The significance of TRIP11 and T3 signalling pathway in renal cancer progression and survival of patients

Abstract

Introduction: TRIP11 is a multifunctional protein localising either to Golgi apparatus, acting as a golgin, or in the nucleus, acting as coactivator of transcription mediated by thyroid hormone receptor (THR) and hypoxia-inducible factor (HIF). Triiodothyronine (T3) regulates nuclear localisation of TRIP11 by inducing its phosphorylation. The exact mechanism of this regulation is unknown. The expressions of THR and HIF are disturbed in various cancers, including renal cell cancer (RCC). In this study, we aimed to analyse: 1) the mechanism of T3-dependent subcellular localisation of TRIP11; and 2) the significance of TRIP11 and T3 signalling pathway in RCC progression. Materials and methods: TRIP11 subcellular localisation was analysed using immunocytochemistry in RCC-derived cell line treated with T3, T3-agarose, and PI3K inhibitor, wortmannin. The expressions of TRIP11 and genes involved in T3 signalling and hypoxia were investigated using qPRC in 36 pairs of RCC tumour-control samples, followed by validation/survival analysis in an independent cohort of > 450 renal cancer patients. Results: Wortmannin disrupted T3-dependent nuclear transport of TRIP11. T3-agarose did not change TRIP11 localisation, precluding extracellular T3-mediated mechanism. The expressions of TRIP11, HIF-1β, THRA, THRB, FURIN, VEGFA, and GLUT1 were disturbed in renal cancer. Expressions of TRIP11 and HIF-1β correlated with tumour grades. Decreased expressions of TRIP11, THRA, and THRB correlated with poor survival of RCC patients. Conclusions: 1) T3 induces nuclear TRIP11 localisation via PI3K-dependent mechanism; 2) disturbed expression of T3 signalling pathway genes correlates with RCC progression. The specific mechanisms by which altered T3 signalling may contribute to RCC progression require further investigation.