Short-Form Thymic Stromal Lymphopoietin (sfTSLP) Is the Predominant Isoform Expressed by Gynaecologic Cancers and Promotes Tumour Growth

Abstract

Thymic stromal lymphopoietin (TSLP) is an epithelial cell derived cytokine belonging to the IL-7 family and a key initiator of allergic inflammation. Two main isoforms of TSLP, classified as long- (lfTSLP) and short-form (sfTSLP), have been reported in human, but their expression patterns and role(s) in cancers are not yet clear. mRNA expression was examined by isoform-specific RT-PCR and RNA in situ hybridisation. Epigenetic regulation was investigated by chromatin immunoprecipitation-PCR and bisulfite sequencing. Tumour progression was investigated by gene overexpression, cell viability assay, cancer organoid culture and transwell invasion. Signals were investigated by proteome profiler protein array and RNA-sequencing. With the use of isoform-specific primers and probes, we uncovered that only sfTSLP was expressed in the cell lines and tumour tissues of human ovarian and endometrial cancers. We also showed the epigenetic regulation of sfTSLP: sfTSLP transcription was regulated by histone acetylation at promoters in ovarian cancer cells, whereas silencing of the sfTSLP transcripts was regulated by promoter DNA methylation in endometrial cancer cells. In vitro study showed that ectopically overexpressing sfTSLP promoted tumour growth but not invasion. Human phosphokinase array application demonstrated that the sfTSLP overexpression activated phosphorylation of multiple intracellular kinases (including GSK3α/β, AMPKα1, p53, AKT1/2, ERK1/2 and Src) in ovarian cancer cells in a context-dependent manner. We further investigated the impact of sfTSLP overexpression on transcriptome by RNA-sequencing and found that EFNB2 and PBX1 were downregulated in ovarian and endometrial cancer cells, suggesting their role in sfTSLP-mediated tumour growth. In conclusion, sfTSLP is predominantly expressed in ovarian and endometrial cancers and promotes tumour growth.

Role of thymic stromal lymphopoietin in allergy and beyond

“…Single nucleotide polymorphisms (SNPs) rs2289276 and rs2289278 in the TSLP promoter confer augmented binding by AP1 and enhanced lfTSLP production, which may explain why these SNPs are associated with increased incidence of childhood atopic disease and adult asthma 27 . In ovarian and endometrial cancers, sfTSLP is predominantly expressed and promotes tumour growth through the activation of signalling pathways in cancer cells 40 . Further elucidating the different roles of these isoforms may provide new insights into TSLP biology.…”

Protein expression profiling identifies a prognostic model for ovarian cancer

“…GSK3α/β is a serine-threonine kinase and plays a role in glycogen metabolism and neurogenesis. GSK3α/β was found to be involved in tumor growth of ovarian cancer [24]. HSP70 has been correlated with poor prognosis of several cancers, such as cervical cancer, melanoma, gastric cancer, and prostate cancer, and could elicit a strong autoantibody response in ovarian cancer, serving as a tumor-associated antigen [25].…”

Circular RNA SESN2 aggravates gestational trophoblast cell damage induced by high glucose by binding to IGF2BP2

“…Human chorionic trophoblast cells (HTR‐8/SVneo cells) were purchased from ATCC, and cultured at 37°C with 5% CO 2 in Roswell Park Memorial Institute (RPMI) 1640 (Gibco) supplemented with 10% fetal bovine serum (FBS). Based on the previous method (Chan et al, 2021), when the third passage of HTR‐8/SVneo cells reached 80% confluence, the cells were randomly divided into control group and a high‐glucose (HG) group. Cells in the control group were treated with 5.5 mM glucose (Sigma‐Aldrich; the medium with a final concentration of 5.5 mM glucose was obtained by adding 991 mg glucose to 1 L RPMI 1640), and 25 mM glucose was used for cell cultures in the HG group (the medium with a final concentration of 25 mM glucose was obtained by adding 450 mg glucose to 100 ml RPMI 1640).…”