miR-191: an emerging player in disease biology

Specific microRNAs have emerged as key players in disease biology by playing crucial role in disease development and progression. This review draws attention to one such microRNA, miR-191 that has been recently reported to be abnormally expressed in several cancers (>20) and various other diseases like diabetes-type 2, Crohn’s, pulmonary hypertension and Alzheimer’s. It regulates important cellular processes such as cell proliferation, differentiation, apoptosis and migration by targeting important transcription factors, chromatin remodelers and cell cycle associated genes. Several studies have demonstrated it to be an excellent biomarker for cancer diagnosis and prognosis leading to two patents already in its kitty. In this first review we summarize the current knowledge of the regulation, functions and targets of miR-191 and discuss its potential as a promising disease biomarker and therapeutic target

Rak oskrzelikowo-pęcherzykowy pod postacią nacieku nieustępującego w okresie 2 lat

Bronchioloalveolar carcinoma (BAC), a rare form of lung malignancy, is usually seen in non-smokers and women. Three distinct histological forms have been identified viz, mucinous, non-mucinous and mixed or indeterminate. The mucinous variety of BAC may present as a consolidation which is very difficult to differentiate from an infective pneumonia. We present a case of a middle aged female who was evaluated for a “non-resolving consolidation” for a period of two years. She had undergone an inconclusive bronchoscopy and had received several courses of antibiotics including anti-tuberculous therapy without relief. The size of the lesion had remained largely unchanged during this period and there was no significant clinical deterioration in the patient. Transbronchial biopsy done on presentation revealed BAC of the mucinous variety. BAC presenting as a large consolidation without significant change for a period of two years has rarely been documented in the literature.Rak oskrzelikowo-pęcherzykowy, rzadka postać nowotworu występuje częściej u osób niepalących i u kobiet. Wyróżnia się trzy postacie histopatologiczne: śluzową, nieśluzową oraz mieszaną lub nieokreśloną. Odmiana śluzowa może przebiegać pod postacią nacieku trudnego do zróżnicowania z zapaleniem płuc. Przedstawiamy przypadek raka oskrzelikowo-pęcherzykowego u kobiety diagnozowanej przez 2 lata z powodu nieustępującego nacieku. Początkowo wykonano u pacjentki badanie bronchofiberoskopowe, które nie wyjaśniło przyczyny. Była kilkakrotnie nieskutecznie leczona antybiotykami oraz odbyła leczenie przeciwgruźlicze, które również nie przyniosło poprawy. Rozmiar nacieku nie ulegał zasadniczym zmianom w ciągu całego okresu obserwacji a stan pacjentki nie ulegał pogorszeniu. Przezoskrzelowa biopsja płuca wykonana przy przyjęciu wykazała odmianę śluzową raka oskrzelikowo- pęcherzykowego. Opisano dotychczas zaledwie pojedyncze przypadki raka oskrzelikowo-pęcherzykowego przebiegającego w postaci nieustępujących w tak długim okresie rozległych nacieków w płucach

Analysis of microRNA transcriptome by deep sequencing of small RNA libraries of peripheral blood

<p>Abstract</p> <p>Background</p> <p>MicroRNAs are a class of small non-coding RNAs that regulate mRNA expression at the post - transcriptional level and thereby many fundamental biological processes. A number of methods, such as multiplex polymerase chain reaction, microarrays have been developed for profiling levels of known miRNAs. These methods lack the ability to identify novel miRNAs and accurately determine expression at a range of concentrations. Deep or massively parallel sequencing methods are providing suitable platforms for genome wide transcriptome analysis and have the ability to identify novel transcripts.</p> <p>Results</p> <p>The results of analysis of small RNA sequences obtained by Solexa technology of normal peripheral blood mononuclear cells, tumor cell lines K562 and HL60 are presented. In general K562 cells displayed overall low level of miRNA population and also low levels of DICER. Some of the highly expressed miRNAs in the leukocytes include several members of the let-7 family, miR-21, 103, 185, 191 and 320a. Comparison of the miRNA profiles of normal versus K562 or HL60 cells revealed a specific set of differentially expressed molecules. Correlation of the miRNA with that of mRNA expression profiles, obtained by microarray, revealed a set of target genes showing inverse correlation with miRNA levels. Relative expression levels of individual miRNAs belonging to a cluster were found to be highly variable. Our computational pipeline also predicted a number of novel miRNAs. Some of the predictions were validated by Real-time RT-PCR and or RNase protection assay. Organization of some of the novel miRNAs in human genome suggests that these may also be part of existing clusters or form new clusters.</p> <p>Conclusions</p> <p>We conclude that about 904 miRNAs are expressed in human leukocytes. Out of these 370 are novel miRNAs. We have identified miRNAs that are differentially regulated in normal PBMC with respect to cancer cells, K562 and HL60. Our results suggest that post - transcriptional processes may play a significant role in regulating levels of miRNAs in tumor cells. The study also provides a customized automated computation pipeline for miRNA profiling and identification of novel miRNAs; even those that are missed out by other existing pipelines. The Computational Pipeline is available at the website: <url>http://mirna.jnu.ac.in/deep_sequencing/deep_sequencing.html</url></p

miR-22 regulates expression of oncogenic neuro-epithelial transforming gene 1, NET1

MicroRNAs control cellular processes by regulating expression of their target genes. Here we report that neuro-epithelial transforming gene 1 (NET1) is a target of tumor suppressor microRNA 22 (miR-22). miR-22 is downregulated in peripheral blood mononuclear cells derived from chronic myeloid leukemia (CML) patients and in CML cell line K562. NET1 was identified as one of the targets of miR-22 using both in vitro and in vivo experiments. Either mutations or naturally occurring single-nucleotide polymorphisms in NET1 3′-UTR that map at the miR-22 binding site were found to affect binding of miR-22 to NET1 mRNA. Over expression of NET1 in K562 cells resulted in increased proliferation. However decreased proliferation and alteration in cell cycle were observed on either overexpression of miR-22 or knockdown of NET1 expression respectively. We also found that overexpression of miR-22 or NET1 knockdown inhibits actin fiber formation, probably by downregulation of NET1 as NET1 knockdown also resulted in depletion of actin fiber formation. We suggest that the oncogenic properties of CML cells are probably due to deregulated expression of NET1 as a result of altered expression of miR-22

ApoptomiRs of Breast Cancer: Basics to Clinics

Apoptosis is a highly regulated process, the deregulation of which has been associated with the tumor initiation, progression, metastasis and response to therapy in various cancers including breast cancer. High levels of apoptosis have been correlated to malignant phenotype and worse prognosis in breast cancer. Breast cancer therapy relies on the induction of apoptosis for mediating cancer cell death. Thus, identifying apoptotic mediators and regulators is imperative for molecular biologists and clinicians for benefit of patients. The regulation of apoptosis is complex and involves a tight equilibrium between the pro- and anti-apoptotic factors. Recent studies have highlighted the role of miRNAs in the control of apoptosis and their interplay with p53, the master guardian of apoptosis. However, there has been no report so far that reviews the miRNAs in breast cancer that are involved in the regulation of apoptosis. Here we summarize and integrate the data on the role of miRNAs in apoptosis in breast cancer and the clinical advantage it may offer for the prognosis or treatment of breast cancer patients

Engineered smart materials for RNA based molecular therapy to treat Glioblastoma

Glioblastoma (GBM) is an aggressive malignancy of the central nervous system (CNS) that remains incurable despite the multitude of improvements in cancer therapeutics. The conventional chemo and radiotherapy post-surgery have only been able to improve the prognosis slightly; however, the development of resistance and/or tumor recurrence is almost inevitable. There is a pressing need for adjuvant molecular therapies that can successfully and efficiently block tumor progression. During the last few decades, non-coding RNAs (ncRNAs) have emerged as key players in regulating various hallmarks of cancer including that of GBM. The levels of many ncRNAs are dysregulated in cancer, and ectopic modulation of their levels by delivering antagonists or overexpression constructs could serve as an attractive option for cancer therapy. The therapeutic potential of several types of ncRNAs, including miRNAs, lncRNAs, and circRNAs, has been validated in both in vitro and in vivo models of GBM. However, the delivery of these RNA-based therapeutics is highly challenging, especially to the tumors of the brain as the blood-brain barrier (BBB) poses as a major obstacle, among others. Also, since RNA is extremely fragile in nature, careful considerations must be met while designing a delivery agent. In this review we have shed light on how ncRNA therapy can overcome the limitations of its predecessor conventional therapy with an emphasis on smart nanomaterials that can aide in the safe and targeted delivery of nucleic acids to treat GBM. Additionally, critical gaps that currently exist for successful transition from viral to non-viral vector delivery systems have been identified. Finally, we have provided a perspective on the future directions, potential pathways, and target areas for achieving rapid clinical translation of, RNA-based macromolecular therapy to advance the effective treatment of GBM and other related diseases