TRAIL receptor upregulation and the implication of KRAS/BRAF mutations in human colon cancer tumors.

TRAIL raises hopes as a promising anti-tumor agent due to its selectivity toward cancer cells. Higher expression of its pro-death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) attenuates higher sensitivity to TRAIL-induced apoptosis, and represents a marker for better cancer prognosis and treatment. Since receptor availability can be analogous to ligand efficacy, we performed RT-PCR analysis of DR4 and DR5 in 51 colon cancer biopsy specimens and respective normal mucosa, while 11 of these tumors were determined immunohistochemically for protein expression. Transcriptional analysis showed that DR4 and DR5 were significantly upregulated in 37 and 47% of the tumor samples respectively, while both DR4 and DR5 were coinstantaneously upregulated in 31% of the samples analyzed. Positive transcriptional regulation of DRs was recorded as early as Dukes' A stage. Furthermore, protein expression analysis yielded results comparable to DR4 and DR5 increased mRNA levels. Possible contributing events to DR upregulation involve presence of frequent oncogenic mutations in the MAPK pathway, and was investigated by direct sequencing in all 51 tumors. Samples (6/8) hosting either a KRAS(G12V) or BRAF(V600E) mutation, significantly amplified the upregulated expression of DR4 and DR5, showing strong inter-relation between overexpression and presence of oncogenic KRAS/ BRAF mutations. In the light of recent data concerning TRAIL receptor distribution, we contribute further by presenting DR5 as the most frequently upregulated DR in colon cancer. Furthermore, oncogenic mutations may directly or indirectly enhance DR expression, potentially sensitizing these tumors to TRAIL-based therapies.