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Roles of MicroRNAs in the Cell Cycle

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Evaluate the roles of microRNAs in the cell cycle and explain the consequences of disruption to microRNA activity in named diseases

Introduction

The presence and activity of various proteins are required in the cell cycle progression.(1) The regulation of these protein levels is vital for the understanding of the cell cycle control and its dysregulation. The dysregulation results genetic mutation related diseases. For instance, overexpression of cyclins or the elimination of CDK inhibitors or pRB due to genetic mutation are common cause in human cancer.(2) Therefore, the proper control of protein levels is crucial for the cell cycle.

MicroRNAs are ~22-25 nucleotide non-coding RNAs.(3) It is post- transcriptional repressor of mRNA; control the stability and translation of protein-coding mRNAs. (1, 3). MiRNAs bind the 3’ untranslated region (3’UTR) of target mRNAs. The binding of miRNA- protein complexes to mRNA causes translation inhibition or destabilisation of target transcripts.(1) This is resulting in the downregulation of the protein encoded by mRNA.

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Figure 1 : microRNA as post-transcription inhibitor in protein encoding (4)

MicroRNAs control the levels of numerous cell cycle regulators that controls cell proliferation.(1) The alternation of protein levels of critical oncogenes or tumour suppressor genes, which causes by miRNAs deregulation may also lead to proliferative diseases such as cancer. MiRNAs that linked to human cancers, known as “oncomirs”. These are divided into two group, those miRNAs that are upregulated in cancer which are likely to be acting as oncogenes and those downregulated in cancer which are likely to be acting as tumour suppressors.(5)

Approximately 30-60 % of the human genome, regulated by miRNAs. As a consequence, any modulations of the target transcript expression, miRNAs can affect various signalling pathways and cellular process such as apoptosis, proliferation or differentiation. Therefore, miRNAs could consider as cancer targets.

Besides cancer, some miRNAs genes cause or contribute in many inherited and genetic based diseases. For instance, miR-26b upregulated in Alzerimer’s disease, (6) miR - 96 causes nonsyndromic progressive hearing loss (7) and miR -184 causes Familial Keratoconus with Cataract.(8)

Nevertheless, some miRNAs’ genes are beneficial; display antiproliferative properties.(1) For example, the down-regulation of miR15s and miR – 16 – 1 in chronic lymphocytic leukaemia, prostate cancer and pituitary tumours, leading to the inhibition of tumour growth and induce cell cycle arrest at the G1­ phase by target cell cycle regulators ( cyclin D1, cyclin E1, cyclin D3 and CDK6). (9)

As miRNAs proposed to control the expression up to one third of all genes and possibly utilised as diagnostic and prognostic marker for many genetic based diseases.(10) Therefore, it is important to evaluate its role in the cell cycle and its dysregulation.

The different roles of MicroRNAs in the cell cycle

The understanding of miRNA has increased over the past 10 years, and particularly the involvement of miRNAs in cancer. Nowadays, cancer is a common disease, which occurs to one third of the population. There are lots of cancer treatments available, however to identify an effective treatment is still challenging.(9) Therefore, it is important to develop a new treatments with less side effect are greatly demanded. A greater understanding of miRNA could possibly lead to better diagnostic and treatment of cancer.(9)

Let-7 Let-7 has an essential role in cell cycle and the differentiation of cell cycle terminals. Let-7 is coded by 12 genes; these are produced from the eight genomic loci. These 12 genes are located at a region, which is frequently deleted in cancer. Throughout the lung cancer examination, it has been showed that a low level of let-7 relates to the poor prognosis. The expression of let-7 induces the suppression growth of cell and human tumour cell lines.(12) Over-expression of let-7 in lung cancer causes the lowered cell division and stopped the progression of cell cycle. Ras, Caspase-3 and HMGA2 genes are targeted by let-7 for controlling tumour growth. Furthermore, let-7 represses number of cell cycle regulator gene: cyclin D1, cyclin A, cyclin D3, CDK4 and CCNA2, CDK6, CDC25A and CDK8. (13)

MiR-15a/16 Chromosome 13q14 region is frequently deleted in more than 50% of the B-cell chronic lymphocytic leukaemia (CLL). This region of the chromosome includes the expression of miR-15a/16 cluster. Further studies have identified that miR-15a/16 is located at the 30 kb region of the loss chromosome in CLL. (14) In CCL patients, about 70% of the patients have miR-15a and miR-16 either deleted or down regulated; same applies to gastric cancer and pituitary adenomas cell lines. The miR-15a and miR-16 target cell cycle regulators such as cyclin D1, cyclin D3, cyclin E1 and CDK6, this causes the cell cycle arrest during the G1 phase.(13) miR-15 and miR-16 in colon cancer cell lines presented with a high level of down-regulated transcripts for gene related to cell-cycle progression. Moreover, the high expression of miR16 which leads to increase G0 and G2 phase accumulation through down-regulating the gene expression of cell cycle, CARD10, CDK6 and CDC27. These evidenced the miR15a and miR16 associated with complex gene expression.(12)

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Figure 2: Cell cycle and proteins that are involved in the cycle. (11)

MiR-17/20 The miR-17/20 induces suppression of tumour growth in the breast cancer and human B-cell line; it encodes 6 mature miRs in a 1 kb region. MiR-17/20 target several cell cycle regulators, including E2F, Rb, c-myc and cyclin D1, for the time control of cell cycle. At G1 phase (figure 2) , Cyclin D1 and c-myc are induced and inactivation of E2F1 when bind to Rb. The transition of G1 to S phase of the cell cycle requires the miR-17/20 cluster.(13) The miR-17 family might involve in inhibit or promote cellular proliferation. In a low level of mitogenic stimulation, miR-17 possible involves in the E2F signalling maintenance to be at a level below threshold for proliferation. Furthermore, the missing miR-17-19 cluster has been identified in many malignancies, and disruption of miR-17 expression possible reduces the proliferation of certain breast cancer cell lines. The suppression of irregularly high E2F activation, the apoptosis response might be eliminated by the miR-17-92 cluster, then this function as an oncogene. Subsequently, in various solid and haematopoietic malignancies are found to have amplificated and over-expressed miR-17 family. These have indicated that miR-17/20 play a essential role in cellular proliferation and progression of malignancies. (12)

MiR-221/222

The regulation of cell cycle by miR-221/222, which it targets the CDK inhibitors. The miR-221 and miR-222 ectopic expression initiate CDK2, aiding the transition of G1 to S phase of cell cycle and p27kip2 and p57kip2 are negatively regulated which lead to increase tumour growth. This is frequently identified in human breast cancer tissues.(13) In addition, miR-221 and miR-222 act as a direct regulator of p27. The over-expression of this cluster increases cellular proliferation and allowed anchorage growth independently. The suppression of miR221 and miR-222 initiated G1 phase arrest in breast cancer cell lines. It is found that miR-221/222 is over-expressed in several human tumors. (12)

Table 1: miRNA genes and clusters that target cell cycle regulators and its deregulation in cancer. (1)

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MiRNA related diseases

Chronic Lymphocytic Leukaemia

Chronic Lymphocytic Leukaemia (CLL) occurs due to the homozygous or heterozygous deletion of the chromosomal region 13q14.3. MiR – 15a and miR -16-1 are located in this region as shown in Calin et al’s study.(9, 15) This provided evidence that miRNAs might be involved in the pathogenesis of CLL and other human cancers.(9) These genes were found to be deleted in 68 % of CLL patients.(15) MiR-15a and miR-16-1 leads to the inhibition of tumour growth by negatively regulate BCL2; anti-apoptotic gene.(9) They also induce cell cycle arrest at the G1 phase by targeting cell cycle regulators ; cyclin D1, cycline D3, cyline E1 abd CDK6.(9) The deletion of miR-15a and miR-16-1 associated with CLL patients’ phenotypes; the loss of these two genes accelerates B- lymphocytes proliferation by modulating genes’ expression controlling cell-cycle progression.(9) As consequences, CLL clinical features occurs.

Breast cancer

breast cancer is oestrogen hormone dependant disease. Breast cancer occurs when the number of oestrogen receptors (ER) increase abnormally. Alb1 genes are oncogenes in breast cancer. It enhances the transcriptional activity of the ER and E2F1 and other transcription factors. (16) Alb1 is a rate-limiting factor for oestrogen. (16) E2F1 is involving in growth hormone–signalling pathway and mediated breast cancer cells growth. (16) From the Hossain et al’s study, mir-17-5p play a role of tumour suppressor, which controls the cell proliferation of breast cancer cells. (16) In cell culture experiment, AlB1 expression was downregulated by mir-17-5p through translational inhibition. This resulted in decreased ER and cancer cells’proliferation. As mir-17-5p binds to the cyclin D1 3’UTR in the MCF-7 breast cancer cells . It inhibits cyclin D1 expression, resulting in suppressed cell proliferation and cell cycle arrest.(9)

Conclusion

MicroRNAs are crucial in the cell cycle. The Mitchell et al’s study has shown that miRNAs displayed high stability in tissue from human plasma. (17) It is possible that miRNA might be useful biomarker to indicate disease state. Moreover, the demonstration of miRNA profiles are potential for distinguishing a development of tumour’s origin and miRNA that acts like tumour suppressor in cancer.(18) From Lu et al’s study, they have demonstrated that there are lower miRNA expression in poorly differentiated as compared to highly differentiate tumour; which is very interesting fact and provide evidence to shoe that possibility that miRNA could utilised in disease diagnostics. (19) Therefore, further researches should carry out to gain more understandings and invent more effective treatment.

References

1. Bueno J, María., Malumbres M. MicroRNAs and the cell cycle. 2011;1812(5):592–601.

2. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer. 2001;1(3):222-31.

3. Carleton MC, A., Michele. Linsley,S.,Peter. MicroRNAs and Cell Cycle Regulation. Cell cycle. 2007 September 1;6(17):2127-32.

4. The image of microRNA [image on the internet]. 2013 [cited 2014 February 4]. Available from : http://www.fireflybio.com/introduction_to_microRNA.

5. Johnson CD, Esquela-Kerscher A, Stefani G, Byrom M, Kelnar K, Ovcharenko D, et al. The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res. 2007;67(16):7713-22.

6. Absalon S, Kochanek DM, Raghavan V, Krichevsky AM. MiR-26b, upregulated in Alzheimer's disease, activates cell cycle entry, tau-phosphorylation, and apoptosis in postmitotic neurons. J Neurosci. 2013;33(37):14645-59.

7. Mencía Áea. Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nature Genetics. 2009;41(5):609-13.

8. Hughes AE, Bradley DT, Campbell M, Lechner J, Dash DP, Simpson DA, et al. Mutation Altering the miR-184 Seed Region Causes Familial Keratoconus with Cataract. The American Journal of Human Genetics. 2011;89(5):628-33.

9. MicroRNA in Cancer: Spinger Science and Business Media Dordrecht; 2013 [cited 2014 February 2]. Available from: http://books.google.co.uk/books/about/MicroRNA_in_Cancer.html?id=RS8qLrSkdkgC.

10.Yang MM, Joerg. Discovery, biology and therapeutic potential of RNA interference, microRNA and antagomirs. 2008;117(1):94–104.

11. Cohen B. The image of cell cycle [image on the internet]. 2013 [cited 2014 February 4]. Available from : http://www.studyblue.com/notes/note/n/neoplasia-vii-cancer-critical-genes-and-familial-cancer-syndromes/deck/6316935.

12. Chivukula R, Raghu. Mendell,T., Joshua. Circular reasoning: microRNAs and cell-cycle control. October 2008;33(10):474-81.

13. Yu Z, Baserga R, Chen L, Wang C, Lisanti MP, Pestell RG. microRNA, Cell Cycle, and Human Breast Cancer. American Journal of Pathology, The. 2010;176(3):1058-64.

14. Cho WC. OncomiRs: the discovery and progress of microRNAs in cancers. Molecular Cancer [Internet]. 2007 2007-09-25 [cited 2014 Febuary 5]; 6(1):[60 p.]. Available from: http://www.molecular-cancer.com/content/6/1/60.

15. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. 2002;99(24).

16. Hossain A, Kuo MT, Saunders GF. Mir-17-5p Regulates Breast Cancer Cell Proliferation by Inhibiting Translation of AIB1 mRNA. Molecular and Cellular Biology. Novemble 2006;26(20).

17. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105(30):10513-8.

18. Hydbring PV-B, Gayane. Clinical applications of microRNAs - F1000Research. 2014.

19. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834-8.


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