Current Pharmaceutical Design - Volume 20, Issue 33, 2014

Recent studies have highlighted the pivotal role of microRNAs (miRNAs) in tumorigenesis. A growing body of data implicates that miRNAs are critically involved in regulation of cell growth, cell cycle, apoptosis, migration, invasion, angiogenesis, metastasis, epithelial to mesenchymal transition (EMT), cancer stem cell renewal, and drug resistance. Therefore, our special issue reviewed the important role of miRNAs in the development and progression of human cancers. It has been accepted that miRNAs play an essential role in human malignancies. Dr. Markel et al. reviewed the diverse roles of miRNAs in regulation of cell cycle, proliferation, migration, invasion and drug resistance in melanoma cell biology [1]. Moreover, Dr. Zhou et al. discussed the oncogenic miRNAs in the genesis of leukemia and lymphoma, suggesting that miRNAs could be novel targets for anti-leukemia and anti-lymphoma drug discovery [2]. Dr. Sarkar et al. summarized the function of miRNAs in breast cancer tumorigenesis and metastasis, and provided the current knowledge of miRNAs as molecular targets for diagnosis, prognosis and therapy in breast cancer [3]. Emerging evidence has suggested that miRNAs exert its biological functions through governing key signaling pathways. To support this concept, Dr. Azmi et al. summarized that a number of miRNAs control Kras-PAK4 (p21 activated kinase 4) axis in cancer [4]. Dr. Xie et al. discussed that miRNAs are key players in pancreatic cancer initiation and progression through regulating FOXM1 signaling pathway [5]. Furthermore, Dr. Batra and colleagues summarized miRNAs as biomarkers for prognosis and diagnosis of gastrointestinal cancers and gastrointestinal tract associated organs including esophagus, gastric, liver, pancreas, and colon [6]. Intriguingly, Dr. Lu et al. discussed the developments on the regulatory role of miRNAs in circulating tumor cells and thrombosis, suggesting that targeting miRNAs could be useful for the treatment and prevention of metastasis and thrombosis in cancer [7]. It is noteworthy that miRNAs have been demonstrated to be involved in EMT progress. Dr. Yang et al. described that multiple miRNAs regulated EMT-inducing transcription factors such as Notch and TGF-β, leading to regulation of EMT in cancer [8]. Since EMT and miRNAs are associated with cancer stem cells (CSCs), Dr. Watabe et al. discussed how miRNAs regulate CSCs through different self-renewal pathways in various types of human cancers [9]. More importantly, Dr. Croce et al. discussed approaches towards therapeutic miRNA-based intervention including viral or non-viral approaches of miRNA replacement therapy [10]. Remarkably, Dr. Fan et al. summarized the implication of miRNAs in clinical use and challenge for miRNA based therapy such as miRNA delivery [11]. Notably, Dr. Wang et al. demonstrated that natural agent genistein down-regulated oncomiR-27a in pancreatic cancer cells, indicating that genistein could be a miR-27a inhibitor [12]. Dr. Chen et al. observed that arsenic trioxide exerts its anti-tumor activity partly through regulation of miR-125b in glioma cells [13]. Taken together, targeting miRNAs could be a novel strategy for treatment of cancer. Lastly, as the editor, I would like to thank the authors for their contributions. I also would like to appreciate the referees for their timely reviews. We hope that this special issue will help identify novel therapeutic targets to treat human cancers.

Melanoma is a high-grade, poorly differentiated malignant tumor of pigment-producing cells (melanocytes), accounting for more than 70% of the skin cancer related deaths. Although new lines of targeted therapy and immunotherapy were introduced lately, durable responses are not common as it is hard to target the elusive metastatic phenotype. microRNAs (miRNAs) are short non-coding RNA molecules that function as specific epigenetic regulators of the transcriptome. miRNAs are involved in a broad spectrum of physiological and pathological processes, including cancer-related functions such as proliferation, cell cycle, migration, invasion, immune evasion and drug resistance. These functions are mostly regulated in melanoma through four molecular deregulated pathways, including the RAS/MAPK pathway, the MITF pathway, the p16INK4A-CDK4-RB pathway and the PI3K-AKT pathway. miRNAs provide a strong platform for delineation of cancer mechanisms. Here we review the diverse roles of miRNAs in melanoma cell biology. Studying miRNA-mediated regulation of aggressive and tumor related features is expected to provide novel mechanistic insights that may pave the way for new diagnostic, prognostic and predictive tools as well as new molecular targets for future therapy.

Emerging evidence has shown that microRNAs (miRNAs) can act as oncogenes in the initiation and progression of leukemia and lymphoma. Aberrant expression of oncogenic miRNAs, including miR-155, miR-17-92, miR-21, miR-125b, miR-93, miR-143-p3, miR-196b, and miR-223 promotes leukemogenesis through increasing the leukemic stem/progenitor cell population, promoting cell proliferation, blocking cell differentiation, and diminishing cell apoptosis. In addition, abnormal expression of oncogenic miRNAs, such as miR-155, miR-17-92, the miR15a/16-1 cluster, miR21, miR34a, and miR125b has been implicated in lymphomagenesis. Notably, miR- 155 and miR-17-92 profoundly changed the gene expression signatures and signal transduction pathways in various hematopoietic cells, and triggered leukemogenesis and lymphomagenesis. Therefore, miRNAs play an important role in the genesis of leukemia and lymphoma. Accordingly, oncogenic miRNAs may serve as diagnostic and prognostic factors for patients with leukemia or lymphoma, and could be used as targets for novel anti-leukemia and anti-lymphoma drug discovery.

Breast cancer is one of the most common type of cancers as well as a principal cause of cancer-related deaths in women worldwide. Although research has provided a better understanding and diagnosis of breast cancer, studies in breast cancer therapeutics are still far from satisfactory. Recent research on microRNAs (miRNAs) has implicated these tiny regulatory molecules in progression of breast cancer with the possibility of exploiting them as diagnostic and/or prognostic biomarkers. The loss of tumor suppressor miRNAs or overexpression of oncogenic miRNAs can lead to breast cancer tumorigenesis or metastasis. However, the next step – linking miRNAs to cancer therapeutics – is still under progression. The roles of miRNAs exhibit much potential in breast cancer therapy, but currently need to be further studied and evaluated in order to better understand how to apply laboratory results to clinical medicine. Here we provide an update on our current understanding of miRNAs as molecular targets for diagnosis, prognosis and therapy of breast cancers.

MicroRNAs (miRNAs), often aberrantly expressed in cancer, have been implicated in the regulation of a number of critical cell survival pathways including the genes in the Kras signaling. Kras mutations are observed in more than half of cancers and its inhibition has been the focus of intense research for the past 30 years. However, Kras itself has proven to be non-druggable due in part to the absence of binding pockets for small molecule drugs. These hurdles resulted in researchers shifting their focus on targeting proteins downstream to Kras pathways. P21 activated kinase 4 (PAK4) belongs to the family of serine/threonine kinases comprising of 6 isoforms (PAK 1-6) and is considered as a key effector of Rho family of GTPases downstream of RAS. PAK4 controls critical processes such as cellular motility, proliferation and survival. Recently a number of small molecule PAK4 antagonists have been investigated in preclinical and clinical setting; albeit without any success. Emerging evidence shows that PAK is tightly regulated by a number of miRNAs that are also recognized to promote hyper-activation of oncogenic Kras signaling. Therefore, the understanding of the role of miRNAs in the regulation of PAK4 is critical to the development of therapies against this important player in the Kras pathway. Through this review, we bring forward mechanistic insights on PAK4 regulation by aberrantly expressed miRNAs in cancer and its implications on Kras signaling. We anticipate that enhanced knowledge of the miRNA-PAK4 interaction network will allow the development of successful therapies targeting this critical protein to ultimately rein in Kras.

Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the United States and has a median 5-year survival rate less than 5%. Although surgery offers the best chance for a cure for pancreatic cancer, less than 20% of patients are eligible for potentially curative resection, because in most cases, the cancer has already spread locally or to distant organs at diagnosis, precluding resection. MicroRNAs (miRNAs) are small noncoding, endogenous, single-stranded RNAs that are pivotal regulators of posttranscriptional gene expression. Extensive studies of miRNAs over the past several years have revealed that the expression of miRNAs is frequently deregulated in pancreatic cancer patients and that this deregulation contributes to the pathogenesis and aggressiveness of the disease. Currently, investigators are studying the use of miRNAs as diagnostic and/or prognostic biomarkers and therapeutic tools for pancreatic cancer. Rapid discovery of many miRNA targets and their relevant pathways has contributed to the development of miRNA-based therapeutics. In particular, the transcription factor Forkhead box M1 (FOXM1) is overexpressed in the majority of cancer patients, including those with pancreatic cancer. This overexpression is implicated to have a role in tumorigenesis, progression, and metastasis. This important role of FOXM1 affirms its usefulness in therapeutic interventions for pancreatic cancer. In this review, we summarize the current knowledge and concepts concerning the involvement of miRNAs and FOXM1 in pancreatic cancer development and describe the roles of the miRNA-FOXM1 signaling pathway in pancreatic cancer initiation and progression. Additionally, we describe some of the technical challenges in the use of the miRNA-FOXM1 signaling pathway in pancreatic cancer treatment.

Gastrointestinal (GI) cancers remain one of the most common malignancies and are the second common cause of cancer deaths worldwide. The limited effectiveness of therapy for patients with advanced stage and recurrent disease is a reflection of an incomplete understanding of the molecular basis of GI carcinogenesis. Major advancements have improved our understanding of pathology and pathogenesis of GI cancers, but high mortality rates, unfavorable prognosis and lack of clinical predictive biomarkers provide an impetus to investigate new sensitive and specific diagnostic and prognostic markers for GI cancers. MicroRNAs (miRNAs) are short (19-24 nucleotides) noncoding RNA molecules that regulate gene expression at the posttranscriptional level thus playing an important role in modulating various biological processes including, but not limited to developmental processes, proliferation, apoptosis, metabolism, differentiation, epithelial-mechenchymal transition and are involved in the initiation and progression of various human cancers. Unique miRNA expression profiles have been observed in various cancer types at different stages, suggesting their potential as diagnostic and prognostic biomarkers. Due to their tumor-specific and tissue-specific expression profiles, stability, robust clinical assays for detection in serum as well as in formalin-fixed tissue samples, miRNAs have emerged as attractive candidates for diagnostic and prognostic applications. This review summarizes recent research supporting the utility of miRNAs as novel diagnostic and prognostic tools for GI cancers.

Metastasis and thrombosis are serious threats to cancer patients and generally associated with poor prognosis. The elusive mechanisms underlying the pathogenesis of metastasis and thrombosis have been subjects of extensive investigations. The presence of circulating tumor cells (CTCs) is closely related to tumor metastasis, and these cells play an important role in thrombosis in cancer patients. In this review, we describe the latest findings on the role of CTCs in tumor metastasis and cancer-related thrombosis and the regulatory role of microRNAs in CTCs and thrombosis. Additionally, we discuss anticoagulant-based strategies for the prevention of thrombosis and reduction of cancer metastasis and the potential to translate current knowledge on these strategies to the treatment of cancer.

The epithelial-mesenchymal transition (EMT) is a process by which epithelial tumor cells acquire migratory and invasive abilities that enable them to spread to other organs. During this process, the tight junction molecule, E-cadherin, is often downregulated through transcription repression by the EMT-inducing transcription factors (EMT-TFs). MicroRNAs (miRNAs) are a class of small noncoding RNA molecules which bind to the complementary sequences within mRNA molecules. They post-transcriptionally govern gene silencing, thus affecting a broad range of physiological conditions, including EMT. In this review, we will discuss some well-known as well as brand-new EMT-related miRNAs and the signaling pathways in the tumor milieu that regulate their expressions and control cancer invasion and metastasis. Finally, we will discuss the application of miRNAs as therapeutic targets for treatment of cancer.

In the past decade, cancer stem cells (CSCs) have been isolated, characterized, and studied in a variety of cancers and they are believed to be responsible for tumor initiation and progression. Like normal stem cells, these cells retain self-renewal property and therefore, can differentiate into multiple tumor types. Despite this clinical importance, how CSCs are regulated and their exact pathological role are yet to be elucidated. Recent studies have shed light on the potential role of miRNAs in regulating CSCs. In this review, we summarize the current findings of miRNAs in the regulation of CSCs through different self-renewal pathways and the potential therapeutic implications of miRNAs in clinical settings by targeting CSCs.

MicroRNAs (miRNAs) are endogenously expressed and evolutionarily conserved small non-coding RNAs, which regulate gene expression. Several studies have shown that they are involved in fundamental biological processes, such as proliferation and apoptosis. MicroRNA dysregulation plays an important role in cancer onset and progression where miRs can function as both tumor promoters (oncomiRs) or tumor suppressors by targeting numerous biomolecules that are important in carcinogenesis. MicroRNA molecules are already entering the clinic as diagnostic and prognostic biomarkers for patient stratification and also as therapeutic targets and agents. Their role as biomarkers and therapeutic targets is appealing but several obstacles have as yet limited our ability to translate this potential into a clinical reality. This review provides a comprehensive overview of miRNAs with established functional relevance in cancer. Furthermore, approaches towards therapeutic miRNA-based intervention are discussed. Those include viral or non-viral approaches of miRNA replacement therapy in the case of tumor-suppressing miRNAs and strategies for the inhibition of oncogenic miRNAs.

From chemotherapy and radiotherapy to molecular targeted therapy, in recent decades, we have witnessed the acceleration of cancer treatments. However, nowadays, it has encountered obstacles due to multi-drug resistance, drug-induced toxicity and the insufficient disruption of cancer pathways. Thus, it is required to have more efficient approaches for cancer treatments. MicroRNAs (miRNAs) are perhaps the most researched genes in the last decade. They have been reported to play significant roles in cancers and are considered to be applied in targeted cancer therapies. Here, we will firstly review the implications of miRNAs in clinical use from the aspects of miRNA biogenesis and biological functions, followed by the diagnostic and prognostic values of miRNAs. Furthermore, the application of miRNAs in pre-clinical cancer models and clinical trials regarding miRNAs will also be discussed. Moreover, since miRNA delivery is the biggest challenge for miRNA based therapy, the commonly used delivery methods will then be reviewed. The miRNA combinational therapy with chemotherapy, radiotherapy, molecular targeted therapy and immunotherapy will be reviewed and discussed at last.

Background: Although genistein has been reported to exert its anti-tumor activity, the exact mechanism of its action is poorly elucidated. Recently, it has been found that genistein could regulate the expression of microRNAs. Therefore, our aim in the present study was to find whether genistein regulates specific miR-27a in pancreatic cancer cells. Methods: We performed our studies using multiple methods including MTT assay, RT-PCR, Western blotting analysis, migration, invasion assay, and transfection. Results: We observed that genistein significantly inhibited the expression of miR-27a in pancreatic cancer cells. Moreover, inhibition of miR-27a suppressed cell growth and induced apoptosis as well as inhibited invasion in pancreatic cancer cells. Furthermore, we found a synergy effect between miR-27a and genistein on cell growth inhibition, apoptosis, and invasion, suggesting that targeting miR-27a may represent a potential strategy for treatment of pancreatic cancer. Conclusions: Our findings demonstrated that genistein plays a tumor suppressor role in part through inhibition of miR-27a in pancreatic cancer cells.

Background: Arsenic trioxide (As2O3) has been demonstrated to suppress tumorigenesis in human glioma. However, the exact molecular mechanisms by which As2O3 exerts its tumor suppressor functions are elusive. Therefore, it is warranted to explore the underlying mechanism of As2O3–mediated anti-tumor activity in glioma. Methods: To achieve our goal, we used multiple approaches including MTT assay, apoptosis, Real-time RT-PCR, Western blotting, invasion assay, and gene transfection. Results: We observed that A22O3 inhibited cell growth and induced apoptosis as well as suppressed migration and invasion in human glioma cells. Moreover, we found that As2O3 down-regulated miR-125b expression and subsequently up-regulated its target gene Bak1 expression. Furthermore, we identified that As2O3 exerts its anti-tumor activity partly through regulation of miR-125b. Conclusions: Our present study suggests that As2O3 could be a potential therapeutic agent for treatment of human glioma.