Chaar Ines, Amara Sameh, Elamine Olfa Elhadj, Khiari Mariem, Ounissi Donia, Khalfallah Taher, Ben Hmida Abdelmajid, Mzabi Sabeh, Bouraoui Saadia
Laboratory of Colorectal Cancer Research UR03ES04, Science University Tunis, Tunis, Tunisia,
Tumour Biol. 2014 Feb;35(2):1439-49. doi: 10.1007/s13277-013-1198-9. Epub 2013 Sep 25.
One of the most important pathways which are frequently affected in colorectal cancer is p53/ (MDM2)/p14ARF pathway. We aim to determine the methylation pattern of p14/ARF in relation to mutation of p53. This correlation was studied to investigate whether their alterations could be considered as a predictor factor of prognosis in colorectal cancer and whether it can be useful in early-stage diagnosis. Statistical analyses show that p14/ARF hypermethylation was correlated with rectum location (p = 0.004), primary TNM stage (p = 0.016), and advanced Astler-Coller stage (p = 0.024). The RT-PCR that revel 31 % of patients did not express p14/ARF mRNA or at very low level. A high concordance between CpG hypermethylation and the low levels (p < 0.005) was shown. In addition, our analyses demonstrate that patients with mutation in the p53 gene have a lack of the protein expression (p < 0.005). This category with negative expression of p53 had a shorter survival rate (p < 0.005). On the one hand, MSP pattern of p14/ARF were correlated with a lack of p53 expression (p = 0.007). We found that p53/p14ARF pathway was frequently deregulated among our patients. In our study, we demonstrate that hypermethylation of p14/ARF occurs early during CRC tumorogenesis. However, we did not find correlation between p14/ARF and survival. These results suggest that p14/ARF methylation pattern may constitute a predictor factor of CRC in early stage but it could not be considered as a prognostic factor. On the other hand and because of the reversibility of the methylation mechanism, it may be appropriate to target the demethylation of p14/ARF to develop new drogues for CRC.
在结直肠癌中经常受到影响的最重要途径之一是p53/（MDM2）/p14ARF途径。我们旨在确定p14/ARF的甲基化模式与p53突变的关系。研究这种相关性是为了调查它们的改变是否可被视为结直肠癌预后的预测因素，以及它是否有助于早期诊断。统计分析表明，p14/ARF高甲基化与直肠位置（p = 0.004）、原发性TNM分期（p = 0.016）和进展期Astler-Coller分期（p = 0.024）相关。逆转录聚合酶链反应（RT-PCR）显示31%的患者不表达p14/ARF mRNA或表达水平极低。CpG高甲基化与低水平之间显示出高度一致性（p < 0.005）。此外，我们的分析表明，p53基因发生突变的患者缺乏蛋白表达（p < 0.005）。p53表达阴性的这一类患者生存率较短（p < 0.005）。一方面，p14/ARF的甲基化特异性PCR（MSP）模式与p53表达缺失相关（p = 0.007）。我们发现p53/p14ARF途径在我们的患者中经常失调。在我们的研究中，我们证明p14/ARF的高甲基化在结直肠癌肿瘤发生的早期就会出现。然而，我们没有发现p14/ARF与生存率之间的相关性。这些结果表明，p14/ARF甲基化模式可能构成结直肠癌早期的预测因素，但不能被视为预后因素。另一方面，由于甲基化机制的可逆性，针对p14/ARF的去甲基化来开发用于结直肠癌的新药物可能是合适的。
