Trove 2 as a Biomarker in Kidney Cancer - Literature review Example

Introduction Today cancer stands as one of the most important challenges to the world of medicine. Cancer is caused by various factors, both genetic and epigenetic in nature. Cancer is incurable, beyond a certain stage, and this fact calls for measures to be taken for early detection and diagnosis. One of the most useful tools as a result of advances in the field of molecular biology and genetics is the development of biomarkers. Biomarkers can be used easily for detection of cancer and thereby assist in early detection and subsequent diagnosis since they are sensitive and enhances the specificity of the stages of cancer (Basil et al, 2006, p.2953). Biomarkers may also be sued to predict the result of different therapies as well. Ro60 protein (Trove 2) and YRNAs have been studied and researched upon and even though both have pivotal roles to play in autoimmune disorders they may also be used as biomarkers. Trove2 RO60 is also known as Sjogren’s syndrome Antigen 2 (SSA2). In 1988, Deutscher et al, reported the discovery of Ro60 complemetary DNA sequence (cdna) while it was about 6 years later in 1994 that, using hybridization technique, researchers found that the Ro60 gene’s position was located to chromosome 1q31 (Millard et al, 2002, p.210).The Ro60 protein is present in many animals and molecular studies in all of some of the animal species have shown the presence of Ro60 in association with YRNA (a small non-coding RNA molecule) (Wolin and Reinisch, 2006, p.368). In most vertebrates along with Ro60 and YRNA another nuclear phosphoprotein is also present which is known as the La protein. Studies have shown that Ro60 is a ring-like structure with a hole in the middle. The structure of Ro60 and YRNA was also determined and it was seen that the later bound to Ro60 residues on the outer ring of the structure (Perreault et al, 2007, p.1677). The structure of Ro60 reveals that it has a role in stabilization of RNA helix. In an in-vivo study of Escherichia coli showed that the protein was capable of promoting correct folding of misfolded RNA while the Ro60-YRNA complex act as transporters where they transport RNA-binding proteins to their target molecules (Belisova et al, 2005, p.1084). YRNA It was during investigation into the autoimmunity of systemic lupus erythromatosus or SLE that YRNA’s were discovered sometime in the 1980’s as an important component of the Ro ribonucleoprotein particles or Ro RNPs (Gardiner et al, 2009, p.1375).YNA gene is present in all vertebrates and in some invertebrates as well. YRNAs are non-coding RNAs and are expressed in each of the human cells i.e. they are RNA polymerase III transcripts comprising of about 100 nuceotides. In humans four different kinds of YRNAs are expressed- hY1, hY2, hY3 and hY4 (Langley et al, 2010, p.1). Each of these hYRNAs are encoded by a single gene. The function of YRNA remains unclear however its ability to form a complex with Ro60 protein has been well researched upon. Recent studies have shown that non-coding RNAs are responsible for regulation of a number of processes ranging from expression of genes to developmental processes (Christove et al, 2006, p.6993). Ro-RNP The Human Ro-RNPs are made up of Ro protein, La protein and one of the four types of YRNAs. Other protein such as Ro52 and calreticulin may also be a part of the complex (Fabini et al, 2000, p.2778). Even though Ro-RNPs are expressed in all cells of the human body , some difference are present among Ro-RNPs of different tissues. Erythrocytic extracts of RoRNps show only two kinds o YRNA- hY3 and hY4.Studies on model organisms have shown that Ro-RNP associated YRNA level depends on rop-1 gene (Labbe et al, 2000, p.13233). Even though some studies indicate the important role of YRNA for replication initiation in mammalian cells but Ro RNPs do not play a role in replication and are primarily responsible for RNA stability and quality control (Langley et al, 2010, p.1). Detection of Ro-RNP is primarily done with the help of autoantibodies that are produced in patients suffering from autoimmune disorders such as SLE. (Guerrero et al, 1996, p.1055). These autoantibodies are called Anti-Ro/ SS-A. Anti-Ro bodies are known to be present in patients suffering from SLE, autoimmune hepatic problems, celiac diseases etc. ELISA or Enzyme Linked Immunosorbent Assay maybe used to detect the presence of these autoantibodies which helps in diagnosis. CAKI-1 CELLS CAKI-1 cells are human renal cancer cell line. There are other kidney cancer cell lines such as A498 and 786-0 etc. CAKI-1 was invented by Jorgen Fogh and Germain Tremph. CAKI-1 cell line displays morphology of the epithelium and therefore are useful models to study kidney cancer (Memorial Sloan Kettering Cancer Centre, 2014) .These cells provide the perfect in-vitro model system for studying the proximal tubule epithelium of the human nephrons (Glube et al, 2007, p.47). CAKI-1 cells can be used to study efficacy of biomarkers. Toiyama et al investigated the efficiency of TRAIL level (Tumor necrosis factor-related apoptosis-inducing ligand) as a biomarker for Renal carcinoma using CAKI-1 cells ( 2013, p.69). Thus, the efficacy of potential biomarkers can be investigfated with the help of the CAKI-1 cell line. Discovery of Trove and YRNA in autoimmunity Studies by Chen and Wolin (2004) showed that mice lacking the Ro protein develop a disease that shares clinical features seen in patients with SLE. The results of this study indicate that Ro function may play a pivotal role in prevention of autoimmunity. In autoimmunity disorders such as SLE or Sjogren’s syndrome Ro60 is easily recognized by the autoantibodies (Prujin et al, 1993, p.396). Deshmukh et al showed that immunization of mice with Ro60 induced production of autoantibodies which had more than one kind of specificity (2000). In autoimmune diseases such as Sjogren’s Syndrome major autoantibodies are produced that are directed against SSA. SSA constitutes of Ro52 and Ro60. Y RNA’s are capable of triggering innate immune responses and they also have an influence on symptoms of autoimmunity. Studies have also shown that Y RNAs may be processed into miRNAs which are involved in development of autoimmunity (Verhagen and Prujin, 2011, p.674). Cancer and Biomarkers A normal body cell replicates, grows and dies off however when the growth of body cells get out of control or there are problems with the programmed cell death pathways, cancer develops. There are different kinds of cancer and it can develop up in any tissue of the body. Biomarker or a biological marker has become an important tool for both clinical and diagnostic purposes. For clinical purposes biomarkers refers to biological signs which may be studied and evaluated and which provides an indication of different biological processes and responses (Strimbu & Tavel, 2011, p.463). Study of biomarkers for cancer detection has become the prime focus of cancer research since most cancer biomarkers not only help in cancer detection but also have the ability to predict possible outcomes of different cancer management strategies (Bhatt et al, 2010, p.129). Trove2 and YRNA as Cancer Biomarker- focussing on Kidney Cancer Autoantibodies that are produced by the immune system and are directed against the person’s own proteins have become an accurate, specific and sensitive biomarker. Autoantibodies are therefore considered one of the best biomarkers for detection of several types of carcinomas (Zaenkar and Ziman, 2013, p.2161). Studies have shown that RoRNA initiates production of protein specific autoantibodies. Previously the presence of these anti Ro-SSA antibodies was solely associated to autoimmune disorders such as SLE. However these autoantibodies have also been associated with vasculitis, photosensitivity and haematological disorders and they have earned clinical importance as well ( Yoshimi et al, 2012, p.1). Antibodies against Ro60 have been found in breast cancer patients whose serum was tested for the presence of the antibodies and the results showed that most of the cancer patients showed presence of the Autoantibodies thereby making these antibodies potential biomarkers for tumours and carcinomas (Mercado et al, 2013, p.1). TRIM21 is a recently identified autoantibody to Ro60 and even though their clinical mechanisms and associations is not yet well understood, the presence of these antibodies have been seen in sclerosis patients (Hudson et al, 2012). One of the prime reasons for onset of cancer is failure of apoptosis. According to some studies, in the occurrence of apoptosis, RoRNPs present in the cytoplasm, are degraded very fast (Rutjes et al,1999, p.247990). Therefore these maybe evaluated and used as biomarkers to detect the failure of programmed cell death and predict onset of cellular proliferation which may subsequently lead to cancer. Expression levels of YRNAs may be done using Reverse Transcriptase polymerase chain reaction (RT-PCR) method. Christov et al in 2008 calculated the expression values of YRNA and saw that the expression was similar in all human body cells and tissues. In order to see the efficacy of Y RNA as potential biomarkers, they investigated the presence and expression of YRNAs in tumour cells. Upregulation of hYRNA occurs in cancer cell lines and are needed for the growth of the tumour cells. The study showed that all four types of YRNAs were over- expressed in tumour tissues almost 4-13 folds more than in normal cells. The expression of hY1 and hY3 were significantly over expressed in cancers of kidney as well as in some others such as colon, bladder and prostrate (Christov et al, 2008, p.981). Other studies have shown the presence of miRNAs especially those derived from YRNAs in solid tumour samples of breast, colon, bladder and lung. The miRNAs detected aligned with hY3 RNA. Thus these YRNA derived micro RNA are also potential molecular biomarkers for tumour cells. Conclusion The evolution of biomarkers as diagnostic tools has gained momentum and popularity in the scientific world. The complex composed of Ro60 and YRNAs are potential biomarkers for different kinds of cancer. The recognition of these potent biomarkers has been practically possible because of research studies that have shown either up regulation or degradation of the proteins and sequences in cells that have turned cancerous. It also needs to be kept in mind that non-coding RNASs also play a role in maintaining replication and apoptosis in cells and the disruption of either can potentially cause cancer. Future research implications need to be directed towards studying the use of these biomarkers in specific cancers such as kidney or colon cancer since studies indicating such uses are yet to be conducted. References Basil,C.F., Zhao,Y., Zavaglia,K., et al. (2006). Common Cancer Biomarkers. Cancer research, 66 (16), p.2953- 2961. Belisova,A., Semrad, K.,Mayer, O. et al. (2005). RNA chaperone activity of protein components of human Ro RNPs.RNA, 11 (7), p.1084-1091. Bhatt,A.N., Mathur,R., Farooque,A., et al. (2010). Cancer biomarkers - Current perspectives. Indian Journal of Medical research, 132, p.129-149. Chen,X. And Wolin,S.L. (2004), The Ro 60 kDa autoantigen: insights into cellular function and role in autoimmunity. Journal of Molecular medicine, 82 (4), p.232-239. Christov, C.,Trivier, E., and Krude, T.(2008), Noncoding human Y RNAs are overexpressed in tumours and required for cell proliferation. British Journal of Cancer, 98 (5), 981-988. Christov, C., Gardiner, T., Szuts, D., and Krude, T. (2006) Functional Requirement of Noncoding Y RNAsfor Human Chromosomal DNA Replication.Molecular and Cellular Biology, 26 (18), p. 6993- 7004. Deshmukh, U.S. et al (2000). Ro60 Peptides Induce Antibodies to Similar Epitopes Shared Among Lupus-Related Autoantigens. Journal of immunology, 164, p.6655-6661. Fabini, G. et al.(2000). Analysis of the molecular composition of Ro ribonucleoprotein complexes Identification of novel Y RNA-binding proteins. European Journal of Biochemistry, 267, p.2778-2789. Glube, N, Giessl,,A., Wolfrum, U., and Langguth, P.(2007), Caki-1 cells represent an in vitro model system for studying the human proximal tubule epithelium. Nephron Exp Nephrol, 107 (2), p.47- 56. Gardiner,T., Christov, C.,Langley, A.r., and Krude,T.(2009) A Y RNAs essential for chromosomal DNA replication.RNA, 15(7), p.1375-1385. Guerrero,J., Lew, R.A., Fossel, A.H. and Schur, P.H. (1996). Utility of anti-Sm, anti-RNP, anti-Ro/SS-A, and anti-La/SS-B (extractable nuclear antigens) detected by enzyme-linked immunosorbent assay for the diagnosis of systemic lupus erythematosus. Arthritis Rheumatism. (1996). 39 (6), p.1055- 1061. Hudson,M et al (2012). Clinical significance of antibodies to Ro52/TRIM21 in systemic sclerosis. Arthritis Research & Therapy , 14 (50), doi:10.1186/ar3763 Labbe,J.C., Burgess, J.,Rokeach,L.A. and Hekimi,S. (2000). ROP-1, an RNA quality-control pathway component,affects Caenorhabditis elegans dauer formation. PNAS, 97 (24), p.13233-13238. Langley, A.R.,Chambers, H., Christov, C.P., and Krude, T.(2010). Ribonucleoprotein Particles Containing Non-Coding YRNAs, Ro60, La and Nucleolin Are Not Required for Y RNAFunction in DNA Replication. PLoS One, 5 (10), e13673. Memorial Sloan Kettering Cancer Centre. (2014). Caki-1: Human Renal Cancer Cell Line. Retrieved from http://www.mskcc.org/research/technology/caki-1-human-renal-cell- line on 26/9/2014. Mercado, M et al. (2013). Autoantibodies Associated With Inflammatory Myopathy And Other Systemic Autoimmune Rheumatic Diseases In Sera From Breast Cancer Patients. Arthritis & Rheumatism, 65, p.1-7. Millard, T.P., Ashton, G.H.S.,Kondeatis, E., et al. (2002) Human Ro60 (SSA2) genomic organization and sequence alterations, examined in cutaneous lupus erythematosus. British Journal of Dermatology, 146, p.210-215. Perreault,J., Perreault,J.P. and Boire, G.(2007). Ro-Associated Y RNAs in Metazoans: Evolution and Diversification. Mol. Biol. Evol. 24 (8), p.1678-1689. Prujin,J.M., et al.(1993). Ro RNP associated Y RNAs are highly conserved among mammals. Biochimica et Biophysica Acta, 1216, p.395-401. Rutjes,S.S.,Van-der Heijden,A., Utz.P., Venrooji,W., and Prujin,J.M. (1999). Rapid Nucleolytic Degradation of the Small Cytoplasmic Y RNAs during Apoptosis. The Journal of Biochemistry, 274 (35), pp. 24799–24807 Strimbu,K and Tavel,J.A. (2011) What are Biomarkers? Curent Opinion HIV/AIDS, 5 (6), p.463-466. Toiyama,D. Et al .(2013). Significance of serum tumor necrosis factor-related apoptosis- inducing ligand as a prognostic biomarker for renal cell carcinoma. Molecular and Clinical Oncology, 1(1), p.69-74. Wolin, S.L. & Reinisch, K.M. (2006). The Ro 60 kDa autoantigen comes into focus: Interpreting epitope mapping experiments on the basis of structure. Autoimmunity Reviews,5, p. 367-372. Verhagen,A.P. and Prujin, G.J. (2011). Are the Ro RNP-associated Y RNAs concealing microRNAs? Y RNA-derived miRNAs may be involved in autoimmunity.Bioessays, 33 (9), p. 674-682. Yoshimi,R., Ueda, A., Ozato, K., and Ishigatsubo,K. (2012). Clinical and Pathological Roles of Ro/SSA Autoantibody System. Clinical and Developmental Immunology, p. 1-12. http://dx.doi.org/10.1155/2012/606195 Zaenkar, P and Ziman,M.R.(2013). Serologic autoantibodies as diagnostic cancer biomarkers--a review. Cancer, Epidemiology, Biomarker and Prevention, 22 (12), p.2161-2181. Read More