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MicroRNA manipulation in colorectal cancer cells: from laboratory to clinical application.

Aslam MI, Patel M, Singh B, Jameson JS, Pringle JH - J Transl Med (2012)

Bottom Line: Strategy based on restoration of silenced miRNAs or inhibition of over expressed miRNAs has opened a new area of research in cancer therapy.Restoration of normal equilibrium for cancer related miRNAs can result in inhibition of tumour growth, apoptosis, blocking of invasion, angiogenesis and metastasis.However, further work is needed on tissue specific delivery systems and strategies to avoid side effects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, P O Box 65, Leicester LE2 7LX, United Kingdom. mia7@leicester.ac.uk

ABSTRACT
The development of Colorectal Cancer (CRC) follows a sequential progression from adenoma to the carcinoma. Therefore, opportunities exist to interfere with the natural course of disease development and progression. Dysregulation of microRNAs (miRNAs) in cancer cells indirectly results in higher levels of messenger RNA (mRNA) specific to tumour promoter genes or tumour suppressor genes. This narrative review aims to provide a comprehensive review of the literature about the manipulation of oncogenic or tumour suppressor miRNAs in colorectal cancer cells for the purpose of development of anticancer therapies. A literature search identified studies describing manipulation of miRNAs in colorectal cancer cells in vivo and in vitro. Studies were also included to provide an update on the role of miRNAs in CRC development, progression and diagnosis. Strategy based on restoration of silenced miRNAs or inhibition of over expressed miRNAs has opened a new area of research in cancer therapy. In this review article different techniques for miRNA manipulation are reviewed and their utility for colorectal cancer therapy has been discussed in detail. Restoration of normal equilibrium for cancer related miRNAs can result in inhibition of tumour growth, apoptosis, blocking of invasion, angiogenesis and metastasis. Furthermore, drug resistant cancer cells can be turned into drug sensitive cells on alteration of specific miRNAs in cancer cells. MiRNA modulation in cancer cells holds great potential to replace current anticancer therapies. However, further work is needed on tissue specific delivery systems and strategies to avoid side effects.

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Related in: MedlinePlus

Figure demonstrates the mechanism of Knockdown of oncomiRs. The downregulation of tumour suppressor mRNAs can be reversed by a) transcriptional inhibition of genes transcribing miRNAs of oncogenic potential b) competitive inhibition of mature miRNAs with antisense oligonucleotides c) mRNA mask constructs causing competitive inhibition to miR/RISC d) sponge constructs mimicking target mRNAs e) induction of SNPs in RISC complex.
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Figure 5: Figure demonstrates the mechanism of Knockdown of oncomiRs. The downregulation of tumour suppressor mRNAs can be reversed by a) transcriptional inhibition of genes transcribing miRNAs of oncogenic potential b) competitive inhibition of mature miRNAs with antisense oligonucleotides c) mRNA mask constructs causing competitive inhibition to miR/RISC d) sponge constructs mimicking target mRNAs e) induction of SNPs in RISC complex.

Mentions: The demonstration that oncogenic miRNAs are upregulated in cancer provided a rationale to investigate the use of antisense oligonucleotides to block their expression. Antisense oligonucleotides work as competitive inhibitors of miRNAs, presumably by annealing to the mature miRNA guide strand and inducing degradation of mature miRNAs (Figure 5). The stability, and specificity for target miRNAs and the binding affinity of antisense oligonucleotides has been optimised by modifications to the chemical structure of the oligonucleotides [57]. In particular the introduction of 2′-O-methyl or 2′-O-methoxyethyl groups to oligonucleotides enhances resistance to nuclease enzyme and improves the binding affinities to RNA [58]. The silencing of endogenous miRNAs by this novel method has shown to be long lasting, specific and efficient both in vitro [59,60] and in vivo. In CRC cells lines, antimiR based blockage of oncogenic miRNAs (miR-20a, miR-21, miR-31, miR-95, miR-672) has not only shown to reduce cell proliferation, transformation and migration, but it has resulted in enhanced sensitivity to chemotherapy agents [61-66]. This strategy of sensitizing the chemotherapy resistant tumour cells with alteration of miRNA expression in tumour cells may result in improved response to traditional chemotherapy agents. Table 3 summarizes the studies manipulating the oncogenic miRNAs in colorectal cell lines.


MicroRNA manipulation in colorectal cancer cells: from laboratory to clinical application.

Aslam MI, Patel M, Singh B, Jameson JS, Pringle JH - J Transl Med (2012)

Figure demonstrates the mechanism of Knockdown of oncomiRs. The downregulation of tumour suppressor mRNAs can be reversed by a) transcriptional inhibition of genes transcribing miRNAs of oncogenic potential b) competitive inhibition of mature miRNAs with antisense oligonucleotides c) mRNA mask constructs causing competitive inhibition to miR/RISC d) sponge constructs mimicking target mRNAs e) induction of SNPs in RISC complex.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539910&req=5

Figure 5: Figure demonstrates the mechanism of Knockdown of oncomiRs. The downregulation of tumour suppressor mRNAs can be reversed by a) transcriptional inhibition of genes transcribing miRNAs of oncogenic potential b) competitive inhibition of mature miRNAs with antisense oligonucleotides c) mRNA mask constructs causing competitive inhibition to miR/RISC d) sponge constructs mimicking target mRNAs e) induction of SNPs in RISC complex.
Mentions: The demonstration that oncogenic miRNAs are upregulated in cancer provided a rationale to investigate the use of antisense oligonucleotides to block their expression. Antisense oligonucleotides work as competitive inhibitors of miRNAs, presumably by annealing to the mature miRNA guide strand and inducing degradation of mature miRNAs (Figure 5). The stability, and specificity for target miRNAs and the binding affinity of antisense oligonucleotides has been optimised by modifications to the chemical structure of the oligonucleotides [57]. In particular the introduction of 2′-O-methyl or 2′-O-methoxyethyl groups to oligonucleotides enhances resistance to nuclease enzyme and improves the binding affinities to RNA [58]. The silencing of endogenous miRNAs by this novel method has shown to be long lasting, specific and efficient both in vitro [59,60] and in vivo. In CRC cells lines, antimiR based blockage of oncogenic miRNAs (miR-20a, miR-21, miR-31, miR-95, miR-672) has not only shown to reduce cell proliferation, transformation and migration, but it has resulted in enhanced sensitivity to chemotherapy agents [61-66]. This strategy of sensitizing the chemotherapy resistant tumour cells with alteration of miRNA expression in tumour cells may result in improved response to traditional chemotherapy agents. Table 3 summarizes the studies manipulating the oncogenic miRNAs in colorectal cell lines.

Bottom Line: Strategy based on restoration of silenced miRNAs or inhibition of over expressed miRNAs has opened a new area of research in cancer therapy.Restoration of normal equilibrium for cancer related miRNAs can result in inhibition of tumour growth, apoptosis, blocking of invasion, angiogenesis and metastasis.However, further work is needed on tissue specific delivery systems and strategies to avoid side effects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, P O Box 65, Leicester LE2 7LX, United Kingdom. mia7@leicester.ac.uk

ABSTRACT
The development of Colorectal Cancer (CRC) follows a sequential progression from adenoma to the carcinoma. Therefore, opportunities exist to interfere with the natural course of disease development and progression. Dysregulation of microRNAs (miRNAs) in cancer cells indirectly results in higher levels of messenger RNA (mRNA) specific to tumour promoter genes or tumour suppressor genes. This narrative review aims to provide a comprehensive review of the literature about the manipulation of oncogenic or tumour suppressor miRNAs in colorectal cancer cells for the purpose of development of anticancer therapies. A literature search identified studies describing manipulation of miRNAs in colorectal cancer cells in vivo and in vitro. Studies were also included to provide an update on the role of miRNAs in CRC development, progression and diagnosis. Strategy based on restoration of silenced miRNAs or inhibition of over expressed miRNAs has opened a new area of research in cancer therapy. In this review article different techniques for miRNA manipulation are reviewed and their utility for colorectal cancer therapy has been discussed in detail. Restoration of normal equilibrium for cancer related miRNAs can result in inhibition of tumour growth, apoptosis, blocking of invasion, angiogenesis and metastasis. Furthermore, drug resistant cancer cells can be turned into drug sensitive cells on alteration of specific miRNAs in cancer cells. MiRNA modulation in cancer cells holds great potential to replace current anticancer therapies. However, further work is needed on tissue specific delivery systems and strategies to avoid side effects.

Show MeSH
Related in: MedlinePlus