TsR-0072 inhibits colorectal cancer progression through modulating lipid and vitamin D(3) metabolic reprogramming and inactivating the Wnt/β-catenin signalling pathway.

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 D(3)-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 D(3) metabolism by decreasing the expression of CYP24A1, thereby increasing 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) secretion and vitamin D receptor (VDR) expression. Both lipid and vitamin D(3) 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 D(3) 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.