Format

Send to

Choose Destination
Gastroenterology. 2018 Aug;155(2):542-556. doi: 10.1053/j.gastro.2018.04.020. Epub 2018 Apr 24.

Germline Duplication of SNORA18L5 Increases Risk for HBV-related Hepatocellular Carcinoma by Altering Localization of Ribosomal Proteins and Decreasing Levels of p53.

Author information

1
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P. R. China; National Engineering Research Center for Protein Drugs, Beijing, P. R. China; National Center for Protein Sciences at Beijing, Beijing, P. R. China.
2
School of Life Sciences, Tsinghua University, Beijing, P. R. China.
3
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P. R. China; National Engineering Research Center for Protein Drugs, Beijing, P. R. China; National Center for Protein Sciences at Beijing, Beijing, P. R. China; Clinical Medical Institute of General Hospital of Xinjiang Military Area, PLA, Urumqi, Xinjiang, P. R. China.
4
Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, P. R. China.
5
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Beijing, P. R. China.
6
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.
7
Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
8
Center for Genetics and Genomics Analysis, Genesky Biotechnologies Inc., Shanghai, P. R. China.
9
Department of Infectious Diseases, Affiliated Youan Hospital, Capital University of Medical Science, Beijing, P. R. China.
10
Interventional Radiology Department of Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, P. R. China.
11
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P. R. China.
12
Department of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P. R. China.
13
Clinical Medical Institute of General Hospital of Xinjiang Military Area, PLA, Urumqi, Xinjiang, P. R. China.
14
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P. R. China; National Engineering Research Center for Protein Drugs, Beijing, P. R. China; National Center for Protein Sciences at Beijing, Beijing, P. R. China; School of Life Sciences, Tsinghua University, Beijing, P. R. China. Electronic address: hefc@nic.bmi.ac.cn.
15
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, P. R. China; National Engineering Research Center for Protein Drugs, Beijing, P. R. China; National Center for Protein Sciences at Beijing, Beijing, P. R. China. Electronic address: zhougq114@126.com.

Abstract

BACKGROUND & AIMS:

Single nucleotide polymorphisms could affect risk for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We performed a germline copy number variation (CNV)-based genome-wide association study (GWAS) in populations of Chinese ancestry to search for germline CNVs that increase risk of HCC.

METHODS:

We conducted a CNV-based GWAS of 1583 HCC cases (persons with chronic HBV infection and HCC) and 1540 controls (persons with chronic HBV infection without HCC) in Chinese populations. Identified candidates were expressed in L-02, HepG2, or TP53-/- or wild-type HCT116 cells, and knocked down with short hairpin RNAs in HepG2, Bel-7402, and SMMC-7721 cells; proliferation, colony formation, and apoptosis were measured. Formation of xenograft tumors from cell lines was monitored in nude mice. Subcellular localization of ribosome proteins and levels or activity of p53 were investigated by co-immunoprecipitation, immunofluorescence, and immunoblot analyses. Levels of small nucleolar RNA H/ACA box 18-like 5 (SNORA18L5) were quantified by quantitative reverse transcription polymerase chain reaction.

RESULTS:

We identified a low-frequency duplication at chromosome 15q13.3 strongly associated with risk of HBV-related HCC (overall P = 3.17 × 10-8; odds ratio, 12.02). Copy numbers of the 15q13.3 duplication correlated with the expression of SNORA18L5 in liver tissues. Overexpression of SNORA18L5 increased HCC cell proliferation and growth of xenograft tumors in mice; knockdown reduced HCC proliferation and tumor growth. SNORA18L5 overexpression in HepG2 and SMMC-7721 cells inhibited p53-dependent cell cycle arrest and apoptosis. Overexpression of SNORA18L5 led to hyperactive ribosome biogenesis, increasing levels of mature 18S and 28S ribosomal RNAs and causing the ribosomal proteins RPL5 and RPL11 to stay in the nucleolus, which kept them from binding to MDM2. This resulted in increased MDM2-mediated ubiquitination and degradation of p53. Levels of SNORA18L5 were increased in HCC tissues compared with nontumor liver tissues and associated with shorter survival times of patients.

CONCLUSIONS:

In a CNV-based GWAS, we associated duplication at 15q13.3 with increased risk of HBV-related HCC. We found SNORA18L5 at this location to promote HCC cell proliferation and tumor growth in mice. SNORA18L5 increases ribosome biogenesis, facilitates ribosomal RNA maturation, and alters localization of RPL5 and RPL11, allowing for increased MDM2-mediated proteolysis of p53 and cell cycle arrest.

KEYWORDS:

Human Genetics; Liver Cancer; SNP; Small Nucleolar RNA

PMID:
29702115
DOI:
10.1053/j.gastro.2018.04.020
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center