Current Pharmaceutical Biotechnology - Volume 15, Issue 5, 2014

Human genome sequencing was started to solve four letter algorithm of the genome to understand the complex nature of human metabolism. However, after completion of Human Genome Project many scientists realized that sequence information alone was not sufficient to solve the biochemical mechanism of the organism through classical approaches. Non-coding parts of the genome produce small conserved ribonucleic acids, miRNAs to control cellular and physiological processes [1, 2]. This breakthrough discovery directed researches to examine role of miRNA in cancer since miRNAs are involved in the development, cell differentiation, and regulation of cell cycle [3]. The first paper of the special issue provides general information of miRNA in cancer research. This thematic issue presents two computational approaches for miRNA identification and their role in cancer. The first one comes from Dr. Wang and his presented work predicts cancer-related miRNAs by using expression profiles in tumor tissues. The work relies on R-squared method to investigate miRNA-mRNA regulatory relationship between miRNAs and mRNAs from different tissues and predicts miRNAs associated with colon, prostate, pancreatic, lung, breast, bladder, and kidney cancer. The second paper by Allmer et al. examines miRNA-gene regulatory networks and their implications in cancer. Their work provides complex network of expression regulation and miRNAs’ role in personalized medicine. miRNAs regulate tumor progression and metastasis by interacting with target genes in the cells. Exosomal shuttle small RNAs mediate cell to cell communication and regulate cancer metastasis. The regulation via heterotypic signals in the microenvironment was explained by Dr. Liang and Dr. Yu groups. The rest of the issue highlights the roles of miRNAs on multiple myeloma, non-small cell lung cancer, urological malignancies, myeloid leukemia, and laryngeal squamous cell carcinoma. Proliferation of bone marrow of malignant plasma cells leads multiple myeloma and this accounts for ten percent of the hematological tumors. miRNAs biology in multiple myeloma and miRNA study methods was discussed by Dr. Cho’s group along with translational therapeutics. Dr. Papavassiliou highlights recent literature on miRNA-colerectal cancer. miRNA in colorectal cancer regulates tumor specific markers and these markers have oncogenic and tumor suppressive functions as other types of cancer. The paper overviews miRNA biomarkers extracted from plasma and fecal samples and also explain novel therapeutic applications by miRNA delivery and inhibition. Lung cancer is the leading cause of cancer deaths and non-small cell lung cancer shows poor prognosis and recurrence. Drug resistance limits current treatments and miRNA based gene therapy provides an alternative and attractive method for cancer inhibition since dysregulation of specific miRNAs involved in cancer cell resistance. Therefore, Dr. Giovannetti group explains current efforts in developing miRNA mimickers or antagomiRs for drug resistance mechanism. Dr. Ellinger and Dr. Müller present a comprehensive review on urological malignancies. The relationship between miRNAs and urological malignancies including prostate, renal cell carcinoma, testicular cancer, and bladder cancer and current literature were provided. The paper stimulates discussion on various bodily fluids and detectable miRNAs in patients’ circulation. Thus, specific emphasis was given on circulating miRNAs and diagnostic-prognostic information. Last two papers of the issue provide roles of specific miRNAs in myeloid leukemia and laryngeal squamous cell carcinoma. Dr. Vasconcelos showed that overexpression of miR-128 decreased acute myeloid leukemia cells and increased the DNA damage. Laryngeal squamous cell carcinoma is the largest subgroup of squamous cell carcinoma in head and neck. And Dr. Guo investigated regulation and expression of three miRNAs; miR-21, miR-106b and miR-375. The paper reported these miRNAs as potential biomarkers for laryngeal squamous cell carcinoma diagnosis. miRNAs involved in several metabolic pathways and their roles are yet to be elucidated. This thematic issue presents current efforts in determination of miRNAs at different cancer types. Each day determined miRNAs are deposited to the databases and scientists give a lot of effort to understand the biogenesis of these small molecules. These scientific studies and approaches are expected to improve current technologies for therapy and biomarker detection.

MiRNAs are a family of small, endogenous, and evolutionarily conserved non-coding ribonucleic acids that have been involved in the regulation of several essential, cellular, and functional processes. MicroRNAs are known to play key roles in all types of cancer and function as oncogenes (oncomirs) or tumour-suppressors in up-regulation or down-regulation processes respectively. MiRNAs have potential power to be examined as prognostic and diagnostic biomarkers. Modulating miRNAs, based on two major approaches (miRNA mimics and miRNA antagonists), is used for clinical development of therapeutic miRNAs. This review emphasizes the latest discovery in the field of miRNA research involved in cancer, biomarkers, and therapeutics.

MicroRNAs (miRNAs) are small, noncoding RNAs with important functions in development, cell differentiation, and regulation of cell cycle and apoptosis. Many studies have now shown that miRNAs are involved in the initiation and progression of cancers. In this study, procedures based on the relative R-squared method (RRSM) are proposed to investigate miRNA-mRNA regulatory relationships between 114 miRNAs and 16063 mRNAs for different organic tissues. These procedures are based on comparing the expression profiles in tumor tissue and those in normal tissues, or based on the expression profiles in tumor tissue only. The analyzed results are used to predict high-confident miRNAs for tumor development and their targets. This study predicts many high-confident miRNAs which are associated with colon cancer, prostate cancer, pancreatic cancer, lung cancer, breast cancer, bladder cancer and kidney cancer, respectively.

MicroRNAs (miRNAs) have attracted heightened attention for their role as post-transcriptional regulators of gene expression. It has become clear that miRNAs can both up- and downregulate protein expression. According to current estimates, most human genes are harboring miRNAs and/or are regulated by them. Thus miRNAs form a complex network of expression regulation which tightly interacts with known gene regulatory networks. Similar to some transcription factors, some miRNAs can have hundreds of target transcripts whose expression they modulate. Thus miRNAs can form complex regulatory networks by themselves, but because their expression is often tightly coordinated with gene expression, they form an intertwined regulatory network with many possible interactions among gene and miRNA regulatory pathways. In this review we first consider gene regulatory networks. Then we discuss microRNAs and their implication in cancer and how they may form regulatory networks. Finally, we give our perspective and provide an outlook including the aspect of personalized medicine.

MicroRNAs (miRNAs) are thought to regulate tumor progression and metastasis via direct interaction with target genes within cells. Emerging evidence has demonstrated the secretion of miRNAs into environment via cancer cell exosomes, called “exosomal shuttle small RNA”. Microenvironmental miRNAs are important mediators of cell-to-cell communication, and they play important roles in regulating cancer metastasis. RNA analysis indicates enrichment of the miRNA population in cell-culturing medium. miRNA-conditioned medium is able to mediate the function of miRNAs in regulating cancer cell migration and invasion. Here we combine our recent work with literature discussing multiple mechanisms through which exosomal miRNAs regulate cancer cell migration, invasion and metastasis. We summarize a heterotypic signaling pathway by which miRNA regulates the cellular secretion and tumor microenvironment in control of breast cancer cell migration and invasion. In conclusion, exosomal miRNAs are able to regulate cancer metastasis via heterotypic signals in the microenvironment.

Multiple myeloma (MM) is due to the proliferation in the bone marrow of malignant plasmacells and accounts for about 10% of all hematological tumors. MM is the natural evolution of a monoclonal gammopathy of uncertain significance. Although the introduction of novel biological agents in the clinical practice has changed the natural history of the disease, MM remains incurable. MicroRNAs (miRNAs) are short non-coding RNAs that control cell functions through mRNA targeting. In the cancer setting, miRNAs have shown prognostic and predictive potentials. Several preclinical findings demonstrate their broad anticancer activities in various types of cancer, including MM. In this article, we provide an overview of the biology of miRNAs focusing on the role of miRNA deregulation in MM pathogenesis. These findings represent the basis to discuss the potential role of miRNAs as therapeutic agents against MM.

MicroRNAs (miRNAs) are small, non-coding RNAs that can post-transcriptionally regulate gene expression via messenger RNA (mRNA) targeting. During the past few years several miRNA groups emerged as critical components of developmental and pathological processes, among them being cancer. In colorectal cancer (CRC) specifically, numerous miRNA molecules have been identified up- or downregulated functioning as tumor-specific markers with oncogenic and tumor-suppressive properties. Their dysregulation impacts impaired cellular processes such as cell proliferation, apoptosis, angiogenesis, invasion and metastasis. The detection of extracellular miRNAs in plasma and fecal samples of CRC patients tends to provide novel, non-invasive biomarkers in favor of CRC diagnosis and, at the same time, data from in vivo and in vitro CRC models reveal promising therapeutic applications through miRNA inhibition and miRNA delivery.

Despite recent advances in understanding the cancer signaling pathways and in developing new therapeutic strategies, non-small cell lung cancer (NSCLC) shows grim prognosis and high incidence of recurrence. Insufficient disruption of oncogenic signaling and drug resistance are the most common causes of tumor recurrence. Drug resistance, intrinsic or acquired, represents a main obstacle in NSCLC therapeutics by limiting the efficacy both of conventional chemotherapeutic compounds and new targeted agents. Therefore, novel and more innovative approaches are required for treatment of this tumor. MicroRNAs (miRNAs) are a family of small non-coding RNAs that regulate gene expression by sequence-specific targeting of mRNAs causing mRNA degradation or translational repression. Accumulating evidence suggests that impairment of candidate miRNAs may be involved in the acquisition of tumor cell resistance to conventional chemotherapy and novel biological agents by affecting the drug sensitivity of cancer cells. The modulation of these miRNAs, using antagomiRs or miRNA mimics, can restore key gene networks and signaling pathways, and optimize anticancer therapies by inhibition of tumor cell proliferation and increasing the drug sensitivity. Therefore, miRNA-based therapeutics provides an attractive anti-tumor approach for developing new and more effective individualized therapeutic strategies, improving drug efficiency, and for predicting the response to different anticancer drugs. In this review, we present an overview on the role of miRNAs in resistance mechanisms of NSCLC, discussing the main studies on the aberrations in apoptosis, cell cycle and DNA damage repair pathways, as well as in novel drug targets.

MicroRNAs are small non-coding RNA molecules which do not code for proteins, but control the expression of a significant proportion of the genome. The microRNA expression differences of normal and malignant tissue, as well as the differences in various tumor entities qualify this RNA species as biomarker for cancer patients. The detection of microRNAs in various bodily fluids stimulated research, and it was demonstrated for most human malignancies that tumorassociated microRNAs are detectable in patients circulation, thereby providing diagnostic and/or prognostic information.

miR-128 has been associated with cancer, particularly with leukemia. In particular, this miR has been described, together with other miRs, to allow the discrimination between AML (acute myeloid leukemia) and ALL (acute lymphoblastic leukemia). In addition, miR-128 is included in miR signatures which not only allow characterizing a particular subtype of AML but are also associated with worse clinical outcome in a subgroup of patients with high-risk molecular features of AML. Nevertheless, all the published studies are based on data from expression arrays and no functional studies have been performed. Therefore, in order to further understand the role of miR-128 in AML cells and in their response to some chemotherapy, overexpression of miR-128 was achieved with miR-mimics in an AML cell line (HL-60). This resulted in decreased cellular viability and increased sensitization to both etoposide and doxorubicin. Overexpression of miR-128 increased programmed cell death but had no effect on cell cycle profile, 1 apoptosis or autophagy, as no alterations were observed in the protein levels of PARP, pro-caspase-3, Vps34, Beclin-1 or LC3-II. In addition, miR-128 overexpression increased the levels of DNA damage, as could be concluded by an increase in the comet’s tail intensity in the comet assay, an increase in the number of DNA repair foci stained with either γ-H2AX or 53BP1 proteins, and an increase in the levels of these two proteins (observed by Western blot). To the best of our knowledge, this is the first association of miR-128 with DNA damage in a leukemia context.

MicroRNAs (miRNAs), the endogenous noncoding RNAs, are involved in carcinogenesis. Laryngeal squamous cell carcinoma (LSCC) is the common cancer in head and neck. Whether miRNAs can be used in the diagnosis of LSCC is largely unknown. The purpose of this study was to identify whether miRNAs could be use as potential biomarkers for LSCC diagnosis. The expression levels of miR-21, miR-106b and miR-375, in LSCC tissues and paired nontumor tissues were first quantitatively analyzed by reverse transcription-polymerase chain reaction. Then, the relationships between their expression levels and clinicopathological parameters of patients with LSCC were further determined. We found that these miRNAs’ expression levels were significantly different between LSCC tissues and adjacent normal tissues. Two miRNAs, miR-21 and miR-106b were found up-regulated in cancer tissues (P=0.0012 and P<0.001, respectively), while miR-375 down-regulated (P<0.001). Moreover, miR-21 and miR-106b levels were found significantly increased in poorly (G3)/moderately differentiated (G2) cancer tissues comparing with well differentiated (G1) and dysplasia (D) tissues (P<0.001, respectively). Their levels were also positively associated with lymph node metastasis (P<0.05) and TNM stages (P<0.01). However, miR-375 expression level was only found negatively associated with TNM stages. Our preliminary data suggest that three miRNAs, miR-21, miR-106b and miR- 375 might become novel tumor markers for LSCC diagnosis.