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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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Figure illustrates the mechanisms of restoration of tumour suppressor miRNAs. The knockdown of oncogenic mRNAs can be achieved by restoration of tumour suppressor miRNAs by a) Transcription activation of miRNA transcribing gene b) Transfection of tumour cells with miRNA transcription gene linked to a virus construct e.g. adenovirus-associated vector (AAV) c) Introduction of synthetic precursor miRNAs in tumour cells d) Synthetic miRNA mimics competing with mature miRNAs for RISC.
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Figure 6: Figure illustrates the mechanisms of restoration of tumour suppressor miRNAs. The knockdown of oncogenic mRNAs can be achieved by restoration of tumour suppressor miRNAs by a) Transcription activation of miRNA transcribing gene b) Transfection of tumour cells with miRNA transcription gene linked to a virus construct e.g. adenovirus-associated vector (AAV) c) Introduction of synthetic precursor miRNAs in tumour cells d) Synthetic miRNA mimics competing with mature miRNAs for RISC.

Mentions: The loss or downregulation of a tumour-suppressor miRNA could be overcome by introducing synthetic oligonucleotides i.e. mature miRNA mimics, miRNA precursors or pre-miRNA mimics into the CRC cells(Figure 6). Introduction of synthetic miRNAs with tumour-suppressor function in cancer cells have been shown to induce cell death and block cellular proliferation, transformation, invasion and migration in several studies as summarized in Table 4. The altered expression of tumour suppressor miRNAs have been studied in the context of cancer-associated transcription factors. P53 mutations have been found in 40–50% of CRCs. The p53 protein is a transcription factor that regulates multiple cellular processes in CRC development, either by regulating mRNA directly or by regulating miRNA indirectly. The absence of p53 mutations in adenomas suggests that loss of p53 is a critical step in progression of adenoma to carcinoma [73,74]. In addition, the miR-34 family has been strongly linked to p53 and loss of p53 has been linked to reduced levels of miR-34 in cancer cells. miR-34a restoration studies [75,76] have clearly demonstrated reduced cell survival, invasion and migration in CRC cell lines. In addition to a link with the p53 pathway, miR-34a encoding genes on their own have been identified as targets for the mutational or epigenetic inactivation in different cancers. Interestingly, miR-34a resides on the chromosomal locus 1p36, which has been proposed to harbor a tumor suppressor gene because it displays homozygous deletions in neuroblastoma and in other tumor types [77]. An unbiased screen for genes with tumor suppressive function on 1p36 also revealed miR-34a as a candidate tumor suppressor gene [78]. Therefore miR-34 targeted gene therapies hold a prime importance in the designing therapies for chemoprevention and to halt the tumour progression. miR-143 is another tumour suppressor miRNA, significantly found downregulated in CRC tissues (Table 1). The most significant study in this respect is restoration of miR-143 with miR-143 precursor resulting in reduced proliferation in SW480 colorectal cell lines and tumour suppression on xenografted tumors of DLD-1 human CRC cells [79,80]. Restoration of tumour suppressor miRNA by intravenous injection in mouse with liver cancer resulted in the suppression of tumorigenicity by reduced tumour growth and enhanced tumour apoptosis without signs of toxicity. This illustrates that tumour suppressor miRNA restoration strategy based gene therapy, if delivered efficiently to specific tissues may prove vital in future cancer treatments.


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 illustrates the mechanisms of restoration of tumour suppressor miRNAs. The knockdown of oncogenic mRNAs can be achieved by restoration of tumour suppressor miRNAs by a) Transcription activation of miRNA transcribing gene b) Transfection of tumour cells with miRNA transcription gene linked to a virus construct e.g. adenovirus-associated vector (AAV) c) Introduction of synthetic precursor miRNAs in tumour cells d) Synthetic miRNA mimics competing with mature miRNAs for RISC.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Figure illustrates the mechanisms of restoration of tumour suppressor miRNAs. The knockdown of oncogenic mRNAs can be achieved by restoration of tumour suppressor miRNAs by a) Transcription activation of miRNA transcribing gene b) Transfection of tumour cells with miRNA transcription gene linked to a virus construct e.g. adenovirus-associated vector (AAV) c) Introduction of synthetic precursor miRNAs in tumour cells d) Synthetic miRNA mimics competing with mature miRNAs for RISC.
Mentions: The loss or downregulation of a tumour-suppressor miRNA could be overcome by introducing synthetic oligonucleotides i.e. mature miRNA mimics, miRNA precursors or pre-miRNA mimics into the CRC cells(Figure 6). Introduction of synthetic miRNAs with tumour-suppressor function in cancer cells have been shown to induce cell death and block cellular proliferation, transformation, invasion and migration in several studies as summarized in Table 4. The altered expression of tumour suppressor miRNAs have been studied in the context of cancer-associated transcription factors. P53 mutations have been found in 40–50% of CRCs. The p53 protein is a transcription factor that regulates multiple cellular processes in CRC development, either by regulating mRNA directly or by regulating miRNA indirectly. The absence of p53 mutations in adenomas suggests that loss of p53 is a critical step in progression of adenoma to carcinoma [73,74]. In addition, the miR-34 family has been strongly linked to p53 and loss of p53 has been linked to reduced levels of miR-34 in cancer cells. miR-34a restoration studies [75,76] have clearly demonstrated reduced cell survival, invasion and migration in CRC cell lines. In addition to a link with the p53 pathway, miR-34a encoding genes on their own have been identified as targets for the mutational or epigenetic inactivation in different cancers. Interestingly, miR-34a resides on the chromosomal locus 1p36, which has been proposed to harbor a tumor suppressor gene because it displays homozygous deletions in neuroblastoma and in other tumor types [77]. An unbiased screen for genes with tumor suppressive function on 1p36 also revealed miR-34a as a candidate tumor suppressor gene [78]. Therefore miR-34 targeted gene therapies hold a prime importance in the designing therapies for chemoprevention and to halt the tumour progression. miR-143 is another tumour suppressor miRNA, significantly found downregulated in CRC tissues (Table 1). The most significant study in this respect is restoration of miR-143 with miR-143 precursor resulting in reduced proliferation in SW480 colorectal cell lines and tumour suppression on xenografted tumors of DLD-1 human CRC cells [79,80]. Restoration of tumour suppressor miRNA by intravenous injection in mouse with liver cancer resulted in the suppression of tumorigenicity by reduced tumour growth and enhanced tumour apoptosis without signs of toxicity. This illustrates that tumour suppressor miRNA restoration strategy based gene therapy, if delivered efficiently to specific tissues may prove vital in future cancer treatments.

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