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.
Laboratory of Biomass Valorisation and Production of Eukaryotic Proteins, Center of Biotechnology of Sfax, University of Sfax, Sidi Mansour street, BP"K"1177, 3018, Sfax, Tunisia.
Rania
R
Abdelmaksoud-Dammak
Imen
I
Miladi-Abdennadher
Amena
A
Saadallah-Kallel
Abdelmajid
A
Khabir
Tahia
T
Sellami-Boudawara
Mounir
M
Frikha
Jamel
J
Daoud
Raja
R
Mokdad-Gargouri
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics* / Q000502:physiology; D000071818:Wnt-5a Protein
D048868:Adaptor Proteins, Signal Transducing; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C485569:WIF1 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein