Endocrine Abstracts

Objective: Transforming growth factor beta receptor 3 like (TGFBR3L) has been recently described as a pituitary-specific membrane protein detected in a proportion of the gonadotroph cells in non-neoplastic and tumour tissue (1). Furthermore, mouse studies have indicated that TGFBR3L is an inhibin B co-receptor that regulates FSH levels (2). We hypothesized that TGFBR3L expression in gonadotroph non-functioning pituitary neuroendocrine tumours (NF-PitNETs) is related to clinical parameters as age, gender and tumour volume. Moreover, we aimed to decipher the possible function of this protein in tumorigenesis and hormone production in gonadotroph NF-PitNETs.

Methods: Gene expression of TGFBR3L was performed by RT-qPCR in immunohistochemically confirmed gonadotroph NF-PitNETs (SF1 and/or FSHβ/lHβ positive) in a cohort of prospectively included patients (n=102) diagnosed between 2014-2021. Clinical parameters as age, sex and tumour volume were recorded. RNA-sequencing was performed in a sub-cohort of 18 age and sex matched patients with high and low TGFBR3L gene expression (n=9 in each group). Posttranscriptional silencing of TGFBR3L by siRNA was performed in the LβT2 gonadotroph cell line and gene expression of FSHβ and LHβ were measured. Ongoing studies are performed on primary gonadotroph tumor cells isolated from gonadotroph NF-PiNETs.

Results: Of 102 patients 39 (32%) were women, age at diagnosis mean±1SD: 61±14 years, tumour volume median (IQR) 5928 (3657-8717) cm3. TGFBR3L did not correlate to age, sex, and tumour volume. RNA-sequencing identified 1921 differentially expressed genes (DEGs) disclosing a distinct genetic profile associated with TGFBR3L expression, with 786 DEG up- and 1135 down- regulated genes. SF1/NR5A1, LHβ, GNRHR, ESR1, and SSTR3 were up-regulated in the high TGFBR3L group. Pathways analysis revealed an up-regulation of genes involved in the Notch signaling pathway along with downregulation of genes in the JAK/STAT pathway and partial suppression in the Wnt signaling pathway in the high-TGFBR3L group. Furthermore, pathways related to proliferation, cell survival and cell adhesion were differentially regulated between the groups. SiRNA-mediated suppression of TGFBR3L in LβT2 cells resulted in a significant increase in LHβ expression (P= 0.001), without affecting FSHβ.

Conclusion: Although TGFBR3L gene expression is not related to primary clinical parameters, it is related to markers of gonadotroph cell differentiation. Analyses of the genes related to TGFBR3L expression and in vitro mechanistic studies may reveal distinct roles for this protein in NF-PitNETs pathogenesis.

References: 1. Sjöstedt et al. PMID:33396509 2. Brûlé et al. PMID:34910520