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Scientists Scrutinize Promising Molecules as Potential Drug Targets and Biomarkers

Genetic Engineering News – Patricia F. Dimond, Ph.D.

MicroRNAs (miRNAs) finely regulate gene expression and play an important role in various cellular processes, including cell growth, differentiation, proliferation, and apoptosis. To date, more than 5,000 of these endogenous, noncoding single-stranded RNAs have been identified. miRNAs act through binding to complementary mRNA sequences, thereby preventing their translation into protein or accelerating mRNA breakdown. Investigators are working on exploiting these molecules for experimental and potential therapeutic applications. (read more)

Presentations:

From Worms to Humans: Understanding the Role of miRNAs in Cancer Progression

Aurora Esquela-Kerscher, Ph.D., Assistant Professor, Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School

miRNAs regulate important developmental events and are often misexpressed in human cancers, but little is known regarding how these molecules contribute to tumor formation. Our laboratory uses a combination of nematode and mammalian model systems to functionally characterize miRNAs and determine the role these factors play in controlling processes related to cellular growth and differentiation. The let-7 miRNA family is postulated to function as tumor suppressor genes in tissues such as the lung by regulating the oncogenes RAS, MYC, and HMGA2 as well as several cell cycle progression genes. We will present recent findings regarding our work on the role of let-7 together with other miRNA families in directing cancer progression pathways during development and in human tissues, particularly of urothelial origin.

Posters:

University of Houston
27. Luisa Helguero; Lars-Arne Haldosen; Cecilia Williams; and Eylem Aydogdu: Regulatory miRNAs in Mammary Stem-Like Cells and Breast Cancer Cells

University of Luxembourg
28. Demetra Philippidou; Dirk Moser; Christiane Margue; Petr V. Nazarov; Arnaud Muller; Laurent Vallar; Dorothee Nashan; Iris Behrmann; Stephanie Kreis; and Martina Schmitt: Signatures of microRNAs and Selected Target Genes in Human Melanoma

Houston (PRWEB) March 19, 2010 — LC Sciences today announced the launch of its new Seq-Array services designed to take full advantage of both the latest deep sequencing capabilities and the proven genomics tool – microarray. This combination of technologies advances microRNA research to the next level of depth and understanding that was not possible before with either of the technologies alone. LC Sciences has been a leading provider of microRNA discovery and profiling services since 2005.  (read more)

More information is available at http://www.lcsciences.com/seqarray.html.

Seq-Array^SM offers a customized solution to high-throughput genome-wide miRNA discovery and profiling, especially in species with limited or no miRNA sequence information available. This unique combination of the latest deep sequencing technology, advanced bioinformatics, and our innovative µParaflo^® custom microarray platform leverages all these technologies to form a comprehensive service package tailored to your specific research needs.

Seq-Array^SM provides an efficient pathway from an initial broad miRNA search to focused biological insights.

by Jeffrey M. Perkel

Once the domain of microarrays – the previous decade’s hot technology — transcriptome analysis (that is, gene expression monitoring on a genome-wide scale) is now associated with the current “it” technology: Next-generation DNA sequencing.

Though such data can be collected using arrays (sequencing was previously used mostly for transcript discovery), with sequencing “You are not limited to what you probe,” he explains. “You can discover new things.” In other words, sequencing approaches, unlike microarrays, are unbiased – “hypothesis-neutral,” in Baker’s words – meaning you can find things you weren’t looking for, and reanalyze the data later as new discoveries come to light…

[Gene-expression microarrays still hold some advantages over sequencing.]

…Not everyone has access to a next-gen DNA sequencer for one thing, and even if they do, they may not be able to get instrument time when they need it.

More critically, sequencing is generally time-consuming (one to two weeks per run, typically), expensive, and bioinformatically challenging – all of which presents a problem for independent researchers outside of major sequencing centers, and especially, for diagnostics developers.  (read more)

As high-throughput techniques accelerate mapping of epigenetic marks, researchers are racing to find the biological meaning of these marks.

Thanks to the Human Genome Project, researchers worldwide can search a database to see what a gene ’says’. In just a few years, researchers may also be able to look up when a gene is ‘read’. Or, rather, they will be able to pull up the epigenome, the set of chemical modifications to DNA and DNA-spooling proteins that coordinate how cells use genes.

Even with international enthusiasm, coordination and funding, epigenome mapping will be a long, complicated slog. Although an individual’s genome sequence varies little from cell to cell, each of the 200 or so human cell types has its own epi-genome. Epigenomes also change during development and in response to the environment. Cancer, aging and even behavioral disorders are all associated with epigenetic lesions. “The epigenome space is so much larger than the genome space,” says John Stamatoyannopoulos of the University of Washington in Seattle, who heads one of four epigenome mapping centers funded by the US National Institutes of Health. “The measurement space is absolutely gigantic. No single technology is going to penetrate this with anything approaching completeness,” he says.

Baker M. (2010) Epigenome: mapping in motion. Nat Meth 7, 181 – 86. [article]

Table 1: Suppliers Guide: Companies offering epigenetics services and products

Frank Breitling¹ , Christopher Schirwitz², Thomas Felgenhauer², Ines Block², Volker Stadler² and Ralf Bischoff²

3/22/10 – 3/24/10  Boston, MA

TOPICS INCLUDE:

microRNA in Cancer
microRNA in Biomarker and Diagnostic Development
microRNA in Therapeutic Development
microRNA in Human Development and Disease
microRNA Pathways and Mechanisms

Don’t miss the Technology Showcase Wed 3/24/10

12:35-12:50 Seq-Array – miRNA Discovery and Profiling Using a Customizable Workflow

Christoph Eicken, Ph.D., Head of Technical Services – Microarrays, LC Sciences
Current miRNA profiling methods rely on the limited sequence information available, hence the focus on a few model species. Seq-Array is a customized solution high-throughput genome-wide miRNA profiling to overcome these limitations. It combines and leverages three technologies: the latest deep sequencing technology, advanced bioinformatics, and μParaflo™ custom microarrays. This talk will present the workflow and a case study with 777 newly discovered miRNAs.

Here is the latest list of publications from our customers making use of our microRNA Discovery and Profiling Services.  The current list includes more than 140 publications by some of the leading researchers in the microRNA field.  Enjoy!

It is known that Rho-associated kinase (ROCK) signaling plays a fundamental role in regulating cell morphology, adhesion, and motility and that aberrant expression of ROCK is related to tumor metastases and poor clinical outcome. Researchers at Tufts University proposed that ROCK may enhance the metastatic propensity of breast cancer cells by promoting the c-Myc pathway, including transcription of c-Myc–regulated miRNAs (miR-17-92 cluster)¹. They used LC Sciences microRNA microarray services to show a 2- to 6-fold increase in expression of the miR-17-92 cluster in two metastatic breast cancer cell lines compared with non metastatic cells. The miR-17-92 expression in the three cell lines was validated by endpoint and qRT-PCR. Additionally, they showed that an anti-miR can block the ROCK signaling pathway resulting in decreased breast cancer cell invasion/ migration and metastasis. Therefore, inhibition of ROCK-mediated signaling appears to be a promising and potentially specific approach to suppress breast cancer metastases.

Numerous miRNAs have been shown to act as positive and negative regulators of the phosphoinositide-3-kinase (PI3K)/Akt-signaling pathway. The miR-29 family and miR-126 negatively affect the pathway through repression of PI3K regulatory subunits and many miRNAs positively influence PI3K/Akt signaling by targeting phosphatase and tensin homolog (PTEN) for inhibition which negatively affect phosphoinositide-3-kinase (PI3K)/Akt signaling. Researchers at the University of Texas Southwestern Medical Center, Dallas made use of LC Sciences microRNA microarray analysis and found that miR-486 showed a dramatic increase in expression in myocardin-related transcription factor-A (MRTF-A)–transduced cells². The induction of miR- 486 by MRTF-A was confirmed by Northern blot and real-time RT– PCR. PTEN is a strongly predicted target of miR-486 and they further demonstrated that inhibition of miR-486 expression enhances the expression of PTEN and dampens signaling through the PI3K/Akt-signaling pathway.  These findings implicate miR- 486 as another potential modulator of PI3K/Akt signaling.

1. Liu S, Goldstein RH, Scepansky EM, Rosenblatt M.  (2009) Inhibition of rho-associated kinase signaling prevents breast cancer metastasis to human bone.  Cancer Res 69(22), 8742-51. [abstract]
2. Small EM, O’Rourke JR, Moresi V, Sutherland LB, McAnally J, Gerard RD, Richardson JA, Olson EN. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. Proc Natl Acad Sci U S A 107(9), 4218-23. [abstract]

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