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

Abstract

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. © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.