Loss of desmocollin 1-3 and homeobox genes PITX1 and CDX2 are associated with tumor progression and survival in colorectal carcinoma.

BACKGROUND:Genomewide expression profiling has identified a number of genes differentially expressed in colorectal carcinomas (CRCs) compared to normal tissue. Some of these genes were linked to epithelial-mesenchymal transition. We tested whether genes including desmocollins and homeobox genes were distinct on the protein level and correlated the expression with clinicopathological data. METHODS:Tissue microarrays of 402 R0-resected colorectal carcinomas of UICC stage II or III were constructed to evaluate ten biomarkers. Furthermore, mRNA expression of desmocollins was evaluated in eight colon cancer cell lines. Demethylation test was performed by treatment with 5-aza-2´-deoxycytide in five colon cancer cell lines. RESULTS:On protein level, high expression of desmocollin 1 (DSC1) was observed in 41.6%, DSC2 in 58.0%, DSC3 in 61.4%, E-cadherin in 71.4%, CDX2 in 58.0%, PITX1 in 55.0%, CDK4 in 0.2%, TLE1 in 1.3%, Factor H in 42.5%, and MDM2 in 0.2%. Reduced expression of DSC1-3 was statistically linked to higher grading and DSC2, E-cadherin and CDX2 with shorter survival in high-grade carcinomas. Multivariate analysis showed that pathological stage and low PITX1 expression were statistically associated with shorter patients survival. On mRNA level, seven out of eight cell lines exhibited no expression of DSC1, and four out of seven restored DSC1 expression after demethylation test. CONCLUSIONS:Reduced expression of PITX1 was independently correlated to shorter patients survival and could serve as a prognostic marker. Decreased expression of DSC1-3 is significantly correlated with higher tumor grading. Downregulation of DSC1 could be explained by DNA hypermethylation in colon cancer cells.

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