Emerging roles of microRNAs in cancer
Introduction
Cancer is a leading cause of death worldwide. In the last three decades, researchers have identified new cancer-specific targets that have allowed to develop anti-cancer target therapies with an important reduction of side effects. Clonal evolution of cancer cells leads to a variety of survival pathways allowing cancer cells to survive and become resistant to current treatments. Small molecules have been discovered to affect the signal transduction pathways for the survival and proliferation of cancer cells [1]. Among these, microRNAs (miRNAs) are important modifiers of transcription and translation of key regulatory proteins involved in cancer development and progression. They can inhibit or enhance the expression of oncogenes or tumor suppressor genes, therefore profoundly affecting the biology of cancer. MiRNAs belong to a large and growing family of small non-coding RNAs. They have a nucleotide sequence of 19–24 bases in length and they control gene expression by targeting specific mRNAs usually at the level of the 3′ untranslated region (3′-UTR) of the transcript, albeit other less conventional targeting sequences have been identified. A specific mRNA may be targeted by different miRNAs and a single miRNA can have several mRNA targets. MiRNAs are involved in the communication between cancer cells and the surrounding tumor microenvironment (TME). The interaction between tumor cells and components of TME may directly influence all aspects of cancer biology. Extracellular vesicles (EVs) are mediators of the inter-cellular cross-communication occurring within the TME [2, 3]. EVs are characterized by a lipidic bilayer membrane analogue to the plasma membrane and a size ranging from 30 nm to a few microns. EVs are classified into three categories based on their size: exosomes with a size of 30–100 nm, microvesicles with a size ranging from 100 to 1000 nm, and large oncosomes with a size ranging 1–10 μm. Furthermore, all EVs carry a complex cargo composed of proteins, mRNAs, DNA, short and long non-coding RNAs such as miRNAs that can influence the cancer growth. Exosomal miRNAs contribute to angiogenesis by modulating the expression of pro-angiogenic and anti-angiogenic factors. In this review, we will focus on the most important miRNAs dysregulated in tumor cells and their molecular mechanisms to regulate the expression of target genes involved in cancer growth. Finally, we will discuss the key role of miRNAs in the communication between the TME and tumor cells through EVs.
Section snippets
miRNAs expression regulations
miRNAs are dysregulated through different mechanisms. One of these was described by Nawaz et al. They discovered that the miR-4484 is a downregulated tumor suppressor in glioblastoma and it located on chromosome 10 at a fragile locus that undergoes a somatic copy number alteration through a deletion of miRNA sequence [4]. Zhou et al. showed that the amplification of the gene encoding for miR-30d promotes cervical carcinoma growth and progression [5].
Furthermore Yin et al. demonstrated that
miRNAs as oncogenes or tumor suppressor genes
MiRNAs are often dysregulated in cancer patients compared to the normal tissue counterpart. The predicted targets of these miRNAs include both oncogenes and tumor suppressor genes. MiR-155 is upregulated in many human cancers and in more aggressive and therapy-resistant cancers as Van Roosbroeck et al. demonstrated [7•]. The authors of this study observed that downregulation of miR-155 achieved through a treatment with anti-miR-155 successfully re-sensitized tumors to chemotherapy in an in vivo
Vesicular miRNAs in cancer
Recently, EVs have emerged as a prominent way of communication between cells of TME, and they are currently also accepted as mediators of carcinogenesis [16]. Interestingly, EVs from cancer cells show a specific molecular profile both in terms of content and surface markers, allowing their differentiation from EVs released by normal cells [17•, 18]. Since Valadi et al. first demonstrated that miRNAs and other genetic material could be transferred from one cell to another by EVs, miRNAs have
Extra-vesicular miRNAs in cancer
It was previously demonstrated that miRNAs circulate in plasma and serum in a highly stable cell-free form, with a profile that can be altered in cancer and other diseases [27, 28, 29]. The high concentration of RNase activity in the bloodstream has prompted the scientific community to try to explain the mechanism underlying the surprising stability of circulating miRNAs (c-miRNAs). Initially, the release of c-miRNAs in membrane-bound vesicles (exosomes and microvesicles) with protective
Summary and future directions
MiRNAs regulate human carcinogenesis and affect the biology of the TME. They are also key mediators of inter-cellular communication both as c-miRNAs and as cargo of EVs. While the plethora of targets of frequently dys-regulated miRNAs has been the object of several studies, one of the biggest challenges is a better understanding of the selective mechanisms of secretion and delivery of extracellular miRNAs to the cells of the TME. Also, the specificity of uptake (if it exists) will improve our
Authors’ contributions
All the authors were involved in drafting the manuscript, revising it for intellectual content, and reading and approving the final manuscript.
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgments
Dr. Fabbri is a St. Baldrick Foundation's Scholar and is supported by the NIH/NCI grant R01CA215753, a Hyundai Hope on Wheels grant, a Jean Perkins Foundation grant, the Nautica Malibu Triathlon Funds, a STOP Cancer grant, the Hugh and Audy Lou Colvin Foundation grant, an Alex's Lemonade Stand Foundation grant, and the award number P30CA014089 from the National Cancer Institute.
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These authors contributed equally to this work.