MicroRNAs: Emerging Novel Targets of Cancer Therapies

During the past ten years, microRNAs (miRNAs) have been shown to play a more significant role in the formation and progression of cancer diseases than previously thought. With an increase in reports about the dysregulation of miRNAs in diverse tumor types, it becomes more obvious that classic tumor-suppressive molecules enter deep into the world of miRNAs. Recently, it has been demonstrated that a typical tumor suppressor p53, known as the guardian of the genome, regulates some kinds of miRNAs to contribute to tumor suppression by the induction of cell-cycle arrest and apoptosis. Meanwhile, miRNAs directly/indirectly control the expression level and activity of p53 to fine-tune its functions or to render p53 inactive, indicating that the interplay between p53 and miRNA is overly complicated. The findings, along with current studies, will underline the continuing importance of understanding this interlocking control system for future therapeutic strategies in cancer treatment and prevention. Lung cancer is the leading cause of cancer-related deaths. Biomarkers for lung cancer have raised great expectations in their clinical applications for early diagnosis, survival, and therapeutic responses. MicroRNAs (miRNAs), a family of short endogenous noncoding RNAs, play critical roles in cell growth, differentiation, and the development of various types of cancers. Current studies have shown that miRNAs are present in the extracellular spaces, packaged into various membrane-bound vesicles. Tumor-specific circulating miRNAs have been developed as early diagnostic biomarkers for lung cancer. Remarkably, some studies have succeeded in discovering circulating miRNAs with prognostic or predictive significance. Extracellular vesicles (EVs), such as exosomes and microvesicles, are recognized as novel tools for cell-cell communication and as biomarkers for various diseases. Their vesicle composition and miRNA content have the ability to transfer biological information to recipient cells and play an important role in cancer metastasis and prognosis. This review provides an in-depth summary of current findings on circulating miRNAs in lung cancer patients used as diagnostic biomarkers. We also discuss the role of EV miRNAs in cell-cell communication and explore the effectiveness of these contents as predictive biomarkers for cancer malignancy. MicroRNAs (miRNAs) are short noncoding RNA which regulate gene expression by messenger RNA (mRNA) degradation or translation repression. The plethora of published reports in recent years demonstrated that they play fundamental roles in many biological processes, such as carcinogenesis, angiogenesis, programmed cell death, cell proliferation, invasion, migration, and differentiation by acting as tumour suppressor or oncogene, and aberrations in their expressions have been linked to onset and progression of various cancers. Furthermore, each miRNA is capable of regulating the expression of many genes, allowing them to simultaneously regulate multiple cellular signalling pathways. Hence, miRNAs have the potential to be used as biomarkers for cancer diagnosis and prognosis as well as therapeutic targets. Recent studies have shown that natural agents such as curcumin, resveratrol, genistein, epigallocatechin-3-gallate, indole-3-carbinol, and 3,3 󸀠 -diindolylmethane exert their antiproliferative and/or proapoptotic effects through the regulation of one or more miRNAs. Therefore, this review will look at the regulation of miRNAs by natural agents as a means to potentially enhance the efficacy of conventional chemotherapy through combinatorial therapies. It is hoped that this would provide new strategies in cancer therapies to improve overall response and survival outcome in cancer First discovered in 1993, microRNAs (miRNAs) have been one of the hottest research areas over the past two decades. Oftentimes, miRNAs levels are found to be dysregulated in cancer patients. The potential use of miRNAs in cancer therapies is an emerging and promising field, with research finding miRNAs to play a role in cancer initiation, tumor growth, and metastasis. Therefore, miRNAs could become an integral part from cancer diagnosis to treatment in future. This review aims to examine current novel research work on the potential roles of miRNAs in cancer therapies, while also discussing several current challenges and needed future research.

MicroRNAs (miRNAs) are a large family of small noncoding RNAs (∼22 nucleotide long) that negatively regulate proteincoding gene expression posttranscriptionally by interacting with messenger RNAs (mRNAs), causing either their degradation or translation inhibition. While miRNAs were first discovered as important regulators of developmental timing, subsequent studies have shown that their deregulations are critically involved in various diseases, including cancer. This is evident from the crucial roles they play in regulating a wide range of cellular processes such as cell survival, apoptosis, cell cycle progression and proliferation, cell-cell interaction, differentiation, and motility.
It has been found that miRNA expression levels are altered in all types of cancer and they play important roles in almost all aspects of cancer pathogenesis such as initiation, promotion, metastasis, and responses to drug treatment. These recognitions and other accumulating evidences clearly suggest that miRNAs can serve as novel targets for cancer therapies. Indeed, targeting abnormally-expressed miRNAs has been shown to have great potential in suppressing primary tumor growth, reducing tumor metastasis, and overcoming anticancer drug resistance. It is anticipated that miRNAs can be valuable cancer-specific targets and novel miRNA-based targeted therapies can be formulated to provide effective treatments for cancer. The purpose of this special issue is to provide readers with an overview of research findings on the roles of miRNAs in cancer development, progression, diagnosis and treatment, and how miRNA expression may be regulated. This issue will also update the readers about the challenges and possibilities of miRNAs to emerge as future cancer therapeutics.
A. L. Oom et al. first briefly review the potential value of miRNAs as cancer diagnostic markers, which is followed by the detailed discussion on the potential role of miRNAs in cancer therapy. The authors review literatures reporting the role of miRNAs in sensitizing of or mediating resistance to traditional and targeted cancer therapies. A nice summary about studies on miRNAs in combination with traditional cancer therapies is provided in a table. The authors also discuss the current studies on miRNA delivery systems. This review ends with discussion on challenges and perspectives of developing miRNAs as effective cancer therapies.
The review paper, authored by K. Otsuka and T. Ochiya, discusses the role of miRNAs in tumor development by uniquely focusing on the interplay between the classic tumor suppressor p53 and the emerging tumor regulatory miRNAs. The authors review recent findings showing both the regulation of expression of various miRNAs by p53 and the direct targeting of p53 by miRNAs. Particularly, this review summarizes up to date research findings about the critical roles of various miRNAs in regulation of cell cycle and apoptosis in the p53 pathways. Y. Fujita, K. Kuwano, T. Ochiya, and F. Takeshita provide an in-depth review of current findings showing the potential of circulating miRNAs as diagnostic biomarkers for lung cancer. This review discusses the general mechanism of miRNA release into extracellular spaces and the impact of extracellular vesicle-encapsulated circulating miRNAs on cancer progression. Moreover, this review also summarizes current studies in detail showing the potential of miRNAs as circulating biomarkers in cancer diagnosis, particularly for lung cancer.
N. H. Phuah and N. H. Nagoor review the regulation of miRNAs by natural compounds. Recent studies have shown that natural agents such as curcumin, resveratrol, genistein, epigallocatechin-3-gallate, indole-3-carbinol, and 3,3 -diindolylmethane exert their antiproliferative and/or proapoptotic effects through the regulation of one or more miRNAs. This review summarizes current research findings about the regulation of miRNAs by above natural compounds. The review also discusses the potential of integrating natural agents with conventional chemotherapeutic drugs, thus, enhancing their efficacy.
The review article by S. K. Srivastava, S. Arora, C. Averett, S. Singh, and A. P. Singh discusses the effect of naturally occurring phytochemicals on miRNA expression. Particularly, the authors focus on the underlying molecular mechanisms of miRNA regulation by phytochemicals and their functional significance in cancer development and progression. Moreover, the translational potential of the relevant research findings is also discussed.
In closing, the guest editors of this special issue would like to thank all the reviewers for their timely and excellent review and journal management team for efficient processing of papers from submission through publication.