miRNA Blog

MicroRNA Regulation of Kinase Activity

Chris — Wed, 10 Mar 2010 15:56:03 +0000

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 microRNA microarray analysis 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. 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 performed microarray analysis and found that miR-486 showed a dramatic increase in expression in myocardin-related transcription factor-A (MRTF-A)–transduced cells². 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.

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]
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]

Nominate your favorite microRNA

Chris — Fri, 05 Mar 2010 14:47:03 +0000

Leave a comment naming your favorite microRNA and a quick explanation of why its your favorite.

The winner will be featured as the “microRNA of the week” in an upcoming post.

No related posts.

Transfer of genetic material from human to human occurs by means other than through sexual reproduction?

Chris — Tue, 02 Mar 2010 15:23:44 +0000

microRNA as a New Immune-Regulatory Agent in Breast Milk

Background

Breast milk is a complex liquid that provides nutrition to the infant and facilitates the maturation of the infant’s immune system. Recent studies indicated that microRNA (miRNA) exists in human body fluid. Because miRNAs are known to regulate various immune systems, we hypothesized that human breast milk contains miRNAs that may be important for the development of the infant’s immune system.

Findings

We profiled miRNA expression in human breast milk and detected high expression levels of immune-related miRNAs in the first 6 months of lactation. Furthermore, these miRNA molecules are stable even in very acidic conditions, indicating that breast milk allows dietary intake of miRNAs by infants.

Conclusions

Our findings provide new insight into how breast milk can modulate the development of the infant’s immune system. This study suggests the transfer of genetic material as miRNA from human to human occurs by means other than through sexual reproduction.

Kosaka N, Izumi H, Sekine K, Ochiya T. (2010) microRNA as a new immune-regulatory agent in breast milk. Silence [Epub Ahead of Print]. [abstract]

microRNA of the Week: microRNA-451

Chris — Fri, 26 Feb 2010 14:47:12 +0000

Hypoxia and monocrotaline induced strong upregulation of miR-451 suggesting a role in the development of pulmonary arterial hypertension (PAH)¹, a complex disorder leading to right-sided heart failure and death. Head and neck squamous cell carcinomas (HNSCC) constitute the fifth most common malignancy worldwide. Significant downregulation of miR-451 was observed in relapsed HNSCC patients suggesting that downregulation of miR-451 could be a viable candidate marker for HNSCC². Underexpression of miR-451 has been associated with worse prognosis in gastric cancer, with macrophage inhibitor factor suggested as its potential mRNA target³. Increasing Evidence has suggested that bronchioalveolar stem cell (BASC) is the progenitor cells of lung cancer stem cells. It has been shown that BASCs possess a unique miRNA profile, with altered expression of several microRNAs, such as miR-451 in BASCs compared to control cells. These results suggest that microRNAs might play important roles in maintaining the self-renewal capacity of BASCs, and that aberrant expression of microRNAs could be involved in turning BASCs into lung cancer stem cells⁴. Finally, miR-451 seems to be a key molecule in normal erythroid differentiation and has also been shown to regulate the multidrug resistance 1 gene in cervix, ovarian, and breast cancer cell lines⁵.

Caruso P, Maclean MR, Khanin R, McClure J, Soon E, Southwood M, McDonald RA, Greig JA, Robertson KE, Masson R, Denby L, Dempsie Y, Long L, Morrell NW, Baker AH. (2010) Dynamic Changes in Lung MicroRNA Profiles During the Development of Pulmonary Hypertension Due to Chronic Hypoxia and Monocrotaline. Arterioscler Thromb Vasc Biol [Epub ahead of print] [abstract]
Hui AB, Lenarduzzi M, Krushel T, Waldron L, Pintilie M, Shi W, Perez-Ordonez B, Jurisica I, O’Sullivan B, Waldron J, Gullane P, Cummings B, Liu FF. (2010) Comprehensive MicroRNA profiling for head and neck squamous cell carcinomas. Clin Cancer Res. 16(4):1129-39. [abstract]
Bandres E, Bitarte N, Arias F, et al. (2009) microRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells. Clin Cancer Res 15:2281–90. [abstract]
Qian S, Ding JY, Xie R, An JH, Ao XJ, Zhao ZG, Sun JG, Duan YZ, Chen ZT, Zhu B. (2008) MicroRNA expression profile of bronchioalveolar stem cells from mouse lung. Biochem Biophys Res Commun 377(2), 668-73. [abstract]
Kovalchuk O, Filkowski J, Meservy J, Ilnytskyy Y, Tryndyak VP, Chekhun VF, Pogribny IP. (2008) Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther 7(7), 2152-59. [abstract]

microRNA Deal Struck

Chris — Thu, 25 Feb 2010 15:24:17 +0000

Regulus Therapeutics and GlaxoSmithKline Establish New Collaboration to …
MarketWatch (press release)‎
Regulus Therapeutics Inc. today announced the establishment of a new collaboration with GlaxoSmithKline (GSK) to develop and commercialize microRNA …

Market Report — In Play (GSK)
MSN Money
GlaxoSmithKline and Regulus Therapeutics establish new collaboration to develop and commercialize microRNA Therapeutics Targeting miR-122 Co and Regulus …

Regulus, the MicroRNA Child of Isis and Alnylam, Strikes Potential $150M Deal …
Xconomy
Two years have passed since GlaxoSmithKline anointed a startup called Regulus Therapeutics as a leader in the bleeding-edge world of microRNA drugs, …

microRNA of the week: microRNA-29

Chris — Fri, 19 Feb 2010 15:01:09 +0000

There are several groups making headlines that are studying the mir-29 family.

Rosetta Genomics

Headlines – Joint Study By Rosetta Genomics And NYU Langone Medical Center Identifies Single MicroRNA Biomarker For Prognosis Of Mesothelioma Patients

Single microRNA exhibits potential to forecast outcomes of MPM

The results clearly demonstrate that higher levels of miR-29c* in MPM predict a more favorable prognosis. Not only was the microRNA able to separate MPM patients by time to progression after surgery, but it also stratified these patients by their survival. Furthermore, the study found that over-expression of miR-29c* in mesothelioma cell lines resulted in significantly decreased proliferation, migration, invasion and colony formation.

Pass HI, Goparaju C, Ivanov S, Donington J, Carbone M, Hoshen M, Cohen D, Chajut A, Rosenwald S, Dan H, Benjamin S, Aharonov R. (2010) hsa-miR-29c* Is Linked to the Prognosis of Malignant Pleural Mesothelioma. Cancer Res [Epub ahead of print]. [abstract]

UT Southwestern Medical Center – Dr. Eric Olson

Headlines – UT Southwestern Researchers Publish Link Between miRNA Dysregulation, Heart Attack

van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, Marshall WS, Hill JA, Olson EN. (2008) Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci USA 105(35), 13027-32. [abstract]

The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression.

Ohio State University – Dr. Carlo Croce

Headlines – Posted Interview with Carlo Croce of Ohio State University -5/26/2009

The researchers showed that forced expression of MIR29A, MIR29B and MIR29C leads to the re-expression of tumor suppressor genes such as WWOX and FHIT and triggers cell death by apoptosis in lung cancer cell lines, and reduces the size of engrafted tumors by 56 to 94 percent compared with controls. MIR29 is also lost in prostate cancer, and a subset of breast cancers.

Garzon R, Heaphy CE, Havelange V, Fabbri M, Volinia S, Tsao T, Zanesi N, Kornblau SM, Marcucci G, Calin GA, Andreeff M, Croce CM. (2009) MicroRNA 29b functions in acute myeloid leukemia. Blood 114(26), 5331-41. [abstract]
Wang H, Garzon R, Sun H, Ladner KJ, Singh R, Dahlman J, Cheng A, Hall BM, Qualman SJ, Chandler DS, Croce CM, Guttridge DC. (2008) NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell 14(5), 369-81. [abstract]
Garzon R, Garofalo M, Martelli MP, Briesewitz R, Wang L, Fernandez-Cymering C, Volinia S, Liu CG, Schnittger S, Haferlach T, Liso A, Diverio D, Mancini M, Meloni G, Foa R, Martelli MF, Mecucci C, Croce CM, Falini B. (2008) Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci U S A 105(10), 3945-50. [abstract]
Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, Liu S, Alder H, Costinean S, Fernandez-Cymering C, Volinia S, Guler G, Morrison CD, Chan KK, Marcucci G, Calin GA, Huebner K, Croce CM. (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A 104(40), 15805-10. [abstract]

Upcoming miRNA Conference: microRNA in Human Disease & Development

Chris — Tue, 16 Feb 2010 15:24:49 +0000

Monday, March 22nd – Wednesday, March 24 – 2010 in Cambridge, MA – USA

miRNA as Diagnostic Biomarkers and Targets for Therapeutic Development

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

PRE-CONFERENCE SHORT COURSE:

microRNA Identification, Profiling and Validation Techniques

microRNA of the week: microRNA-206

Chris — Fri, 12 Feb 2010 16:43:53 +0000

When you consider that microRNAs have now been linked to almost every biological function, how is it possible that the detection of microRNAs had escaped scientists for so long? For example, a single microRNA, miR-206 with functions that range from estrogen regulation to suppression of breast cancer metastasis to regulation of neuromuscular signaling. Amazing!

Williams AH, Valdez G, Moresi V, Qi X, McAnally J, Elliott JL, Bassel-Duby R, Sanes JR, Olson EN. (2009) MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326(5959), 1549-554 [abstract]
Song G, Wang L. (2009) Nuclear receptor SHP activates miR-206 expression via a cascade dual inhibitory mechanism. PLoS One 4(9), e6880. [abstract]
Klinge CM. (2009) Estrogen Regulation of MicroRNA Expression. Curr Genomics 10(3), 169-83. [abstract]
Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massagué J. (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451(7175), 147-52. [abstract]

The many complex roles of microRNA in breast cancer

Chris — Wed, 10 Feb 2010 17:02:02 +0000

There have been several studies involving microRNAs and breast cancer to date. The findings of these studies collectively demonstrate the wide range of function that microRNA can play in just a single disease. Researchers at Baylor College of Medicine and the University of Houston found that dysregulation of certain microRNAs have significant effect on morphological and molecular changes such as an expansion of the progenitor cell population, decreased cell size, increased cellular proliferation, and colony-forming potential [1]. They suggest that the dysregulation of these microRNAs might be important in the causation, or origination of breast cancer.

Cancer cells that develop resistance to chemotherapeutic agents are a major clinical obstacle in the successful treatment of breast cancer. Researchers at the University of Lethbridge, Canada found that chemoresistance may be linked to drug-induced dysregulation of microRNA function [2]. They found many dysregulated microRNAs in drug resistant MFC-7 human breast adenocarcinoma cells and that some of these microRNAs target a human multidrug resistance-associated protein. Their results suggest that dysregulated microRNA expression may underlie the abnormal functioning of critical cellular processes associated with the chemoresistance phenotype.

A major complication of breast cancer is its metastatic potential and now, some new studies have shown that microRNAs can affect breast cancer metastasis either by over or under expression. In this first example, researchers show that over expression of a specific microRNA plays a key role in a cancer signaling pathway. 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 found that addition of an anti-miR can block the ROCK signaling pathway resulting in decreased breast cancer cell invasion/ migration and metastasis [3].

In another study, it was found that microRNAs function in an opposite manner. Researchers at Memorial Sloan-Kettering Cancer Center found a specific set of microRNAs for which expression is specifically lost as human breast cancer cells develop metastatic potential [8]. Furthermore, they show that restoring the expression of these microRNAs in malignant cells reduces overall tumor growth and proliferation and suppresses metastatic cell invasion.

Greene SB, Gunaratne PH, Hammond SM, Rosen JM. (2010) A putative role for microRNA-205 in mammary epithelial cell progenitors. J Cell Sci [Epub ahead of print] [abstract]
Pogribny IP, Filkowski JN, Tryndyak VP, Golubov A, Shpyleva SI, Kovalchuk O. (2010) Alterations of microRNAs and their targets are associated with acquired resistance of MCF-7 breast cancer cells to cisplatin. Int J Cancer [Epub ahead of print] [abstract]
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), 8742-751. [abstract]
Dykxhoorn DM, Wu Y, Xie H, Yu F, Lal A, Petrocca F, Martinvalet D, Song E, Lim B, Lieberman J. (2009) miR-200 enhances mouse breast cancer cell colonization to form distant metastases. PLoS One 4(9), e7181. [abstract]
Wickramasinghe NS, Manavalan TT, Dougherty SM, Riggs KA, Li Y, Klinge CM. (2009) Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells. Nucleic Acids 37(8), 2584-95. [abstract]
Sun Y, Wu J, Wu SH, Thakur A, Bollig A, Huang Y, Joshua Liao D. (2008) Expression profile of microRNAs in c-Myc induced mouse mammary tumors. Breast Cancer Res Treat 118(1), 185-96. [abstract]
Kovalchuk O, Filkowski J, Meservy J, Ilnytskyy Y, Tryndyak VP, Chekhun VF, Pogribny IP. (2008) Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther 7(7), 2152-59. [abstract]
Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massagué J. (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451(7175), 147-52. [abstract]
Kovalchuk O, Tryndyak VP, Montgomery B, Boyko A, Kutanzi K, Zemp F, Warbritton AR, Latendresse JR, Kovalchuk I, Beland FA, Pogribny IP. (2007) Estrogen-induced rat breast carcinogenesis is characterized by alterations in DNA methylation, histone modifications and aberrant microRNA expression. Cell Cycle 6(16), 2010-18. [abstract]

New expression analysis software tool: Expander

Chris — Mon, 08 Feb 2010 15:45:29 +0000

EXPANDER (EXpression Analyzer and DisplayER) is a java-based tool for analysis of gene expression data[1].

data preprocessing and normalization
identification of differential genes
clustering and biclustering;
down-stream enrichment analyses of:
- GO functional categories
- TF binding sites in promoter regions
- microRNA sites in 3′-UTRs
- chromosomal locations
network-based analysis of the expression data

Expander (EXPression ANalyzer and DisplayER) is an integrated software platform for the analysis of gene expression data, which is freely available for academic use. It is designed to support all the stages of microarray data analysis, from raw data normalization to inference of transcriptional regulatory networks.

microRNA target predictions for Human, Mouse, Fly, and C. elegans

Ulitsky I, Maron-Katz A, Shavit S, Sagir D, Linhart C, Elkon R, Tanay A, Sharan R, Shiloh Y, Shamir R. (2010) Expander: from expression microarrays to networks and functions. Nat Protoc 5(2), 303-22. [abstract]