Prognostic significance of TRAIL death receptors in Middle Eastern colorectal carcinomas and their correlation to oncogenic KRAS alterations

Molecular Cancer

Research

Luai H Ashari¹  Samar Alhomoud¹  Nasser Al-Sanea¹  Alaa Abduljabbar¹  Shahab Uddin²  Thara George²  Azhar R Hussain²  Sarita E Prabhakaran²  Jehad Abubaker²  Prashant Bavi²  Zeeshan Qadri²  Khawla S Al-Kuraya²  Fouad Al-Dayel³ 

[1] Department of Colorectal Surgery, King Faisal Specialist Hospital and Research Centre, PO Box 3354, 11211, Riyadh, Kingdom of Saudi Arabia;Department of Human Cancer Genomic Research, MBC 98-16,Research Centre at KFNCCC, King Faisal Specialist Hospital and Research Centre, PO Box 3354, 11211, Riyadh, Kingdom of Saudi Arabia;Department of Pathology, King Faisal Specialist Hospital and Research Centre, PO Box 3354, 11211, Riyadh, Kingdom of Saudi Arabia;

关键词: KRAS Mutation;    Independent Prognostic Marker;    Trail Receptor;    KRAS Gene;    Trail Expression;   

DOI  :  10.1186/1476-4598-9-203

 received in 2010-02-11, accepted in 2010-07-30,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundTumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumour necrosis factor cytokine family that induces apoptosis upon binding to its death domain containing receptors, TRAIL receptor 1 (DR4) and TRAIL receptor 2 (DR5). Expression of TRAIL receptors is higher in colorectal carcinoma (CRC) as compared to normal colorectal mucosa and targeted therapy with TRAIL leads to preferential killing of tumor cells sparing normal cells.MethodsWe investigated the expression of TRAIL and its receptors in a tissue microarray cohort of 448 Middle Eastern CRC. We also studied the correlation between TRAIL receptors and various clinico-pathological features including key molecular alterations and overall survival.ResultsCRC subset with TRAIL-R1 expression was associated with a less aggressive phenotype characterized by early stage (p = 0.0251) and a histology subtype of adenocarcinomas (p = 0.0355). Similarly CRC subset with TRAIL-R2 expression was associated with a well-differentiated tumors (p < 0.0001), histology subtype of adenocarcinomas (p = 0.0010) and tumors in left colon (p = 0.0009). Over expression of pro apoptotic markers: p27KIP1 and KRAS4A isoforms was significantly higher in CRC subset with TRAIL-R1 and TRAIL-R2 expression; TRAIL-R1 expression was also associated with cleaved caspase-3(p = 0.0011). Interestingly, TRAIL-R2 expression was associated with a microsatellite stable (MS--S/L) phenotype (p = 0.0003) and with absence of KRAS mutations (p = 0.0481).ConclusionTRAIL-R1 expression was an independent prognostic marker for better survival in all CRC samples and even in the CRC group that received adjuvant therapy. The biological effects of TRAIL in CRC models, its enhancement of chemosensitivity towards standard chemotherapeutic agents and the effect of endogenous TRAIL receptor levels on survival make TRAIL an extremely attractive therapeutic target.

【 授权许可】

Unknown   
© Bavi et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.