Abstract: Based on the size of the RNAs non-coding

Abstract:

The data regarding RNA editing in various cancers was obtained and compiled through a thorough review of various published research articles of international reputed journal and relevant books. In this article we review the applications of microRNAs and various types of RNAs for the clinical assessment of patient as well as in cancer monitoring and therapy. MiRNAs are a class of small non-coding RNA molecules that can regulate gene expression by specifically recognizing their complementary sites on their target mRNAs. It is recommended to examine to avoid its destructive effects on human health.   1 2 4

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Keywords: RNA editing, microRNA, non-coding RNA, complementary sites.

Introduction:-

RNA editing is a post transcriptional process which alters the nucleotide sequence of RNA transcripts. Early studies revealed that RNA editing plays important roles in the central nervous system. For example glutamate receptor subtype A2 and 5 hydroxy tryptamine receptor subtype 2C were known to be subjected to RNA editing and the disruption of RNA editing in these genes leads to amyotrophic lateral sclerosis. 1

 

There are various types of RNA which plays a very diverse role in cancer study as well as to cure various dangerous types. Basically we have focused on kinds of cancer which effects in human health and cause cell death. Various harmful types such as breast cancer, lung cancer, colon cancer and cervical cancer. 1 2

Diagnosis of cancer takes place by predictive or prognostic signatures. It can also diagnose by prediction of treatment response and with the help of microRNA based therapeutics. 1 

Non-coding RNAs have played a key role in various cancers. Based on the size of the RNAs non-coding RNAs are usually known as small RNAs due to very small size with less than 50 nucleotides such as microRNAs. Long non-coding RNAs consists of more than 200 nucleotides so named as long non-coding RNAs. It has been classified into various types such as:-

1)    long intergenic non coding RNAs

2)    long intronic non coding RNAs

3)     circular RNAs

4)    circular intronic RNAs

MiRNAs are a class of small non coding RNA molecules that can regulate gene expression by specifically recognizing their complementary sites on their target mRNAs. MiRNAs are involved in many biological processes i.e. cell cycle, differentiation, development and metabolism. Because miRNAs are critical regulators if their deregulation takes place then it may lead to deregulated genes which results in severe diseases such as cancers. 1

Circular RNAs are a class of non coding RNAs that are formed by back splicing of exons and lariats production takes place in splicing process. Evidences show that circRNAs play roles in diseases such as cancer, Alzheimer’s disease and heart failure. 2

We have barely begun to investigate RNA regulatory networks in mammals. The majority of the mammalian genome is transcribed into non-protein-coding RNA. Numerous short RNAs are processed from longer transcripts and possess various expression patterns, but the biological functions and targets are known for very few of them. The mechanism of RNAi is relatively well studied but our knowledge of chromatin modification by siRNAs is incomplete to say the least. It also seems likely that other short non-coding RNAs exist in the cell that may regulate many other processes and utilize other mechanisms, which remain to be discovered. 10

RNA editing is an RNA modification mechanism that introduces specific nucleotide changes into certain RNA transcripts. The most common type of RNA editing in humans is adenosine to inosine is recognized as guanosine by the translational machinery. As a result of advances in next-generation sequencing technology more than one million A to I RNA editing sites have been detected. Various studies have been done for RNA based studies are as follows:- 1 13

MicroRNAs play very important role in embryonic or developmental origin of the tumor this greatly facilitates tumor classification based on microRNAs. The study of 22 different tumor types showed microRNA expression classified tumors according to tissue of origin with accuracy higher than 90%. Classification of leukemia is done according to cell lineage and microRNA expression across leukemia subtypes also reflects the cell of origin. 2

It has been reported in 2002 that micro RNA works against cancer when two types were identified i.e. miR15 and miR16 these two types work in chronic lymphocytic leukemia. Through higher expression against anti apoptotic target B cells lymphoma 2 it has been revealed that micro RNAs have roles in all types of cancers and are implicated in the clinical management of cancers at every stage. 2

Cervical cancer is the most common cancer among female mostly occur in developing countries. It is caused 265,700 deaths worldwide in 2012. Human papillomavirus (HPV) is well established as the major environmental risk factor for the occurrence of cervical cancer the multiple processes of genetic and epigenetic alterations leading to this disease still need to be eradicate.67

BLCAP is a highly effective gene with two exons and an intron that encodes a 10kDa protein which was originally identified from invasive bladder carcinoma. We previously published data from in vitro and in vivo experiments indicated that BLCAP is an anti-tumor gene which has potential in cervical cancer. 3

Oncomir provides miRNA expression in colon cancer. Oncomir collects experimentally verified oncogenic and tumor suppressive miRNAs by using text mining. 23

Increasing evidences show that many lncRNAs contain DNA binding motifs and can bind to DNA to induce methylation. The functions of these lncRNAs it is critical to predict putative lncRNA binding sites on DNA or to find target targets of lncRNAs. Long Target provides lncRNA DNA binding motifs and binding sites. 24

AnnoLnc is a tool to annotate novel human lncRNAs. AnnoLnc generates sequence and structure features, regulation, expression, protein interaction, genetic association and evolution for input lncRNA sequences. 24

CHARACTERISTICS OF ncRNA:-

FUNCTIONAL VERSUS NON-FUNCTIONAL

Less than 1% of lncRNAs have been associated with a function. Their cell and tissue specific expression that changes in response to external factors such as stress and other environmental signals implies that their presence is dependent on the need of the cell. 2Their involvement varies from transcriptional to post transcriptional regulation to translational control. There is evidence that some of these are essential for development. For example Mirg is a maternal ncRNA from the Dlk Dio3 imprinted cluster is expressed in different tissues at different time during embryonic development. 234

 The functional role of A-to- I RNA editing in human cancer is in liver cancer.

 RNA editing is a dynamic posttranscriptional mechanism of base recoding catalyzed by specific classes of editing enzymes that can significantly modify the functional properties and levels of expression of a spectrum of protein coding mRNAs as well as influence a potentially broad array of ncRNAs. Although various forms of RNA editing are known to occur throughout the metazoa a dramatic increase of RNA editing has occurred during mammalian evolution with the hominid lineage exhibiting the highest levels and the most complex forms of editing of individual transcripts. Moreover adenosine to inosine RNA editing is particularly active in the brain. 24

A growing body of evidence indicates that deregulation of epigenetic mechanisms collaborates with genetic alterations in the development and progression of cancer. 3

Comparison of editing in coding regions of malignant and normal tissues:-

Editing is found in noncoding regions as well as editing sites are also exists in coding sequences where they are expected to alter the gene product. Bioinformatics analysis identified editing sites in an evolutionarily conserved region in the coding sequence of the CYFIP2, FLNA and BLCAP transcripts. The editing levels of these sites were analyzed in three different types of human tumors and their normal parts: brain, oral cavity, and lung.

The editing ratio was also tested in malignant, normal lung and oral cavity tissues. In all cases the normal tissue was obtained from a distal region in the same individual from whom the tumor was obtained. The overall level of editing of CYFIP2 was significantly lower in these tissues as compared to the brain tissues. The average editing percentage in six oral cavity tumor samples was 4.3% as compared to 7.5% in six normal controls. In lung cancer samples the average editing percentage was 1.16% in tumors. Due to the small number of oral cavity and lung samples these differences are not significant however the trend was similar to that found in the brain tissues.

Role of microRNA in cancer:

There are many specific examples that have been reported to describing microRNA functions. Two major categories are as follows: 1.Homeostatic regulation of gene expression according to cellular requirements 2. Robustness in cellular responses which is important in cell fate decisions in which groups of microRNAs can perform the cellular differentiation state and acting as locks to maintain cell identity by complex reciprocal negative feedback mechanism.

Prediction of metastatic outcomes takes place in breast cancer by the help of microRNA. 1 This is seen in many cancers in which microRNAs associated with terminal differentiation are weakly expressed in order to promote a proliferative state. Robustness has play very important role in responses to stress in which microRNAs perform function as switches to allow cells to adapt to various changes in their environment.  When energy levels are sufficient then higher levels of miR-451 act to promote mammalian cell activation and cell proliferation.

MicroRNAs in Adult Brain and Brain Disease

MiRNAs are expressed in high levels within the mature and even the senescent brain and function to the maintenance of adult neural cell traits to promote cellular homeostasis and to modulate multiple parameters associated with synaptic plasticity. By repressing the expression of genes involved in maintaining the undifferentiated neural cell state miRNAs promote the fidelity of specific differentiated neural phenotypes. 9

Discussion:

Paired end reads were assigned quality scores and aligned to the reference genome. We searched for RNA editing events by examining all very high confidence predictions from the RNA sequencing library of the metastatic tumors that were not found with extreme confidence in past. 7 13

Taking together this study presents a comprehensive view of A-to-I RNA editing events in the cancer genome that provides the first evidence that how RNA editing could selectively affect drug sensitivity. Just like the somatic mutations some RNA editing events act as drivers for tumor growth and serve as predictive markers for patient stratification. Further efforts are required to investigate RNA editing together with other emerging players in cancer. 9 15

Our understanding of the mammalian genome is undergoing vast changes. We used to consider non-coding regions to be junk but the extent of noncoding RNA transcription the rapidly emerging evidence of regulatory networks controlled by RNA and a new logic about the genetic structure of complex organisms suggest that most of the mammalian genome may be functional or this possibility should be more seriously considered. 10 12

This review provides some evidence of the multidimensional role of lncRNAs in cancer. It undergoes the importance of the functional existence of these transcripts that are proving to be much more than transcriptional noise. 4 6

Future Applications:

More accurate detection in bio fluids, urine, CSF, blood circulating exosomes 1

More precise signatures leads to specific therapies 1

Trends of more therapeutic applications i.e. antisense, therapeutic miR delivery nanoparticles, cell-based and exosomes, combination therapies. 1

It tells us about diagnostic or predictive biomarkers. They may be further developed into cancer specific RNA targets that improve treatment sensitivity for various cancers. 4

Educational and awareness programs should be organized to control the cancer.

REFERNECES:

1.        Josie Hayes, Pier Paolo Peruzzi, and Sean Lawler et.al microRNAs in biomarkers, function and therapy Trends in Molecular Medicine August 2014, Vol. 20, No. 8

2.        Yun Zheng a, Li Liu b, Girish C. Shukla et.al a comprehensive review of web-based non-coding RNA resources for cancer research in Cancer Letters 407 (2017) 1-8

3.        Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65: 87-108. doi: 10.3322/caac.21262.

4.        Sheetal A. Mitra, Anirban P. Mitra and Timothy J. Triche et.al a central role for long non-coding RNA in cancer in frontiers in GENETICS February2012|Volume3|Article17| 1

5.        Nurit Paz, Erez Y. Levanon et.al Altered adenosine-to-inosine RNA editing in human cancer 17:1586–1595 ©2007 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/07;

6.        Masataka Nakano, Tatsuki Fukami, Saki Gotoh, et.al A-to-I RNA editing up-regulates human dihydrofolate reductase in breast cancer in JBC Papers in Press. Published on February 10, 2017 as Manuscript M117.775684

7.        Sohrab P. Shah, Ryan D. Morin et.al Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution in nature Vol 461|8 October 2009| doi: 10.1038/nature08489

8.        MARK F. MEHLER AND JOHN S. MATTICK et.al Noncoding RNAs and RNA Editing in Brain Development, Functional Diversification, and Neurological Disease in  Physiol Rev 87: 799–823, 2007; doi:10.1152/physrev.00036.2006. Copyright © 2007 American Physiological Society.

9.        Leng Han & Han Liang (2016) RNA editing in cancer: Mechanistic, prognostic, and therapeutic implications, Molecular & Cellular Oncology, 3:2, e1117702, DOI: 10.1080/23723556.2015.1117702

10.      John S. Mattick and Igor V. Makunin et.al Small regulatory RNAs in mammals in human Molecular Genetics, 2005, Vol. 14, Review Issue 1doi:10.1093/hmg/ddi101

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12.    Debora Fumagalli, David Gacquer et.al Principles Governing A-to-I RNA Editing in the Breast Cancer Transcriptome in Cell Reports. 2015 Oct 13; 13(2): 277–289. Published online 2015 Oct 1. doi:  10.1016/j.celrep.2015.09.032

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