O‐GlcNAcylated LARP1 positively regulated by circCLNS1A facilitates hepatoblastoma progression through DKK4/β‐catenin signalling

作者：Zhongqi Cui, Jiangtu He, Jiabei Zhu, Wenxuan Ni, Li Liu, Zhixuan Bian, Siwei Mao, Song Gu, Yuhua Shan, Zhexuan Chu, Qi Wu, Jiayi Lu, Ya Liu, Fenyong Sun, Qiuhui Pan, Yue Zhang, Nan Huang, Ji Ma · 发表于：Clinical and Translational Medicine · 年份：2023 · DOI：10.1002/ctm2.1239 · 被引用次数：15 · 研究领域：Glycosylation and Glycoproteins Research、RNA Research and Splicing、Erythrocyte Function and Pathophysiology

BACKGROUND: Accumulating studies have shown that La-related protein 1 (LARP1) is involved in the occurrence and development of various tumours. However, the expression pattern and biological role of LARP1 in hepatoblastoma (HB) remain unclear so far. METHODS: LARP1 expression level in HB and adjacent normal liver tissues was analysed by qRT-PCR, Western blotting and immunohistochemistry assays. The prognostic significance of LARP1 was evaluated by Kaplan-Meier method and multivariate Cox regression analysis. In vitro and in vivo functional assays were implemented to clarify the biological effects of LARP1 on HB cells. Mechanistically, the regulatory roles of O-GlcNAcylation and circCLNS1A in LARP1 expression were investigated by co-immunoprecipitation (co-IP), immunofluorescence, RNA immunoprecipitation (RIP), RNA pull-down and protein stability assays. Moreover, RNA-sequencing, co-IP, RIP, mRNA stability and poly(A)-tail length assays were performed to investigate the association between LARP1 and DKK4. The expression and diagnostic significance of plasma DKK4 protein in multi-centre cohorts were evaluated by ELISA and ROC curves. RESULTS: LARP1 mRNA and protein levels were remarkably elevated in HB tissues and associated with worse prognosis of HB patients. LARP1 knockdown abolished cell proliferation, triggered cell apoptosis in vitro as well as prohibited tumour growth in vivo, whereas LARP1 overexpression incited HB progression. Mechanistically, O-GlcNAcylation of LARP1 ...