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

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

Cellular and Molecular Gastroenterology and Hepatology (Jan 2023)

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

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

Affiliations

Ni Zhen: Department of Laboratory Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Jiabei Zhu: Department of Laboratory Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Siwei Mao: Department of Laboratory Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Qi Zhang: Department of Laboratory Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Song Gu: Department of Surgery, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Ji Ma: Department of Laboratory Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Yue Zhang: Department of Central Laboratory, Clinical Medicine Scientific and Technical Innovation Park, Shanghai Tenth People’s Hospital, Shanghai, China
Minzhi Yin: Department of Pathology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Haojie Li: Department of Laboratory Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
Nan Huang: Department of Laboratory Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
Han Wu: Department of Laboratory Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Fenyong Sun: Department of Laboratory Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China; Dr Fenyong Sun, Shanghai Tenth People’s Hospital of Tongji University, No. 301 Yanchang Road, Jingan District, 200072, Shanghai, People’s Republic of China.
Binwu Ying: Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Dr Binwu Ying, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Wuhou District, 610041, Chengdu, Sichuan, People’s Republic of China.
Lin Zhou: Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China; Dr Lin Zhou, Changzheng Hospital of Naval Medical University, No. 415 Fengyang Road, Huangpu District, 200003 Shanghai, People’s Republic of China.
Qiuhui Pan: Department of Laboratory Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, China; Sanya Women and Children’s Hospital Managed by Shanghai Children’s Medical Center, Hainan, China; Correspondence Address correspondence to: Dr Qiuhui Pan, Shanghai Children’s Medical Center of Shanghai Jiao Tong University School of Medicine, No.1678 Dongfang Road, Pudong New District, Shanghai 200127, People’s Republic of China.

Journal volume & issue: Vol. 16, no. 5
pp. 735 – 755

Abstract

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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.

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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