Downregulation of WIF-1 and Wnt5a in patients with colorectal carcinoma: clinical significance
Activation of the wingless-type (Wnt) signaling pathway is common in various human cancers including colorectal cancer (CRC). Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist that can bind Wnt ligands and therefore inhibits the Wnt signaling pathway. In this study, we aimed to analyze the expression of two members of Wnt signaling (WIF-1 and Wnt5a) in Tunisian patients with sporadic CRC. WIF-1 was frequently methylated in tumor tissues (87.95 %) compared to normal mucosa (39.54 %) and correlated with distant metastasis and vascular invasion (P = 0.001 and 0.037, respectively). The unmethylated profile of the WIF-1 promoter conferred a benefit to patients in terms of overall survival (P log rank = 0.024). In addition, in the group of patients with methylated WIF-1 promoter, the overall survival rate was significantly prolonged for those with small tumor size (<5 cm) and absence of distant metastasis (P log rank = 0.007 and 0.036, respectively). Aberrant CpG methylation of the WIF-1 promoter leads to transcriptional silencing of this tumor suppressor gene in tumor tissues (P = 0.001). Furthermore, we showed that the level of Wnt5a mRNA was significantly lower in tumor compared to normal tissues (P = 0.031) and lower still in those showing more aggressive behavior (presence of lymph nodes and advanced TNM stage). Our finding supports that WIF-1 is frequently methylated and that Wnt5a acts as a tumor suppressor gene in CRC. Loss of WIF-1 and Wnt5a functions results in more aggressive behavior of the disease.
KeywordsColorectal cancer CpG methylation Wnt signaling Wnt5a Tumor suppressor
This work was supported by a grant of the Tunisian Ministry of High Education and Scientific Research.
Conflicts of interest
- 8.Kondo Y, Issa JP. Epigenetic changes in colorectal cancer. Cancer Med. 2004;23:29–39.Google Scholar
- 34.Bauer M, Bénard J, Gaasterland T, Willert K, Cappellen D. WNT5A encodes two isoforms with distinct functions in cancers. PLoS One. 2013;18:8(11).Google Scholar
- 44.Rawson JB, Mrkonjic M, Daftary D, Dicks E, Buchanan DD, Younghusband HB, et al. Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients. Br J Cancer. 2011;104(12):1906–12.PubMedCentralPubMedCrossRefGoogle Scholar
- 46.Trifa F, Karray-Chouayekh S, Jmal E Jmaa ZB, Khabir A, Sellami-Boudawara T, Frikha M, Daoud J, Mokdad-Gargouri R. Loss of WIF-1 and Wnt5a expression is related to aggressiveness of sporadic breast cancer in Tunisian patients. Tumor Biol. 2013Google Scholar