Review
Non-coding RNAs and potential therapeutic targeting in cancer

https://doi.org/10.1016/j.bbcan.2020.188491Get rights and content

Abstract

Recent advances have begun to clarify the physiological and pathological roles of non-coding RNAs (ncRNAs) in various diseases, including cancer. Among these, microRNAs (miRNAs) have been the most studied and have emerged as key players that are involved in the regulation of important growth regulatory pathways in cancer pathogenesis. The ability of a single ncRNA to modulate the expression of multiple downstream gene targets and associated pathways, have provided a rationale to pursue them for therapeutic drug development in cancer. In this context, early data from pre-clinical studies have demonstrated that synthetic miRNA-based therapeutic molecules, along with various protective coating approaches, has allowed for their efficient delivery and anti-tumor activity. In fact, some of the miRNA-based cancer therapeutic strategies have shown promising results even in early-phase human clinical trials. While the enthusiasm for ncRNA-based cancer therapeutics continue to evolve, the field is still in the midst of unraveling a more precise understanding of the molecular mechanisms and specific downstream therapeutic targets of other lesser studied ncRNAs such as the long-non-coding RNAs, transfer RNAs, circular RNAs, small nucleolar RNAs, and piwi-interacting RNAs. This review article provides the current state of knowledge and the evolving principles for ncRNA-based therapeutic approaches in cancer, and specifically highlights the importance of data to date and the approaches that are being developed to overcome the challenges associated with their delivery and mitigating the off-target effects in human cancers.

Introduction

Decades of accumulating research indicates that dysregulated expression of certain genes in critical growth regulatory pathways is a major driver of oncogenesis in human malignancies. Although the prevailing consensus is that altered gene expression is causally related to cancer pathogenesis, the underlying mechanisms driving the neoplastic growth of cancer cells are far more complex. Extensive investigations in the context of genetic causes of cancer have revealed that aberrant gene expression is not only a consequence of protein-coding genes, but to a large extent is also mediated by the regulatory actions of non-coding genomic elements in the human genome. The Encyclopedia of DNA Elements (ENCODE) transcriptome project concluded that only ~1.2% of the genome comprises protein-coding genes, whereas ~80% of it is actively transcribed into a variety of non-coding RNAs (ncRNAs), some of which have been characterized, and some of which are under active interrogation [1]. Although ncRNAs were initially deemed as “transcriptional noise,” “junk DNA,” or “dark genomic matter,” research in the past two decades has provided convincing and irrefutable evidence favoring biological roles for various types of ncRNAs in various diseases, including cancer [2]. Broadly speaking, all ncRNAs can be divided into two categories based on size: small ncRNAs (sncRNAs), which are shorter than 200 nucleotides and long ncRNAs (lncRNAs) that are longer than 200 nucleotides. The sncRNA category includes microRNAs (miRNAs), transfer RNAs (tRNAs), piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs) [3]. Although specific biological functions for some sncRNAs continue to be realized and appreciated, a fascinating theme that has emerged to date is that hierarchically, ncRNAs represent a higher-level gene regulatory domain, and a single ncRNA is theoretically capable of controlling the expression of many downstream gene (messenger RNA (mRNA)) targets.

In view of the increased recognition of the biological roles of ncRNAs in various diseases, it is not surprising that recent years have seen a concerted effort to evaluate the translational and clinical significance of sncRNAs in cancer and other diseases [[4], [5], [6], [7], [8], [9], [10]]. Given that a single sncRNA can control the expression of several mRNA targets in distinct cancer-associated pathways, an early hypothesis was that using a ncRNA-based therapeutic approach would address the issue of the multi-faceted nature of cancer pathogenesis and resultant tumor heterogeneity present in various cancers. Indeed, numerous studies and clinical trials have already been initiated to leverage this aspect of ncRNAs, and ncRNA-based anti-cancer drug development has gained significant momentum and is potentially ripe for breakthroughs [11]. Based upon the evidence gathered to date, this review evaluates the advantages and challenges associated with ncRNA-based cancer therapy, and summarizes the knowledge surrounding emerging therapeutic strategies for the application of ncRNAs in cancer treatment.

Section snippets

Microrna (miRNA)-based therapy in cancer

While the evidence for miRNA-based cancer therapy in cancer is still in relative early stages, burgeoning body of literature and scientific evidence indicates that this concept has merit, while additional research is needed to overcome existing challenges as we improve our understanding for their functional downstream targets.

lncRNAs in cancer

The lncRNAs are a class of ncRNAs that are typically longer than 200 nucleotides; despite lacking protein-coding capability, they are involved in the pathogenesis of cancer. Of the approximately 60,000 lncRNAs identified from human tumor tissues and cancer cell lines, a significant majority (more than 70%) are still awaiting appropriate annotations [99]. Nonetheless, the functional roles of numerous lncRNAs whose expression is often dysregulated in various cancers have been investigated (Table 3

Other ncRNA-based cancer therapeutic targets

Successful miRNA-based cancer research has prompted further investigations to identify other ncRNA families that might serve as potential therapeutic targets in cancer. High-throughput sequencing approaches have resulted in the identification of many new classes of ncRNAs that contribute to the pathogenesis of various diseases, including cancer. We list and illustrate several families of ncRNAs known to be involved in oncogenesis with a promising therapeutic potential (Fig. 2).

Potential clinical implications

The clinical application of ncRNAs as potential therapeutic targets in cancer can manifest in two scenarios: using ncRNAs to “replenish” suppressed or missing RNAs (replacement therapy) or to “block” the effects of over-active oncogenic RNAs. The ncRNA-based replacement therapy primarily benefits patients with reduced tumor-suppressor-miR expression or those with an overexpression of the downstream targets of these miRNAs. Replenishing downregulated miRNAs (or the use of miRNA mimics) that have

Opportunities and challenges

Although our understanding for the roles of ncRNAs in various cancers continues to improve, there is still much to learn. miRNAs are the most well studied among the family of ncRNAs; therefore, their presence at the forefront of ncRNA-based cancer therapeutics is not surprising. Unfortunately, to date, it has been difficult to definitively categorize the majority of miRNAs as either tumor suppressors or oncogenes. However, recent technological advancements and the increased affordability of

Funding

The present work was supported by the grants CA72851, CA181572, CA184792, and CA202797 from the National Cancer Institute, National Institutes of Health.

Declaration of Competing Interest

No conflicts of interest exist for any of the authors.

Acknowledgements

The authors would like to thank Dr. Wenhao Weng for his useful insights, and Dr. Sarah Wilkinson, City of Hope, Beckman Research Institute, Duarte, CA and Dr. Margaret Hinshelwood, manager of the Office of Scientific Publications, Baylor Charles A. Sammons Cancer Center, Dallas, for critical suggestions and editing to further improve the quality of this article.

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