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MicroRNAs in cancer: The tie that binds

by
Maria Celeste Ramirez, Ph.D.
| Jul 15, 2013

MicroRNAs in cancer: the tie that bindsCancer has been referred to as an evolutionary disease1 and survival of the fittest is the name of the game. The growth and survival advantage acquired by tumor cells is a result of multiple pathways that have been dysregulated due to incurred somatic mutations. The goal of cancer genomics is to better understand the how these mutations lead to cells that are able to outsmart cell cycle checkpoints and escape senescence and apoptosis. It is becoming increasingly clear that tumor profiling must assess both genomic changes as well as expression levels to understand how mutations impact the message being transcribed, the signals being transduced within the cell and ultimately the pathways that control overall behavior. This was highlighted by The Cancer Genome Atlas (TCGA) in last month’s Cancer Publication of the Month post and is reinforced this month by a new study showing the crucial role of miRNAs in cancer susceptibility.   

In this study, Hesse et al. investigated changes in miRNA expression as a result of knocking out the ATM gene in a human mammary epithelial cell line. ATM encodes a serine threonine kinase responsible for phosphorylating key proteins that activate the DNA damage checkpoint leading to cell cycle arrest, DNA repair, and if the damage cannot be repaired, apoptosis. Complete loss of ATM function leads to a disease called ataxia telangiectasia, a syndrome characterized by neurological, motor, and immunological defects. Interestingly, patients with this disease also have a predisposition to cancer2 and recent studies have shown that reduced ATM expression whether due to inactivation of one allele3 or through methylation4 can lead to breast cancer susceptibility. This connection between ATM deficiency and cancer led the authors to investigate how loss of ATM function interrupts gene expression enough to promote tumorigenesis using next-generation sequencing. To unravel this question, the authors looked at not only differences in gene expression but also the mediators of these changes. 

MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate target messenger RNA translation or degradation by binding their 3’ UTRs5.  Each miRNA has several targets and conversely, each of these targets can be regulated by multiple miRNAs. The inherent promiscuity of how these miRNAs regulate gene expression make them excellent candidates for initiating tumorigenesis, a process that requires coordinated disruption of key pathways that allow  tumor cells to escape normal checkpoints, proliferate excessively, and spread. 

By performing small RNA sequencing on normal and ATM-deficient human mammary epithelial cells, the authors identified a short list of suspect miRNAs. Within this list were 4 miRNAs considered to be tumor suppressors and 7 oncomirs —miRNAs that have been observed to have oncogenic properties. Tumor suppressor miRNAs were found to be repressed, and oncomirs overexpressed. Furthermore, when the authors looked at the candidate miRNAs and the expression of their potential targets, they observed that a significant number of these differentially expressed targets are transcription factors, proteins that control coordinated expression of a number of genes. This suggests that the mechanism by which ATM deficiency promotes tumorigenesis should affect a number of different signaling pathways to elicit a response that could override cell cycle checkpoints. Among these targets are the oncogenic transcription factors MAF and CEBPA, both of which have been implicated in a number of cancers6,7,8, In addition, the tumor suppressor SOCS1, a negative regulator of IGF-1, is also a target9. Pathways involved in cell cycle, cell growth, proliferation, and cell death were identified which further support the role of ATM through the action of these miRNAs, in promoting tumor initiation and progression.

With the large number of pathways that need to be dysregulated in order to override the checkpoints that govern the cell’s normal functions and turn a once-normal cell into “The Hulk” of cells—one that can withstand a number of hits and still survive—regulators of expression such as epigenetic signatures and miRNAs, become likely candidate effectors for disease pathogenesis. Effectors which, when disturbed, activate a cascade of events that initiates and maintains tumorigenesis. This study highlights the significance of interrogating not only the genome which is the cell’s blueprint, or the transcriptome which is the encoded message, but also the various players that regulate expression and stability of these. Only by looking at the entire picture from several levels can we make sense of the interplay among the mutated networks that lead to disease initiation and progression. 

1Zimmer C. Studying Tumors Differently in the Hopes of Outsmarting Them. The New York Times, 27 June 2013.

2Hesse JE, Liu L, Innes CL, Cui Y,  Palii SS, et al. (2013) Genome-wide small RNA sequencing and gene expression analysis reveals a microRNA profile of cancer susceptibility in ATM-deficient human mammary epithelial cells PLOS One 8(5): e64779.

3Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, et al. (2006) ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38(8):873-875.

4Flanagan JM, Munoz-Alegre M, Henderson S, Tang T, Sun P, et al. (2009) Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients. Hum Mol Genet 18(7):1332-1342.

5Yates LA, Norbury CJ, Gilbert RJ. (2013) The long and short of microRNA. Cell 153(3): 516-519.

6Kienast J, Berdel WE. (2004) C-maf in multiple myeloma: An oncogene enhancing tumor-stroma interactions. Cancer Cell 5(2):109-110.

7Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, et al. (2001) Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet 27(3):263-70.

8Alberich-Jordà M, Wouters B, Balastik M, Shapiro-Koss C, Zhang H, et al. (2012) C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia. J Clin Invest 122(12):4490-4504.

9Ferbeyre G, Moriggl R. (2011) The role of Stat5 transcription factors as tumor suppressors or oncogenes. Biochim Biophys Acta 1815(1):104-114.

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