Loss of expression of an alternatively spliced Deleted in Colorectal Carcinoma (DCC) mRNA variant is related to lymph node metastasis in colorectal carcinoma patients

Y Wettergren, a, E Odin a, R Willén b, G Carlsson a, L Larsson a, and B Gustavsson a

Departments of ^ a General Surgery, and ^ b Pathology and Cytology, Göteborg University, Sahlgrenska University Hospital/Östra, Göteborg, Sweden

The axon guidance receptor DCC (Deleted in Colorectal Carcinoma) is a putative tumor suppressor gene deleted in more than 70% of colorectal carcinomas. Recent studies indicate that DCC functions as a dependence receptor inducing apoptosis when unoccupied by ligand. Tissue-specific isoforms of the DCC protein may result from alternative splicing of the mRNA. A 341 bp RT-PCR product was previously detected in the human neuroblastoma cell line IMR32. These cells also expressed a 281 bp product that arose through alternative splicing. More recently, the 341 bp, but not the 281 bp product, was detected in human endometrial carcinomas. Furthermore, loss of DCC gene expression was found to be related to lymph node metastasis. AIM The aim was to study alternative splicing of the DCC gene in patients with colorectal carcinoma. METHODS - DCC gene expression was detected using the sensitive method of RT-PCR, followed by automated capillary gel electrophoresis and fragment analysis. RESULTS - In contrast to the findings in endometrial carcinoma, the 281 bp product was detected in 98% (43/44) of the mucosa and in 95% (42/44) of the malignant tissues, whereas the 341 bp product was expressed in 61% (27/44) of the mucosa and in 41% (18/44) of the tumors. Patients who had lost the 341 bp fragment in both mucosa and tumor were found to have lymph node metastases more frequently than patients expressing the 341 bp fragment. CONCLUSIONS - The balance between the two DCC mRNA splicing variants seems to be tissue specific, and loss of one of the fragments may be intimately involved with the process of tumorigenesis.

KEY WORDS: tumorigenesis, dependence receptor, axon guidance, apoptosis.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Carcinogenesis.