Hypomethylation-associated up-regulation of TCF3 expression and recurrence in stage II and III colorectal cancer.
OBJECTIVE
Transcription factor 3 (TCF3) implicates Wnt signaling pathway and regulates E-cadherin expression, which is involved in aggressiveness of tumors. This study aims to investigate the role of TCF3 in predicting prognosis of patients with stage II and III colorectal cancer (CRC).


METHODS
Real-Time quantitative PCR was performed in 64 fresh CRC tissues and 6 cell lines to examine TCF3 mRNA expression. TCF3 protein expression dynamics were detected by immunohistochemistry of 118 paraffin-embedded specimens, and the clinical significance of TCF3 was assessed by clinical correlation and Kaplan-Meier analyses. Aberrant hypomethylation of TCF3 promoter was also investigated using bisulfite sequencing and methylation specific PCR.


RESULTS
The up-regulation of TCF3 mRNA was frequently detected both in CRC tissues with recurrence and metastasis-derived cell lines. The expression level of TCF3 protein was significantly correlated with histological type (P = 0.038) and disease-free survival time (P = 0.002). Higher TCF3 expression indicated poor prognostic outcomes (P<0.05, log-rank test). Multivariate analysis also showed strong TCF3 protein expression and perineural invasion were independent adverse prognosticators in CRC (P = 0.010, 0.000). Moreover, it was showed that promoter hypomethylation of TCF3 is associated with its up-expression.


CONCLUSIONS
This study highlighted the prognostic value of TCF3 in stage II and III CRC. The up-regulation of TCF3, which is mainly caused by promoter hypomethylation, is one of the molecular mechanisms involved in the development and progression of CRC.
Laboratory of Medical Genetics, Harbin Medical University, Harbin, Heilongjiang, China.
Chunxiang
C
Li
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Sanjun
S
Cai
Department of Colorectal Cancer Surgery, The 2nd Affiliated Hospital, Harbin Medical University, Harbin, China; Colorectal Cancer Institute of the Heilongjiang Academy of Medical Sciences, Harbin, China.
Xishan
X
Wang
Department of Colorectal Cancer Surgery, The 2nd Affiliated Hospital, Harbin Medical University, Harbin, China; Colorectal Cancer Institute of the Heilongjiang Academy of Medical Sciences, Harbin, China.
Zheng
Z
Jiang
D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic
D051792:Basic Helix-Loop-Helix Proteins; C407909:TCF3 protein, human