| Abstract |
Cancer consists a major Public Health issue worldwide as it is recognized as the second most common cause of death, behind cardiovascular diseases. In particular, colorectal cancer has been associated with the western life-style and dietary habits. The fact that more than one million cases of colorectal cancer are diagnosed worldwide each year, make the discovery of new biological markers more imperative and necessary, not only for diagnostic and prognostic purposes, but also for the development and introduction of new therapeutic approaches. This has been the main motive for the designing and working out of the present thesis.
The biological background of colon cancer disease has already been studied extensively and is under continuous consideration. Nevertheless, there are many genes, that although they are not directly connected to colon cancer, they could offer a great deal of information on the disease progression. Protein Arginine Methyltransferase 1 gene (PRMT1) was thought to be one of them. This gene encodes an enzyme implicating in many important aspects of cell metabolism via arginine methylation of certain protein molecules. PRMT1’s participation in metabolism made us consider studying this molecule and correlating its expression to colon cancer.
In the present study, the expression levels of PRMT1 splice variants were analyzed in a variety of colon tissues (normal, cancerous, adenomas, inflammatory disease tissue).In the course of our study, we were also able to correlate the expression levels of PRMT1 with clinical and pathological parameters and we found that PRMT1-v2 was the only PRMT1 variant associated in a statistically significant manner with all clinicopathological parameters examined. More specifically, PRMT1-v2 expression seemed to increase during the progression process from normal tissue to adenoma and finally carcinoma, whereas it was definitely increased colon cancer tissues versus normal tissues. On the contrary, in inflammatory (IBD) colon tissues, PRMT1-v2 expression was decreased
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versus normal tissues. These findings probably reveal that the positive expression of PRMT1-v2 is indicative of the progression and aggressiveness of the colon cancer disease. Advanced TNM stage (p=0.026), tumor grade (p=0.015)as well as positive nodal status (p=0.016) and patients’ age (p=0.004) were associated in a statistically significant manner with the positive expression of PRMT1-v2 (the percentage of patients expressing PRMT1 v2 was substantially higher in older patients compared to younger ones). Additionally, according to Cox univariate analysis, positive expression of PRMT1-v2 seemed to associate with a higher probability for patients’ relapse (p=0.01) or death (p=0.032) and correlate, also, with a statistically significant manner with OS ( p=0.039) and DFS ( p=0.01). As far as the other two isoforms (PRMT1-v1 and PRMT1-v3) are concerned, no statistically significant difference in expression analysis was recorded between normal and cancerous tissue. All three PRMT1 isoforms (v1, v2 and v3) did not differ concerning their expression, in a statistically significant manner, in adenomas in comparison with normal tissue whereas in IBDs, PRMT1-v2 showed lower expression in inflammatory versus normal tissue (p=0.021). On the other hand, multivariate analysis showed a statistically significant association between the positive expression of PRMT1-v2 and patients’ relapse (p=0.023). Moreover the experiments of immunohistochemical localization of the PRMT1 protein, using an in-house produced anti-PRMT1 antibody, indicated a mainly cytoplasmic presence.
The results of this study converge to the characterization of the high expression of PRMT1-v2 as a marker of unfavorable prognosis for colon cancer patients.
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