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

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...

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Autores principales: Zhen, Ni, Zhu, Jiabei, Mao, Siwei, Zhang, Qi, Gu, Song, Ma, Ji, Zhang, Yue, Yin, Minzhi, Li, Haojie, Huang, Nan, Wu, Han, Sun, Fenyong, Ying, Binwu, Zhou, Lin, Pan, Qiuhui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10520360/
https://www.ncbi.nlm.nih.gov/pubmed/37478905
http://dx.doi.org/10.1016/j.jcmgh.2023.07.007
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author Zhen, Ni
Zhu, Jiabei
Mao, Siwei
Zhang, Qi
Gu, Song
Ma, Ji
Zhang, Yue
Yin, Minzhi
Li, Haojie
Huang, Nan
Wu, Han
Sun, Fenyong
Ying, Binwu
Zhou, Lin
Pan, Qiuhui
author_facet Zhen, Ni
Zhu, Jiabei
Mao, Siwei
Zhang, Qi
Gu, Song
Ma, Ji
Zhang, Yue
Yin, Minzhi
Li, Haojie
Huang, Nan
Wu, Han
Sun, Fenyong
Ying, Binwu
Zhou, Lin
Pan, Qiuhui
author_sort Zhen, Ni
collection PubMed
description 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 role of intron retention in regulating snoRNA expression in hepatoblastoma, explained detailed regulatory mechanism between PABPN1 and the intron retention of SNHG RNAs, and provided insight into the development of new HB treatment options.
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spelling pubmed-105203602023-09-27 Alternative Splicing of lncRNAs From SNHG Family Alters snoRNA Expression and Induces Chemoresistance in Hepatoblastoma Zhen, Ni Zhu, Jiabei Mao, Siwei Zhang, Qi Gu, Song Ma, Ji Zhang, Yue Yin, Minzhi Li, Haojie Huang, Nan Wu, Han Sun, Fenyong Ying, Binwu Zhou, Lin Pan, Qiuhui Cell Mol Gastroenterol Hepatol Original Research 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 role of intron retention in regulating snoRNA expression in hepatoblastoma, explained detailed regulatory mechanism between PABPN1 and the intron retention of SNHG RNAs, and provided insight into the development of new HB treatment options. Elsevier 2023-07-19 /pmc/articles/PMC10520360/ /pubmed/37478905 http://dx.doi.org/10.1016/j.jcmgh.2023.07.007 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Zhen, Ni
Zhu, Jiabei
Mao, Siwei
Zhang, Qi
Gu, Song
Ma, Ji
Zhang, Yue
Yin, Minzhi
Li, Haojie
Huang, Nan
Wu, Han
Sun, Fenyong
Ying, Binwu
Zhou, Lin
Pan, Qiuhui
Alternative Splicing of lncRNAs From SNHG Family Alters snoRNA Expression and Induces Chemoresistance in Hepatoblastoma
title Alternative Splicing of lncRNAs From SNHG Family Alters snoRNA Expression and Induces Chemoresistance in Hepatoblastoma
title_full Alternative Splicing of lncRNAs From SNHG Family Alters snoRNA Expression and Induces Chemoresistance in Hepatoblastoma
title_fullStr Alternative Splicing of lncRNAs From SNHG Family Alters snoRNA Expression and Induces Chemoresistance in Hepatoblastoma
title_full_unstemmed Alternative Splicing of lncRNAs From SNHG Family Alters snoRNA Expression and Induces Chemoresistance in Hepatoblastoma
title_short Alternative Splicing of lncRNAs From SNHG Family Alters snoRNA Expression and Induces Chemoresistance in Hepatoblastoma
title_sort alternative splicing of lncrnas from snhg family alters snorna expression and induces chemoresistance in hepatoblastoma
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10520360/
https://www.ncbi.nlm.nih.gov/pubmed/37478905
http://dx.doi.org/10.1016/j.jcmgh.2023.07.007
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