].…”

“…For example, the systemic delivery of a miR-26a mimic was shown to reduce tumor size in a murine liver cancer model [ 162 ]. MRX34 (Mirna Therapeutics, TX, USA), the fi rst-tested miRNA drug, is a miR-34 mimic designed to restore its tumor-suppressive function in cancer cells, which is currently being evaluated in clinical trials [ 157 ].…”