MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review

doi:10.1002/EMMM.201100209

Home
/
Papers
/
MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review

Journal Article•DOI•

MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review

Marilena V. Iorio, Carlo M. Croce¹•Institutions (1)

Ohio State University¹

01 Mar 2012-Embo Molecular Medicine (Wiley-Blackwell)-Vol. 4, Iss: 3, pp 143-159

TL;DR: Current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools are reviewed.

read less

Abstract: Early studies have shown how aberrantly expressed microRNAs are a hallmark of several diseases like cancer. MicroRNA expression profiling was shown to be associated with tumour development, progression and response to therapy, suggesting their possible use as diagnostic, prognostic and predictive biomarkers. Moreover, based on the increasing number of studies demonstrating that microRNAs can function as potential oncogenes or oncosuppressor genes, with the goal to improve disease response and increase cure rates, miRNA-based anticancer therapies have recently been exploited, either alone or in combination with current targeted therapies. The advantage of using microRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. Here, we review our current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools.

...read moreread less

Citations

PDF

Open Access

More filters

Journal Article•DOI•

MicroRNA therapeutics: towards a new era for the management of cancer and other diseases

[...]

Rajesha Rupaimoole¹, Frank J. Slack¹•Institutions (1)

Beth Israel Deaconess Medical Center¹

01 Mar 2017-Nature Reviews Drug Discovery

TL;DR: Recent advances in the understanding of miRNAs in cancer and in other diseases are described and the challenge of identifying the most efficacious therapeutic candidates is discussed and a perspective on achieving safe and targeted delivery of miRNA therapeutics is provided.

...read moreread less

Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic. In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.

...read moreread less

3,210 citations

Journal Article•DOI•

Evolution of the Cancer Stem Cell Model

[...]

Antonija Kreso¹, John E. Dick¹•Institutions (1)

Princess Margaret Cancer Centre¹

06 Mar 2014-Cell Stem Cell

TL;DR: It is proposed that the genetic and CSC models of cancer can be harmonized by considering the role of genetic diversity and nongenetic influences in contributing to tumor heterogeneity.

...read moreread less

1,833 citations

Cites background from "MicroRNA dysregulation in cancer: d..."

...Epigenetic modifications of DNA, histones, and nucleosomes as well as noncoding RNAs, including miRNA, allow for modification of gene expression (Baylin and Jones, 2011; Iorio and Croce, 2012)....
[...]

Journal Article•DOI•

Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets

[...]

Ádám Nagy, András Lánczky, Otília Menyhárt¹, Balázs Győrffy¹•Institutions (1)

Semmelweis University¹

15 Jun 2018-Scientific Reports

TL;DR: An integrated miRNA expression database was set up and prognostic miRNAs identified as potential prognostic biomarkers for HCC were validated and the expression was significantly altered in 102 mi RNAs in tumors compared to normal liver tissues.

...read moreread less

Abstract: Multiple studies suggested using different miRNAs as biomarkers for prognosis of hepatocellular carcinoma (HCC). We aimed to assemble a miRNA expression database from independent datasets to enable an independent validation of previously published prognostic biomarkers of HCC. A miRNA expression database was established by searching the TCGA (RNA-seq) and GEO (microarray) repositories to identify miRNA datasets with available expression and clinical data. A PubMed search was performed to identify prognostic miRNAs for HCC. We performed a uni- and multivariate Cox regression analysis to validate the prognostic significance of these miRNAs. The Limma R package was applied to compare the expression of miRNAs between tumor and normal tissues. We uncovered 214 publications containing 223 miRNAs identified as potential prognostic biomarkers for HCC. In the survival analysis, the expression levels of 55 and 84 miRNAs were significantly correlated with overall survival in RNA-seq and gene chip datasets, respectively. The most significant miRNAs were hsa-miR-149, hsa-miR-139, and hsa-miR-3677 in the RNA-seq and hsa-miR-146b-3p, hsa-miR-584, and hsa-miR-31 in the microarray dataset. Of the 223 miRNAs studied, the expression was significantly altered in 102 miRNAs in tumors compared to normal liver tissues. In summary, we set up an integrated miRNA expression database and validated prognostic miRNAs in HCC.

...read moreread less

1,013 citations

Journal Article•DOI•

MicroRNA and cancer.

[...]

Martin D. Jansson¹, Anders H. Lund¹•Institutions (1)

University of Copenhagen¹

01 Dec 2012-Molecular Oncology

TL;DR: The current knowledge and concepts concerning the involvement of microRNAs in cancer, which have emerged from the study of cell culture and animal model systems, including the regulation of key cancer‐related pathways, such as cell cycle control and the DNA damage response are summarized.

...read moreread less

985 citations

Cites background from "MicroRNA dysregulation in cancer: d..."

...Importantly, mouse models featuring miRNA overexpression or ablation have demonstrated causal links between miRNAs and cancer development and miRNAs are rapidly entering the clinic as biomarkers and putative therapeutic targets (Iorio and Croce, 2012; Kasinski and Slack, 2011)....
[...]
...Since then, an extensive bulk of literature has reported on specific miRNA signatures for individual cancers and cancer stages (Iorio and Croce, 2012; Kong et al., 2012)....
[...]

Journal Article•DOI•

Therapeutic targeting of microRNAs: current status and future challenges

[...]

Zhonghan Li¹, Tariq M. Rana²•Institutions (2)

Pfizer¹, University of California, San Diego²

01 Aug 2014-Nature Reviews Drug Discovery

TL;DR: Current knowledge of the design and performance of chemically modified miRNA-targeting antisense oligonucleotides is summarized, various in vivo delivery strategies are discussed and ongoing challenges to ensure the specificity and efficacy of therapeutic oligon nucleotides in vivo are analysed.

...read moreread less

Abstract: MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that have crucial roles in regulating gene expression. Increasing evidence supports a role for miRNAs in many human diseases, including cancer and autoimmune disorders. The function of miRNAs can be efficiently and specifically inhibited by chemically modified antisense oligonucleotides, supporting their potential as targets for the development of novel therapies for several diseases. In this Review we summarize our current knowledge of the design and performance of chemically modified miRNA-targeting antisense oligonucleotides, discuss various in vivo delivery strategies and analyse ongoing challenges to ensure the specificity and efficacy of therapeutic oligonucleotides in vivo. Finally, we review current progress on the clinical development of miRNA-targeting therapeutics.

...read moreread less

903 citations

1
2
3
4
…
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200

Collapse

References

PDF

Open Access

More filters

Journal Article•DOI•

The hallmarks of cancer.

[...]

Douglas Hanahan¹, Robert A. Weinberg²•Institutions (2)

University of California, San Francisco¹, Massachusetts Institute of Technology²

07 Jan 2000-Cell

TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.

...read moreread less

28,811 citations

"MicroRNA dysregulation in cancer: d..." refers background in this paper

...…Medicine 149 150 Weinberg described six essential features of cancer progression: self-sufficiency in growth signals, insensitivity to anti-growth signals, apoptosis evasion, limitless replicative potential, sustained angiogenesis and tissue invasion and metastasis (Hanahan & Weinberg, 2000)....
[...]

Journal Article•DOI•

The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14

[...]

Rosalind C. Lee¹, Rhonda L. Feinbaum¹, Victor R. Ambros¹•Institutions (1)

Harvard University¹

03 Dec 1993-Cell

TL;DR: Two small lin-4 transcripts of approximately 22 and 61 nt were identified in C. elegans and found to contain sequences complementary to a repeated sequence element in the 3' untranslated region (UTR) of lin-14 mRNA, suggesting that lin- 4 regulates lin- 14 translation via an antisense RNA-RNA interaction.

...read moreread less

11,932 citations

"MicroRNA dysregulation in cancer: d..." refers background in this paper

...…RNA encoded by the lin-4 locus was associated to the developmental timing of the nematode Caenorhabditis elegans by modulating the protein lin-14 (Lee et al, 1993), have then been revealed as essential part of the uncoding genome, playing a crucial role through a complicated gene regulation in…...
[...]

Journal Article•DOI•

Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets

[...]

Benjamin P. Lewis¹, Christopher B. Burge¹, David P. Bartel¹•Institutions (1)

Massachusetts Institute of Technology¹

14 Jan 2005-Cell

TL;DR: In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of the gene set.

...read moreread less

11,624 citations

"MicroRNA dysregulation in cancer: d..." refers background in this paper

...Bioinformatics analysis predicts that 30-UTRs of single genes are often targeted by several different miRNAs (Lewis et al, 2005)....
[...]
...Considering the different rules regulating the interaction between a microRNA and its target mRNA, it is not surprising that each miRNA has the potential to target a large number of genes (Betel et al, 2008; Friedman et al, 2009; Krek et al, 2005; Lewis et al, 2005)....
[...]

Journal Article•DOI•

MicroRNA expression profiles classify human cancers

[...]

Jun Lu¹, Gad Getz¹, Eric A. Miska², Eric A. Miska³, Ezequiel Alvarez-Saavedra³, Justin Lamb¹, David Peck¹, Alejandro Sweet-Cordero³, Alejandro Sweet-Cordero⁴, Benjamin L. Ebert⁴, Benjamin L. Ebert¹, Raymond H. Mak¹, Raymond H. Mak⁴, Adolfo A. Ferrando⁴, James R. Downing⁵, Tyler Jacks³, H. Robert Horvitz⁶, H. Robert Horvitz³, Todd R. Golub⁴, Todd R. Golub¹, Todd R. Golub⁶ - Show less +17 more•Institutions (6)

Broad Institute¹, Wellcome Trust/Cancer Research UK Gurdon Institute², Massachusetts Institute of Technology³, Harvard University⁴, St. Jude Children's Research Hospital⁵, Howard Hughes Medical Institute⁶

09 Jun 2005-Nature

TL;DR: A new, bead-based flow cytometric miRNA expression profiling method is used to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers, and finds the miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours.

...read moreread less

Abstract: Recent work has revealed the existence of a class of small non-coding RNA species, known as microRNAs (miRNAs), which have critical functions across various biological processes. Here we use a new, bead-based flow cytometric miRNA expression profiling method to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers. The miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours. We observe a general downregulation of miRNAs in tumours compared with normal tissues. Furthermore, we were able to successfully classify poorly differentiated tumours using miRNA expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. These findings highlight the potential of miRNA profiling in cancer diagnosis.

...read moreread less

9,470 citations

"MicroRNA dysregulation in cancer: d..." refers background or methods in this paper

...…an extensive use of custom-made (Liu et al, 2004) and then commercial miRNA microarrays, and bead-based flow cytometric miRNA analysis methods (Lu et al, 2005), the last generation of large-scale profiling method is represented by the high-throughput deep sequencing (Creighton et al, 2009;…...
[...]
...This might be due to the possibility that most microRNAs seem to exert a role as oncosuppressors, and consequently are mostly dowregulated in human neoplasia (Lu et al, 2005)....
[...]
...Genome-wide profiling showed that miRNA expression signatures (miRNome) allowed different types of cancer to be discriminated with high accuracy (Lu et al, 2005; Volinia et al, 2006) and the tissue of origin of poorly differentiated tumours to be identified....
[...]

Journal Article•DOI•

Most mammalian mRNAs are conserved targets of microRNAs

[...]

Robin C. Friedman¹, Kyle Kai-How Farh, Christopher B. Burge, David P. Bartel•Institutions (1)

Massachusetts Institute of Technology¹

01 Jan 2009-Genome Research

TL;DR: This work overhauled its tool for finding preferential conservation of sequence motifs and applied it to the analysis of human 3'UTRs, increasing by nearly threefold the detected number of preferentially conserved miRNA target sites.

...read moreread less

Abstract: MicroRNAs (miRNAs) are small endogenous RNAs that pair to sites in mRNAs to direct post-transcriptional repression. Many sites that match the miRNA seed (nucleotides 2–7), particularly those in 3 untranslated regions (3UTRs), are preferentially conserved. Here, we overhauled our tool for finding preferential conservation of sequence motifs and applied it to the analysis of human 3UTRs, increasing by nearly threefold the detected number of preferentially conserved miRNA target sites. The new tool more efficiently incorporates new genomes and more completely controls for background conservation by accounting for mutational biases, dinucleotide conservation rates, and the conservation rates of individual UTRs. The improved background model enabled preferential conservation of a new site type, the “offset 6mer,” to be detected. In total, >45,000 miRNA target sites within human 3UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. Mammalian-specific miRNAs have far fewer conserved targets than do the more broadly conserved miRNAs, even when considering only more recently emerged targets. Although pairing to the 3 end of miRNAs can compensate for seed mismatches, this class of sites constitutes less than 2% of all preferentially conserved sites detected. The new tool enables statistically powerful analysis of individual miRNA target sites, with the probability of preferentially conserved targeting (PCT) correlating with experimental measurements of repression. Our expanded set of target predictions (including conserved 3-compensatory sites), are available at the TargetScan website, which displays the PCT for each site and each predicted target.

...read moreread less

7,744 citations

"MicroRNA dysregulation in cancer: d..." refers background in this paper

...Considering the different rules regulating the interaction between a microRNA and its target mRNA, it is not surprising that each miRNA has the potential to target a large number of genes (Betel et al, 2008; Friedman et al, 2009; Krek et al, 2005; Lewis et al, 2005)....
[...]