Tsikalakis Spyridon, Chatziandreou Ilenia, Michalopoulos Nikolaos V, Theodoropoulos Georgios E, Sakellariou Stratigoula, Korkolopoulou Penelope, Patsouris Efstratios, Saetta Angelica A
1st Dept. of Pathology, National and Kapodistrian University of Athens, School of Medicine, Mikras Asias 75, Athens, Goudi, Greece.
1st Department of Propaedeutic Surgery Hippokrateion Hospital, National and Kapodistrian University of Athens, School of Medicine, Vas Sofias 114, Athens, Greece.
Pathol Res Pract. 2018 Jun;214(6):826-834. doi: 10.1016/j.prp.2018.04.019. Epub 2018 May 1.
TNF-related, apoptosis-inducing ligand (TRAIL) apoptotic pathway constitutes a promising therapeutic target due to high selectivity and low toxicity of TRAIL targeting agents when administered in combination therapies. 106 colorectal cancers were examined for: relative mRNA expression of TRAIL pathway genes, decoy receptors TRAIL-R3 and TRAIL-R4 promoter methylation and the presence of KRAS, NRAS, BRAF mutations. Elevated mRNA levels were observed in 26%, 15%, 13%, 12% and 10% of the cases for TRAIL-R4, TRAIL-R3, TRAIL-R2, TRAIL-R1 and TRAIL genes respectively. Reduced mRNA levels were detected in 77%, 65%, 64%, 60% and 37% of the cases for TRAIL, TRAIL-R2, TRAIL-R3, TRAIL-R1 and TRAIL-R4 genes respectively. TRAIL-R3 and TRAIL-R4 promoter methylation was detected in 55% and 16% of the analysed samples respectively. TRAIL-R1, TRAIL-R2 elevated relative mRNA levels inversely correlated with tumor stage (p = .036, p = .048). Strong linear correlations of TRAIL receptors' mRNA levels were found: TRAIL-R1/TRAIL-R2 (R = 0.653, p < .001), TRAIL-R2/TRAIL-R3 (R = 0.573, p < .001). Finally, relative expression of TRAIL was correlated with KRAS, BRAF and NRAS mutation status, defining an inverse correlation between increased TRAIL expression and the absence of mutations in Mitogen-activated protein kinase (MAPK) pathway. In conclusion, simultaneous analysis of TRAIL pathway membrane components, pointed towards a significant deregulation of mRNA expression in colorectal tumours. Death receptor overexpression was an indicator of a less aggressive phenotype. The multiple expression patterns of TRAIL pathway components in colorectal tumours underscore the importance of patient selection in order to achieve maximum efficiency with TRAIL targeted therapy.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）凋亡途径是一个很有前景的治疗靶点，因为在联合治疗中使用TRAIL靶向药物时具有高选择性和低毒性。对106例结直肠癌进行了检测：TRAIL途径基因的相对mRNA表达、诱饵受体TRAIL-R3和TRAIL-R4启动子甲基化以及KRAS、NRAS、BRAF突变的存在情况。分别在26%、15%、13%、12%和10%的病例中观察到TRAIL-R4、TRAIL-R3、TRAIL-R2、TRAIL-R1和TRAIL基因的mRNA水平升高。分别在77%、65%、64%、60%和37%的病例中检测到TRAIL、TRAIL-R2、TRAIL-R3、TRAIL-R1和TRAIL-R4基因的mRNA水平降低。分别在55%和16%的分析样本中检测到TRAIL-R3和TRAIL-R4启动子甲基化。TRAIL-R1、TRAIL-R2相对mRNA水平升高与肿瘤分期呈负相关（p = 0.036，p = 0.048）。发现TRAIL受体mRNA水平之间存在强线性相关性：TRAIL-R1/TRAIL-R2（R = 0.653，p < 0.001），TRAIL-R2/TRAIL-R3（R = 0.573，p < 0.001）。最后，TRAIL的相对表达与KRAS、BRAF和NRAS突变状态相关，表明TRAIL表达增加与丝裂原活化蛋白激酶（MAPK）途径无突变之间存在负相关。总之，对TRAIL途径膜成分的同时分析表明，结直肠癌中mRNA表达存在显著失调。死亡受体过表达是侵袭性较小的表型的一个指标。结直肠癌中TRAIL途径成分的多种表达模式强调了患者选择对于实现TRAIL靶向治疗最大疗效的重要性。
