CCK₂ receptor splice variant with intron 4 retention in human gastrointestinal and lung tumours

The wild-type cholecystokinin type 2 (CCK₂) receptor is expressed in many gastrointestinal and lung tumours. A splice variant of the CCK₂ receptor with retention of intron 4 (CCK₂Ri4sv) showing constitutive activity associated with increased tumour growth was described in few colorectal, pancreatic and gastric cancers. Given the potential functional and clinical importance of this spliceoform, its occurrence was quantitatively characterized in a broad collection of 81 gastrointestinal and lung tumours, including insulinomas, ileal carcinoids, gastrointestinal stromal tumours (GIST), gastric, colorectal and pancreatic ductal adenocarcinomas, cholangiocellular and hepatocellular carcinomas, small cell lung cancers (SCLC), non-SCLC (nSCLC) and bronchopulmonary carcinoids, as well as 21 samples of corresponding normal tissues. These samples were assessed for transcript expression of total CCK₂ receptor, wild-type CCK₂ receptor and CCK₂Ri4sv with end-point and real-time RT-PCR, and for total CCK₂ receptor protein expression on the basis of receptor binding with in vitro receptor autoradiography. Wild-type CCK₂ receptor transcripts were found in the vast majority of tumours and normal tissues. CCK₂Ri4sv mRNA expression was present predominantly in insulinomas (incidence 100%), GIST (100%) and SCLC (67%), but rarely in pancreatic, colorectal and gastric carcinomas and nSCLC. It was not found in wild-type CCK₂ receptor negative tumours or any normal tissues tested. CCK₂Ri4sv transcript levels in individual tumours were low, ranging from 0.02% to 0.14% of total CCK₂ receptor transcripts. In conclusion, the CCK₂Ri4sv is a marker of specific gastrointestinal and lung tumours. With its high selectivity for and high incidence in SCLC and GIST, it may represent an attractive clinical target.