Alternative splicing of placental lactogen (CSH2) in somatotroph pituitary adenomas.

OBJECTIVES Somatotroph adenomas secrete supraphysiological amounts of GH, causing acromegaly. We have previously shown epithelial splicing regulator 1 (ESRP1) to play a role in epithelial mesenchymal transition (EMT) progression in these adenomas and account for poor treatment response. We evaluated if the mRNA levels of the GH/CSH gene cluster in somatotroph adenomas are associated with an epithelial phenotype and response to SA treatment. METHODS We investigated the associations between ESRP1 and the growth hormone/chorionic somatomammotropin (GH/CSH) gene cluster by RNA sequencing (RNAseq). CSH2 isoform 3 mRNA was further evaluated in 65 somatotroph adenomas and associations with disease severity and treatment response. RESULTS mRNA for all genes in the GH/CSH cluster were expressed, however, only chorionic somatomammotropin 2/placental lactogen 2 (CSH2) displayed an alternative splicing pattern. CSH2 isoform 3 was associated with a dense granulation pattern and an epithelial phenotype with high levels of ESRP1 and E-cadherin expression. Further, CSH2 isoform 3 was associated with reduced serum GH and IGF-I levels after somatostatin analog treatment. CONCLUSIONS Attenuated CSH2 isoform 3 was associated with mesenchymal phenotype and a blunted clinical response to somatostatin analog treatment in patients with acromegaly.