Epithelial Splicing Regulator Protein 1 and Alternative Splicing in Somatotroph Adenomas

Abstract

Somatotroph adenomas secrete supraphysiological amounts of GH, causing acromegaly. We have previously hypothesized that epithelial mesenchymal transition (EMT) may play a central role in the progression of these adenomas and that epithelial splicing regulator 1 (ESRP1) may function prominently as a master regulator of the EMT process in pituitary adenomas causing acromegaly. To further elucidate the role of ESRP1 in somatotroph adenomas and in EMT progression, we used RNA sequencing (RNAseq) to sequence somatotroph adenomas characterized by high and low ESRP1 levels. Transcripts identified by RNAseq were analyzed in 65 somatotroph adenomas and in GH-producing pituitary rat cells with a specific knockdown of Esrp1. The clinical importance of the transcripts was further investigated by correlating mRNA expression levels with clinical indices of disease activity and treatment response. Many of the transcripts and isoforms identified by RNAseq and verified by quantitative PCR were involved in vesicle transport and calcium signaling and were associated with clinical outcomes. Silencing Esrp1 in GH3 cells resulted in changes of gene expression overlapping the data observed in human somatotroph adenomas and revealed a decreased granulation pattern and attenuated GH release. We observed an alternative splicing pattern for F-box and leucine-rich repeat protein 20, depending on the ESPR1 levels and on changes in circulating IGF-I levels after somatostatin analog treatment. Our study indicates that ESRP1 in somatotroph adenomas regulates transcripts that may be essential in the EMT progression and in the response to somatostatin analog treatment.

Splicing factor derived circular RNA circUHRF1 accelerates oral squamous cell carcinoma tumorigenesis via feedback loop

“…Epithelial splicing regulatory protein 1 (ESRP1), also named as RNA-binding motif protein 35A (RBM35A), is a critical elements in the human cancer epithelial mesenchymal transformation (EMT) [15][16][17][18]. It has been identified that ESRP1 regulate the alternative splicing events associated with epithelial phenotypes in OSCC [19].…”

Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors

“…Gene expression profiling and proteomics studies [38–46] led to the identification of genes associated with invasion and aggressive behavior [42, 47]. Changes in EMT markers have been seen in sporadic somatotroph adenomas with lower E-cadherin and ESRP1 expression [34, 48, 49]. Loss of ESRP1 in ~90% of AIP pos cases indicates that ESRP1 may be an important regulator of tumor invasiveness.…”

Genetic and epigenetic mutations of tumor suppressive genes in sporadic pituitary adenoma

“…Down-regulation of ESRP1 induces EMT phenotypes (Reinke et al, 2012; Warzecha et al, 2009). Very recently, ESRP1 was identified as a master regulator of EMT in human GH-secreting adenomas (Lekva et al, 2012, 2013). ESRP1 is positively correlated with E-cadherin expression in GH-secreting adenomas and its depletion by RNAi results in down regulation of E-cadherin in a GH-adenoma cell line (Lekva et al, 2012).…”