TsR-0072 inhibits colorectal cancer progression through modulating lipid and vitamin D3 metabolic reprogramming and inactivating the Wnt/β-catenin signalling pathway

Abstract

Background tRNA-derived small RNAs (tsRNAs), newly developed non-coding RNAs with specialized biological features, are aberrantly expressed in the majority of malignancies. However, whether tsRNAs are involved in metabolic reprogramming of colorectal cancer (CRC) remains to be elucidated.Methods A novel tsRNA, tsRNA-Ser-3-0072 (tsR-0072), was screened from the tsRFun database and its expression was characterized by real-time quantitative PCR (qRT-PCR). CCK8, 5-ethynyl-2′-deoxyuridine (EdU), colony formation, transwell experiments and nude mice transplantation models were performed to assess CRC cell proliferation and metastasis in vitro and in vivo. The target genes of tsR-0072 were verified using a dual luciferase reporter assay, and enzyme-linked immunosorbent assay (ELISA), Western blotting, and qRT-PCR were employed to analyse the potential mechanisms of CRC.Results TsR-0072 was downregulated in CRC and was found to be associated with TNM stage, T stage, lymph node metastasis and the prognosis of CRC patients. Functional experiments revealed that tsR-0072 inhibited CRC growth and metastasis both in vivo and in vitro. Moreover, sterol O-acyltransferase 1 (SOAT1) and 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were identified as direct targets of tsR-0072. Mechanistic studies revealed that tsR-0072 arrested lipid metabolism by downregulating the expression of SOAT1, which inhibited the activity of sterol regulatory element-binding protein 1 (SREBP1), sterol regulatory element-binding protein 2 (SREBP2) and fatty acid synthase (FASN). In addition, tsR-0072 promoted vitamin D3 metabolism by decreasing the expression of CYP24A1, thereby increasing 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) secretion and vitamin D receptor (VDR) expression. Both lipid and vitamin D3 metabolic reprogramming induced by tsR-0072 resulted in inhibition of CRC progression through inactivation of the Wnt/β-catenin signalling pathway.Conclusions TsR-0072 acted as an anti-oncogene to modulate lipid and vitamin D3 metabolic reprogramming, thereby impeding CRC progression. Consequently, it might be a potential therapeutic target to overcome metabolic disorders in tumours. This study provided a promising transfer RNA (tRNA)-oriented strategy for the treatment of CRC treatment.

Keywords

• Colorectal cancer
• tsR-0072
• tumour marker
• lipid metabolism
• vitamin D3 metabolism