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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

Carcinogenesis of colorectal cancer cells and role of different miRNAs in cancer pathways. In the carcinogenesis of CRC, higher levels of miR-135a & miR-135b are associated with low levels of Adenomatous Polyposis Coli (APC) , which in turn leads to activation of the Wnt signalling pathway. Activation of the Wnt signalling pathway is a major tumour initiating event in the colonic epithelium. The low level of APC associated β-catenin degradation complex results in the formation of free cytoplasmic β-catenin that enters the nucleus and activates Wnt-regulated genes through its interaction with TCF (T-cell factor) family transcription factors and concomitant recruitment of coactivators (Survivin, c-Myc and Cyclin D1). As a consequence, there is a lack of apoptosis and increase proliferation of abnormal cells that results in autonomous growth and formation of adenoma. During the course of carcinogenesis, cells in adenoma accumulate few other genetic alterations leading to activation of other signalling pathways e.g. mitogen activated protein kinase (MAPK), Phosphatidylinositol 3-kinases (PI3K) and transforming growth factor-beta (TGFβ) pathways. The let-7 miRNA family, miR-18a* and miR-143 are adept at inhibiting the KRAS translation hence switching “off” the MAPK phosphorylation and inactivation of downstream transcription factors c-Myc, c-Fos and c-Jun. Furthermore, a targeted degradation of PTEN and p85β by miR-21 and miR-126 respectively , blocks the PI3K-Akt pathway. These changes drive the early adenoma to a large advanced adenoma. The loss of p53 function is associated with low expression levels of miR-34a family, indicating the role of this miRNA family in the transformation of adenoma to the carcinoma.
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Figure 2: Carcinogenesis of colorectal cancer cells and role of different miRNAs in cancer pathways. In the carcinogenesis of CRC, higher levels of miR-135a & miR-135b are associated with low levels of Adenomatous Polyposis Coli (APC) , which in turn leads to activation of the Wnt signalling pathway. Activation of the Wnt signalling pathway is a major tumour initiating event in the colonic epithelium. The low level of APC associated β-catenin degradation complex results in the formation of free cytoplasmic β-catenin that enters the nucleus and activates Wnt-regulated genes through its interaction with TCF (T-cell factor) family transcription factors and concomitant recruitment of coactivators (Survivin, c-Myc and Cyclin D1). As a consequence, there is a lack of apoptosis and increase proliferation of abnormal cells that results in autonomous growth and formation of adenoma. During the course of carcinogenesis, cells in adenoma accumulate few other genetic alterations leading to activation of other signalling pathways e.g. mitogen activated protein kinase (MAPK), Phosphatidylinositol 3-kinases (PI3K) and transforming growth factor-beta (TGFβ) pathways. The let-7 miRNA family, miR-18a* and miR-143 are adept at inhibiting the KRAS translation hence switching “off” the MAPK phosphorylation and inactivation of downstream transcription factors c-Myc, c-Fos and c-Jun. Furthermore, a targeted degradation of PTEN and p85β by miR-21 and miR-126 respectively , blocks the PI3K-Akt pathway. These changes drive the early adenoma to a large advanced adenoma. The loss of p53 function is associated with low expression levels of miR-34a family, indicating the role of this miRNA family in the transformation of adenoma to the carcinoma.

Mentions: MiRNAs play an important role in colorectal tumour biology including; oncogenesis; progression; invasion; metastasis and angiogenesis [19-22]. Initiation and progression of colorectal neoplasia results from sequential accumulation of genetic alterations in oncogenic and tumour suppressor genes in colonic epithelium [23]. MiRNAs interfere with these genetic mutations and are involved in different stages of cancer of colorectal neoplasia. Slaby and colleagues summarized the role of different miRNAs in the development of colorectal cancer and emphasized the importance of Adenomatous Polyposis Coli (APC), Tumour Protein 53 (TP53) gene mutations and the WNT signalling Pathway [24]. The initiation of colonic neoplasia is strongly linked to inactivation of the APC gene and activation of the WNT Signalling Pathway. APC inactivation has been found in more than 60% of colonic tumours and such inactivation is associated with up regulation of miR-135a/b in colonic epithelial cells [23,25,26]. Accumulation of any further somatic mutations leads to further dysregulation of miRNAs and activation of additional downstream pathways. For example let-7, miR-18a* & miR-143 are strongly linked to KRAS knockdown and activation of the EGFR-MAPK pathway [27-29] whereas miR-21 and miR-126 are associated with augmentation or inactivation of the phosphatidylinositol-3-kinase (PI-3-K) pathway repectively [30,31]. Activation of these downstream pathways results in autonomous tumour cell growth, increased cell survival, and initiation of angiogenesis. Loss of P53 is a critical step in transformation of adenoma to adenocarcinoma as nearly 50–70% of colonic adenocarcinomas are found to be P53 mutant [23]. miR-34a has been identified as a direct downstream target of P53 and the replacement of miR-34a has achieved p53 induced effects of apoptosis and cell cycle arrest [32]. A commonly up regulated miR-17-92 cluster (miR-17, miR-18a, miR-19a, miR-20a, miR-19b & miR-92a) also drives the progression of adenoma to adenocarcinoma by up regulation of c-myc [33]. Figure 2 summarises the interaction of different miRNAs in signalling pathways for colorectal cancer development and progression.In the KEGG pathway, it shows the interaction of different miRNAs in the formation of adenoma and its progression to adenocarcinoma.


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)

Carcinogenesis of colorectal cancer cells and role of different miRNAs in cancer pathways. In the carcinogenesis of CRC, higher levels of miR-135a & miR-135b are associated with low levels of Adenomatous Polyposis Coli (APC) , which in turn leads to activation of the Wnt signalling pathway. Activation of the Wnt signalling pathway is a major tumour initiating event in the colonic epithelium. The low level of APC associated β-catenin degradation complex results in the formation of free cytoplasmic β-catenin that enters the nucleus and activates Wnt-regulated genes through its interaction with TCF (T-cell factor) family transcription factors and concomitant recruitment of coactivators (Survivin, c-Myc and Cyclin D1). As a consequence, there is a lack of apoptosis and increase proliferation of abnormal cells that results in autonomous growth and formation of adenoma. During the course of carcinogenesis, cells in adenoma accumulate few other genetic alterations leading to activation of other signalling pathways e.g. mitogen activated protein kinase (MAPK), Phosphatidylinositol 3-kinases (PI3K) and transforming growth factor-beta (TGFβ) pathways. The let-7 miRNA family, miR-18a* and miR-143 are adept at inhibiting the KRAS translation hence switching “off” the MAPK phosphorylation and inactivation of downstream transcription factors c-Myc, c-Fos and c-Jun. Furthermore, a targeted degradation of PTEN and p85β by miR-21 and miR-126 respectively , blocks the PI3K-Akt pathway. These changes drive the early adenoma to a large advanced adenoma. The loss of p53 function is associated with low expression levels of miR-34a family, indicating the role of this miRNA family in the transformation of adenoma to the carcinoma.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Carcinogenesis of colorectal cancer cells and role of different miRNAs in cancer pathways. In the carcinogenesis of CRC, higher levels of miR-135a & miR-135b are associated with low levels of Adenomatous Polyposis Coli (APC) , which in turn leads to activation of the Wnt signalling pathway. Activation of the Wnt signalling pathway is a major tumour initiating event in the colonic epithelium. The low level of APC associated β-catenin degradation complex results in the formation of free cytoplasmic β-catenin that enters the nucleus and activates Wnt-regulated genes through its interaction with TCF (T-cell factor) family transcription factors and concomitant recruitment of coactivators (Survivin, c-Myc and Cyclin D1). As a consequence, there is a lack of apoptosis and increase proliferation of abnormal cells that results in autonomous growth and formation of adenoma. During the course of carcinogenesis, cells in adenoma accumulate few other genetic alterations leading to activation of other signalling pathways e.g. mitogen activated protein kinase (MAPK), Phosphatidylinositol 3-kinases (PI3K) and transforming growth factor-beta (TGFβ) pathways. The let-7 miRNA family, miR-18a* and miR-143 are adept at inhibiting the KRAS translation hence switching “off” the MAPK phosphorylation and inactivation of downstream transcription factors c-Myc, c-Fos and c-Jun. Furthermore, a targeted degradation of PTEN and p85β by miR-21 and miR-126 respectively , blocks the PI3K-Akt pathway. These changes drive the early adenoma to a large advanced adenoma. The loss of p53 function is associated with low expression levels of miR-34a family, indicating the role of this miRNA family in the transformation of adenoma to the carcinoma.
Mentions: MiRNAs play an important role in colorectal tumour biology including; oncogenesis; progression; invasion; metastasis and angiogenesis [19-22]. Initiation and progression of colorectal neoplasia results from sequential accumulation of genetic alterations in oncogenic and tumour suppressor genes in colonic epithelium [23]. MiRNAs interfere with these genetic mutations and are involved in different stages of cancer of colorectal neoplasia. Slaby and colleagues summarized the role of different miRNAs in the development of colorectal cancer and emphasized the importance of Adenomatous Polyposis Coli (APC), Tumour Protein 53 (TP53) gene mutations and the WNT signalling Pathway [24]. The initiation of colonic neoplasia is strongly linked to inactivation of the APC gene and activation of the WNT Signalling Pathway. APC inactivation has been found in more than 60% of colonic tumours and such inactivation is associated with up regulation of miR-135a/b in colonic epithelial cells [23,25,26]. Accumulation of any further somatic mutations leads to further dysregulation of miRNAs and activation of additional downstream pathways. For example let-7, miR-18a* & miR-143 are strongly linked to KRAS knockdown and activation of the EGFR-MAPK pathway [27-29] whereas miR-21 and miR-126 are associated with augmentation or inactivation of the phosphatidylinositol-3-kinase (PI-3-K) pathway repectively [30,31]. Activation of these downstream pathways results in autonomous tumour cell growth, increased cell survival, and initiation of angiogenesis. Loss of P53 is a critical step in transformation of adenoma to adenocarcinoma as nearly 50–70% of colonic adenocarcinomas are found to be P53 mutant [23]. miR-34a has been identified as a direct downstream target of P53 and the replacement of miR-34a has achieved p53 induced effects of apoptosis and cell cycle arrest [32]. A commonly up regulated miR-17-92 cluster (miR-17, miR-18a, miR-19a, miR-20a, miR-19b & miR-92a) also drives the progression of adenoma to adenocarcinoma by up regulation of c-myc [33]. Figure 2 summarises the interaction of different miRNAs in signalling pathways for colorectal cancer development and progression.In the KEGG pathway, it shows the interaction of different miRNAs in the formation of adenoma and its progression to adenocarcinoma.

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