Phospholipase C Isozymes Are Deregulated in Colorectal Cancer – Insights Gained from Gene Set Enrichment Analysis of the Transcriptome

PLoS One

Ragnhild A. Lothe¹  Guro E. Lind¹  Espen Thiis-Evensen¹  Lina Cekaite¹  Anita Sveen¹  Stine A. Danielsen²  Rolf I. Skotheim²  Arild Nesbakken²  Trude H. Ågesen² 

[1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway;Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

关键词: Colorectal cancer;    DNA methylation;    Gene expression;    Colon;    Signaling networks;    Polymerase chain reaction;    Metabolic pathways;    Methylation;   

DOI  :  10.1371/journal.pone.0024419

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Colorectal cancer (CRC) is one of the most common cancer types in developed countries. To identify molecular networks and biological processes that are deregulated in CRC compared to normal colonic mucosa, we applied Gene Set Enrichment Analysis to two independent transcriptome datasets, including a total of 137 CRC and ten normal colonic mucosa samples. Eighty-two gene sets as described by the Kyoto Encyclopedia of Genes and Genomes database had significantly altered gene expression in both datasets. These included networks associated with cell division, DNA maintenance, and metabolism. Among signaling pathways with known changes in key genes, the “Phosphatidylinositol signaling network”, comprising part of the PI3K pathway, was found deregulated. The downregulated genes in this pathway included several members of the Phospholipase C protein family, and the reduced expression of two of these, PLCD1 and PLCE1, were successfully validated in CRC biopsies (n = 70) and cell lines (n = 19) by quantitative analyses. The repression of both genes was found associated with KRAS mutations (P = 0.005 and 0.006, respectively), and we observed that microsatellite stable carcinomas with reduced PLCD1 expression more frequently had TP53 mutations (P = 0.002). Promoter methylation analyses of PLCD1 and PLCE1 performed in cell lines and tumor biopsies revealed that methylation of PLCD1 can contribute to reduced expression in 40% of the microsatellite instable carcinomas. In conclusion, we have identified significantly deregulated pathways in CRC, and validated repression of PLCD1 and PLCE1 expression. This illustrates that the GSEA approach may guide discovery of novel biomarkers in cancer.

【 授权许可】

CC BY