Feb

10

The many complex roles of microRNA in breast cancer

Filed Under Technical Article | 1 Comment

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.

  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]

Jan

29

microRNA-146a

Filed Under Technical Article | Leave a Comment

While it is clear now that microRNAs play an important regulatory role in nearly all areas of biology, what may be more interesting is the breath of function of just a single microRNA.  It is estimated that microRNAs regulate up to 60% of all genes and some say that “each microRNA can target hundreds of genes” and “a single microRNA can regulate entire networks of genes”. So here is an interesting look at a single microRNA that has a far-reaching effect in many biological systems.

Several studies have demonstrated the functional role of microRNA-146a in the immune response. MicroRNA-146a feedback inhibits production in macrophages, is upregulated by HSV-1 infection, has been associated with proinflammatory signaling in stressed brain cells and Alzheimer’s disease (AD) brain, modulates CFH gene expression to regulate an inflammatory response, and plays a functional role in T lymphocyte-mediated immune response. These and other studies demonstrate the great potential for anti-miRNAs as an effective therapeutic strategy against pathogenic inflammatory signaling.

Additionally, there have been many reports describing microRNA-146a’s role in cancer.  MicroRNA-146a suppresses prostate cancer transformation from androgen-dependent to -independent cells, suppresses a  kinase coding gene which reduces cell proliferation, invasion, and metastasis to human bone marrow endothelial cell monolayers, and is dysregulated by latent membrane protein 1 (LMP1) which contributes substantially to the oncogenic potential of Epstein-Barr virus. It is projected that microRNA-146a and other microRNAs may one day become biomarkers for clinical diagnosis of several types of cancer.

  1. Curtale G, Citarella F, Carissimi C, Goldoni M, Carucci N, Fulci V, Franceschini D, Meloni F, Barnaba V, Macino G. (2010) An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes. Blood 115(2), 265-73. [abstract]
  2. Hou J, Wang P, Lin L, Liu X, Ma F, An H, Wang Z, Cao X. (2009) MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J Immunol 183(3), 2150-58.  [abstract]
  3. Hill JM, Zhao Y, Clement C, Neumann DM, Lukiw WJ.  (2009) HSV-1 infection of human brain cells induces miRNA-146a and Alzheimer-type inflammatory signaling.  Neuroreport  20(16), 1500-505.  [abstract]
  4. Lukiw WJ, Zhao Y, Cui JG.  (2008) An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem 283(46), 31315-22.  [abstract]
  5. Cameron JE, Yin Q, Fewell C, Lacey M, McBride J, Wang X, Lin Z, Schaefer BC, Flemington EK. (2008) The Epstein-Barr Virus latent membrane protein 1 (LMP1) induces cellular microRNA-146a, a modulator of lymphocyte signaling pathways. J Virol 82(4), 1946-58. [abstract]
  6. Lin SL, Chiang A, Chang D, Ying SY. (2008) Loss of mir-146a function in hormone-refractory prostate cancer. RNA 14(3), 417-24.  [abstract]

Dec

17

microRNAs Inform Cancer Research

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Alterations in the Expression of miRNA Genes Contribute to Pathogenesis on Broad Basis

Elizabeth Lipp

MicroRNA (miRNA) has a significant role in controlling developmental and cancer processes like cell proliferation, differentiation, cell cycle, apoptosis, and metastasis. This ubiquitousness and their recently revealed role as key regulators of gene expression during development has boosted their use as agents in the fight against cancer. It’s a hot topic “and it’s getting hotter,” said Frank Slack, associate professor of molecular, cellular, and developmental biology at Yale University … (read more)