Alternative Splicing of lncRNAs From SNHG Family Alters snoRNA Expression and Induces Chemoresistance in Hepatoblastoma

作者：Ni Zhen, Jiabei Zhu, Siwei Mao, Qi Zhang, Song Gu, Ji Ma, Yue Zhang, Minzhi Yin, Haojie Li, Nan Huang, Han Wu, Fenyong Sun, Binwu Ying, Lin Zhou, Qiuhui Pan · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2023 · DOI：10.1016/j.jcmgh.2023.07.007 · 被引用次数：20 · 研究领域：RNA Research and Splicing、Cancer-related molecular mechanisms research、RNA modifications and cancer

BACKGROUND & AIMS: Hepatoblastoma (HB) is a common pediatric malignant liver tumor that is characterized by a low level of genetic mutations. Alternative splicing (AS) has been shown to be closely associated with cancer progression, especially in tumors with a low mutational burden. However, the role of AS in HB remains unknown. METHODS: Transcriptome sequencing was performed on 5 pairs of HB tissues and matched non-tumor tissues to delineate the AS landscape in HB. AS events were validated in 92 samples from 46 patients. RNA pull-down and RNA immunoprecipitation assays were carried out to identify splicing factors that regulate the AS of small nucleolar RNA host genes (SNHG). Patient-derived organoids (PDOs) were established to investigate the role of the splicing factor polyadenylate-binding nuclear protein 1 (PABPN1). RESULTS: This study uncovered aberrant alternative splicing in HB, including lncRNAs from SNHG family that undergo intron retention in HB. Further investigations revealed that PABPN1, a significantly upregulated RNA binding protein, interacts with splicing machinery in HB, inducing the intron retention of these SNHG RNAs and the downregulation of intronic small nucleolar RNAs (snoRNAs). Functionally, PABPN1 acts as an oncofetal splicing regulator in HB by promoting cell proliferation and DNA damage repair via inducing the intron retention of SNHG19. Knock-down of PABPN1 increases the cisplatin sensitivity of HB PDOs. CONCLUSIONS: Our findings revealed the rol...