Wild-type and splice-variant secretin receptors in lung cancer: overexpression in carcinoid tumors and peritumoral lung tissue

Abstract

Gastrointestinal peptide hormone receptors, like somatostatin receptors, are often overexpressed in human cancer, allowing receptor-targeted tumor imaging and therapy. A novel candidate for these applications is the secretin receptor recently identified in pancreatic and cholangiocellular carcinomas. In the present study, secretin receptors were assessed in a non-gastrointestinal tissue, the human lung. Non-small-cell lung cancers (n ¼ 26), small-cell lung cancers (n ¼ 10), bronchopulmonary carcinoid tumors (n ¼ 29), and non-neoplastic lung (n ¼ 46) were investigated for secretin receptor protein expression with in vitro receptor autoradiography, using 125 I- [Tyr 10 ] rat secretin and for secretin receptor transcripts with RT-PCR. Secretin receptor protein expression was found in 62% of bronchopulmonary carcinoids in moderate to high density, in 12% of non-small cell lung cancers in low density, but not in small cell lung cancers. In tumors found to be secretin receptor positive by autoradiography, RT-PCR revealed transcripts for the wild-type secretin receptor and for novel secretin receptor splice variants. In the non-neoplastic lung, secretin receptor protein expression was observed in low density along the alveolar septa in direct tumor vicinity in cases of acute inflammation, but not in histologically normal lung. In the autoradiographically positive peritumoral lung, RT-PCR showed transcripts for the wild-type secretin receptor and for a secretin receptor spliceoform different from those occurring in lung and gut tumors. The secretin receptor is a G protein-coupled receptor. Together with VIP, glucagon, and other receptors it forms the secretin receptor family. 6 The secretin receptor has long been known for its important digestive functions in the pancreas and biliary tract. 7 Only recently was it recognized that the secretin receptor also plays a role in pathology, namely in cancer arising from physiological secretin targets.Pancreatic ductal adenocarcinomas, cholangiocellular carcinomas, and gastrinomas were found to show high secretin receptor expression.

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

“…Another group of GPCRs that has been heavily implicated in cancer pathophysiology are the gastrointestinal peptide hormone receptors, including the gastrin/cholecystokinin-B (CCK-B) [31], secretin receptors [76,77] and somatostatin [78]. An alternatively spliced isoform of the CCK-B receptor that retains the fourth intron might play an important role in the development and progression of colon and pancreatic carcinoma [8,31].…”

Alternative Splicing of Pre-mRNA in Cancer

“…In these tissues, a splice variant missing part of exon 1 and all of exons 2 to 4 was identified, while the secretin receptor spliceoforms arising in cancer were not present. 61 This example underlines that splice variants are not restricted to cancer, but can also occur selectively in nonneoplastic pathological conditions.…”

“…It is expressed by a limited number of liver, pancreatic, and lung tumors. 6,7,61 All these tumors exhibit not only wild-type, but also splice variant secretin receptor expression (Table 1). Alternative splicing of the secretin receptor is characterized by several special features.…”

“…However, splice variants typical of pancreas and liver cancer were not identified. 61 Both secretin receptor spliceoforms occurring in lung carcinoids are likely not to signal in response to secretin. Their significance remains to be defined.…”

Secretin receptor

“…While secretin receptors have been reported to be present on various neoplasms, including ductular carcinomas of the pancreas and selected islet cell carcinomas (50), it is not clear that the integrity of the receptor or the signaling responses to secretin are normal in those cells. In fact, the splicing of the secretin receptor mRNA has been reported to be abnormal in some of these tumors (51)(52)(53)(54)(55). A series of secretin receptor spliceoforms have been described (50).…”