Maitri Y. Shah

Tumour angiogenesis regulation by the miR-200 family

The miR-200 family is well known to inhibit the epithelial-mesenchymal transition, suggesting it may therapeutically inhibit metastatic biology. However, conflicting reports regarding the role of miR-200 in suppressing or promoting metastasis in different cancer types have left unanswered questions. Here we demonstrate a difference in clinical outcome based on miR-200s role in blocking tumour angiogenesis. We demonstrate that miR-200 inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 secreted by the tumour endothelial and cancer cells. Using several experimental models, we demonstrate the therapeutic potential of miR-200 delivery in ovarian, lung, renal and basal-like breast cancers by inhibiting angiogenesis. Delivery of miR-200 members into the tumour endothelium resulted in marked reductions in metastasis and angiogenesis, and induced vascular normalization. The role of miR-200 in blocking cancer angiogenesis in a cancer-dependent context defines its utility as a potential therapeutic agent.

MicroRNAs miR-221 and miR-222: a new level of regulation in aggressive breast cancer.

MicroRNAs (miRNAs) are crucial in the initiation and progression of tumors. A recent study has reported that the miRNAs miR-221 and miR-222 are involved in the promotion of an aggressive basal-like phenotype in breast cancer, functioning downstream of the RAS pathway and triggering epithelial-to-mesenchymal transition. These new insights into the roles of miR-221/222 in breast cancer metastasis, drug resistance and RAS pathways could potentially have applications in medical practice.

microRNA Therapeutics in Cancer — An Emerging Concept

MicroRNAs (miRNAs) are an evolutionarily conserved class of small, regulatory non-coding RNAs that negatively regulate protein coding gene and other non-coding transcripts expression. miRNAs have been established as master regulators of cellular processes, and they play a vital role in tumor initiation, progression and metastasis. Further, widespread deregulation of microRNAs have been reported in several cancers, with several microRNAs playing oncogenic and tumor suppressive roles. Based on these, miRNAs have emerged as promising therapeutic tools for cancer management. In this review, we have focused on the roles of miRNAs in tumorigenesis, the miRNA-based therapeutic strategies currently being evaluated for use in cancer, and the advantages and current challenges to their use in the clinic.

Allele-specific reprogramming of cancer metabolism by the long non-coding RNA, CCAT2

Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68). The CCAT2 interaction with the CFIm complex fine-tunes the alternative splicing of Glutaminase (GLS) by selecting the poly(A) site in intron 14 of the precursor mRNA. These findings uncover a complex, allele-specific regulatory mechanism of cancer metabolism orchestrated by the two alleles of a long ncRNA.

MicroRNAs as therapeutic targets in human cancers

MicroRNAs (miRNAs) are evolutionarily conserved, small, regulatory RNAs that negatively regulate gene expression. Extensive research in the last decade has implicated miRNAs as master regulators of cellular processes with essential role in cancer initiation, progression, and metastasis, making them promising therapeutic tools for cancer management. In this article, we will briefly review the structure, biogenesis, functions, and mechanism of action of these miRNAs, followed by a detailed analysis of the therapeutic potential of these miRNAs. We will focus on the strategies presently used for miRNA therapy; discuss their use and drawbacks; and the challenges and future directions for the development of miRNA‐based therapy for human cancers. WIREs RNA 2014, 5:537–548. doi: 10.1002/wrna.1229

The Mix of Two Worlds: Non-Coding RNAs and Hormones

The recent discovery of functional cell-free circulating microRNAs (miRNAs) in human body fluids has opened new avenues for the application of non-coding RNAs (ncRNAs) as noninvasive, specific and sensitive biomarkers for cancers and other human diseases. In this review, we explore the concept of circulating miRNAs as hormones, and discuss their potential functions in cellular communication and transferring of signals. We also provide a brief overview of their identification, processing, and potential functions and applications in human diseases.

N-BLR, a primate-specific non-coding transcript leads to colorectal cancer invasion and migration.

BackgroundNon-coding RNAs have been drawing increasing attention in recent years as functional data suggest that they play important roles in key cellular processes. N-BLR is a primate-specific long non-coding RNA that modulates the epithelial-to-mesenchymal transition, facilitates cell migration, and increases colorectal cancer invasion.ResultsWe performed multivariate analyses of data from two independent cohorts of colorectal cancer patients and show that the abundance of N-BLR is associated with tumor stage, invasion potential, and overall patient survival. Through in vitro and in vivo experiments we found that N-BLR facilitates migration primarily via crosstalk with E-cadherin and ZEB1. We showed that this crosstalk is mediated by a pyknon, a short ~20 nucleotide-long DNA motif contained in the N-BLR transcript and is targeted by members of the miR-200 family. In light of these findings, we used a microarray to investigate the expression patterns of other pyknon-containing genomic loci. We found multiple such loci that are differentially transcribed between healthy and diseased tissues in colorectal cancer and chronic lymphocytic leukemia. Moreover, we identified several new loci whose expression correlates with the colorectal cancer patients’ overall survival.ConclusionsThe primate-specific N-BLR is a novel molecular contributor to the complex mechanisms that underlie metastasis in colorectal cancer and a potential novel biomarker for this disease. The presence of a functional pyknon within N-BLR and the related finding that many more pyknon-containing genomic loci in the human genome exhibit tissue-specific and disease-specific expression suggests the possibility of an alternative class of biomarkers and therapeutic targets that are primate-specific.

Correction to Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2 [Molecular Cell 61, 520-534, (2016)]

Roxana S. Redis1, Luz E. Vela2, Weiqin Lu3,4, Juliana Ferreira de Oliveira5, Cristina Ivan6, Cristian Rodriguez-Aguayo1, Douglas Adamoski5, Barbara Pasculli1, Ayumu Taguchi3, Yunyun Chen8, Agustin F Fernandez9, Luis Valledor10, Katrien Van Roosbroeck1, Samuel Chang1, Maitri Shah1, Garrett Kinnebrew11, Leng Han12, Yaser Atlasi13,¥, Lawrence H Cheung1, Gilbert Yuanjay Huang1, Paloma Monroig1, Marc S Ramirez14, Tina Catela Ivkovic1,15, Long Van2, Hui Ling1, Roberta Gafà16, Sanja Kapitanovic15, Giovanni Lanza16, James A Bankson14, Peng Huang3, Stephan Y Lai8, Robert C Bast1, Michael G Rosenblum1, Milan Radovich11, Mircea Ivan11, Geoffrey Bartholomeusz1, Han Liang17, Mario F. Fraga18, William R Widger2, Samir Hanash7, Ioana Berindan-Neagoe1,19,20, Gabriel Lopez-Berestein1, Andre LB Ambrosio5, Sandra M Gomes Dias5, and George A Calin1,6,#

MicroRNAs as Therapeutic Targets

MicroRNAs (miRNAs) are evolutionarily conserved class of small, regulatory RNAs that negatively regulate gene expression, and control multiple cellular processes involved in cancer initiation, progression, and metastasis. Extensive research in the past decade has identified vital role of miRNAs in hematopoiesis and leukemogenesis, with miRNAs functioning as oncogenes or tumor suppressors. Several miRNAs are extensively dysregulated in acute myeloid leukemia (AML), and their expression patterns are useful diagnostic and prognostic markers in AML. Furthermore, miRNA expression patterns have been associated with specific cytogenetic and molecular aberrations in AML subsets. Based on these observations, miRNAs have emerged as promising therapeutic tools for AML. In this chapter, we focus on the roles of miRNAs in AML tumorigenesis, their widespread deregulation, the rationale and strategies for their use as AML therapeutic targets, and the advantages and current challenges to their use in the clinic.

Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations

The cancer-risk-associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long noncoding RNA CCAT2 in the highly amplified 8q24.21 region have been implicated in cancer predisposition, although causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. We further identified that CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 induces global deregulation of gene expression by down-regulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel non-APOBEC, non-ADAR, RNA editing at the SNP locus in MDS/MPN patients and CCAT2-transgenic mice. The RNA transcribed from the SNP locus in malignant hematopoietic cells have different allelic composition from the corresponding genomic DNA, a phenomenon rarely observed in normal cells. Our findings provide fundamental insights into the functional role of rs6983267 SNP and CCAT2 in myeloid malignancies.