Transcription of SST2 somatostatin receptor gene in human pancreatic cancer cells is altered by single nucleotide promoter polymorphism

Background & Aims: The somatostatin receptor SST2 mediates the antiprolifer ative effect of stable somatostatin analogues, SST2 gene expression is lost in most human pancreatic carcinomas, We investigated the mechanisms that c ould be involved in this defect. Methods: SST2 gene structure was investiga ted by sequencing and restriction fragment length polymorphism. Characteriz ation of the polymorphism was performed by electrophoretic mobility shift, cross-linking, and transcription assays, Results: No major deletion of the SST2 coding sequence was found in pancreatic carcinoma specimens, but 2 poi nt mutations were frequently detected in the promoter sequence at positions -83 (A-->G) and -57 (C-->G) from the major transcription initiation site, These mutations were present in pancreatic cancer but also in normal pancre atic tissues or leukocytes and thus correspond to a genetic polymorphism. I n the 2 human pancreatic cancer cell lines MiaPaCa-2 and AsPC-1, the natura lly occurring mutation -57G had no effect on transcription of SST2 gene, wh ereas -83G mutation reduced it by 60%-70%, We showed that the -83G mutation creates a specific binding site for the nuclear factor 1, Cotransfection e xperiments showed that the nuclear factor I-A1.1 isoform was responsible fo r SST2 promoter repression, Conclusions: The -83G polymorphism identified o n human SST2 gene promoter is responsible for the specific fixation of nucl ear factor I and repression of SST2 transcription in human pancreatic cance r cells. However, its contribution to pancreatic tumorigenesis remains unkn own.