Genomic gain of RRS1 promotes hepatocellular carcinoma through reducing the RPL11-MDM2-p53 signaling

被引：32

作者：

Cao, Pengbo ^{[1
]}

Yang, Aiqing ^{[1
]}

Li, Peiyao ^{[1
]}

Xia, Xia ^{[1
]}

Han, Yuqing ^{[1
]}

Zhou, Guangming ^{[1
]}

Wang, Rui ^{[1
]}

Yang, Fei ^{[1
]}

Li, Yuanfeng ^{[1
]}

Zhang, Ying ^{[1
]}

Cui, Ying ^{[2
]}

Ji, Hongzan ^{[3
]}

Lu, Lei ^{[4
]}

He, Fuchu ^{[5
]}

Zhou, Gangqiao ^{[1
,6
,7
,8
]}

机构：

[1] Beijing Inst Radiat Med, State Key Lab Prote, Natl Ctr Prot Sci Beijing, Beijing, Peoples R China

[2] Guangxi Med Univ, Affiliated Canc Hosp, Nanning, Peoples R China

[3] Nanjing Univ, Jinling Hosp, Sch Clin, Dept Gastroenterol & Hepatol, Nanjing, Peoples R China

[4] Jingdu Hosp, Dept Surg Oncol, Nanjing, Peoples R China

[5] Beijing Inst Life, Natl Ctr Prot Sci Beijing, State Key Lab Prote, Beijing, Peoples R China

[6] Nanjing Med Univ, Sch Publ Hlth, Collaborat Innovat Ctr Personalized Canc Med, Ctr Global Hlth, Nanjing, Peoples R China

[7] Anhui Med Univ, Hefei, Peoples R China

[8] Hebei Univ, Shijiazhuang, Hebei, Peoples R China

来源：

SCIENCE ADVANCES | 2021年 / 7卷 / 35期

基金：

中国国家自然科学基金;

关键词：

5S RIBOSOMAL-RNA; P53; UBIQUITINATION; POOR-PROGNOSIS; PROTEIN; GENE; IDENTIFICATION; BIOGENESIS; CANCER; MUTATION; PROGRESSION;

D O I：

10.1126/sciadv.abf4304

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Hepatocellular carcinomas (HCCs) are characterized by frequent somatic genomic copy number alterations (CNAs), with most of them biologically unexplored. Here, we performed integrative analyses combining CNAs with the transcriptomic data to reveal the cis- and trans-effects of CNAs in HCC. We identified recurrent genomic gains of chromosome 8q, which exhibit strong trans-effects and are broadly associated with ribosome biogenesis activity. Furthermore, 8q gain-driven overexpression of ribosome biogenesis regulator (RRS1) promotes growth of HCC cells in vitro and in vivo. Mechanistically, RRS1 attenuates ribosomal stress through retaining RPL11 in the nucleolus, which, in turn, potentiates MDM2-mediated ubiquitination and degradation of p53. Clinically, higher RRS1 expression levels predict poor clinical outcomes for patients with HCC, especially in those with intact p53. Our findings established that the chromosome 8q oncogene RRS1 promotes HCC development through attenuating the RPL11-MDM2-p53 pathway and provided new potential targets for treatment of this malignancy.

引用

页数：17

共 59 条

[1] Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma [J].

Ally, Adrian ;

Balasundaram, Miruna ;

Carlsen, Rebecca ;

Chuah, Eric ;

Clarke, Amanda ;

Dhalla, Noreen ;

Holt, Robert A. ;

Jones, Steven J. M. ;

Lee, Darlene ;

Ma, Yussanne ;

Marra, Marco A. ;

Mayo, Michael ;

Moore, Richard A. ;

Mungall, Andrew J. ;

Schein, Jacqueline E. ;

Sipahimalani, Payal ;

Tam, Angela ;

Thiessen, Nina ;

Cheung, Dorothy ;

Wong, Tina ;

Brooks, Denise ;

Robertson, A. Gordon ;

Bowlby, Reanne ;

Mungall, Karen ;

Sadeghi, Sara ;

Xi, Liu ;

Covington, Kyle ;

Shinbrot, Eve ;

Wheeler, David A. ;

Gibbs, Richard A. ;

Donehower, Lawrence A. ;

Wang, Linghua ;

Bowen, Jay ;

Gastier-Foster, Julie M. ;

Gerken, Mark ;

Helsel, Carmen ;

Leraas, Kristen M. ;

Lichtenberg, Tara M. ;

Ramirez, Nilsa C. ;

Wise, Lisa ;

Zmuda, Erik ;

Gabriel, Stacey B. ;

Meyerson, Matthew ;

Cibulskis, Carrie ;

Murray, Bradley A. ;

Shih, Juliann ;

Beroukhim, Rameen ;

Cherniack, Andrew D. ;

Schumacher, Steven E. ;

Saksena, Gordon .

CELL, 2017, 169 (07) :1327-+

[2] A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer [J].

Asgharpour, Amon ;

Cazanave, Sophie C. ;

Pacana, Tommy ;

Seneshaw, Mulugeta ;

Vincent, Robert ;

Banini, Bubu A. ;

Kumar, Divya Prasanna ;

Daita, Kalyani ;

Min, Hae-Ki ;

Mirshahi, Faridoddin ;

Bedossa, Pierre ;

Sun, Xiaochen ;

Hoshida, Yujin ;

Koduru, Srinivas V. ;

Contaifer, Daniel, Jr. ;

Warncke, Osinska ;

Wijesinghe, Dayanjan S. ;

Sanyal, Arun J. .

JOURNAL OF HEPATOLOGY, 2016, 65 (03) :579-588

[3] Comprehensive molecular characterization of gastric adenocarcinoma [J].

Bass, Adam J. ;

Thorsson, Vesteinn ;

Shmulevich, Ilya ;

Reynolds, Sheila M. ;

Miller, Michael ;

Bernard, Brady ;

Hinoue, Toshinori ;

Laird, Peter W. ;

Curtis, Christina ;

Shen, Hui ;

Weisenberger, Daniel J. ;

Schultz, Nikolaus ;

Shen, Ronglai ;

Weinhold, Nils ;

Keiser, David P. ;

Bowlby, Reanne ;

Sipahimalani, Payal ;

Cherniack, Andrew D. ;

Getz, Gad ;

Liu, Yingchun ;

Noble, Michael S. ;

Pedamallu, Chandra ;

Sougnez, Carrie ;

Taylor-Weiner, Amaro ;

Akbani, Rehan ;

Lee, Ju-Seog ;

Liu, Wenbin ;

Mills, Gordon B. ;

Yang, Da ;

Zhang, Wei ;

Pantazi, Angeliki ;

Parfenov, Michael ;

Gulley, Margaret ;

Piazuelo, M. Blanca ;

Schneider, Barbara G. ;

Kim, Jihun ;

Boussioutas, Alex ;

Sheth, Margi ;

Demchok, John A. ;

Rabkin, Charles S. ;

Willis, Joseph E. ;

Ng, Sam ;

Garman, Katherine ;

Beer, David G. ;

Pennathur, Arjun ;

Raphael, Benjamin J. ;

Wu, Hsin-Ta ;

Odze, Robert ;

Kim, Hark K. ;

Bowen, Jay .

NATURE, 2014, 513 (7517) :202-209

[4] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[5] The landscape of somatic copy-number alteration across human cancers [J].

Beroukhim, Rameen ;

Mermel, Craig H. ;

Porter, Dale ;

Wei, Guo ;

Raychaudhuri, Soumya ;

Donovan, Jerry ;

Barretina, Jordi ;

Boehm, Jesse S. ;

Dobson, Jennifer ;

Urashima, Mitsuyoshi ;

Mc Henry, Kevin T. ;

Pinchback, Reid M. ;

Ligon, Azra H. ;

Cho, Yoon-Jae ;

Haery, Leila ;

Greulich, Heidi ;

Reich, Michael ;

Winckler, Wendy ;

Lawrence, Michael S. ;

Weir, Barbara A. ;

Tanaka, Kumiko E. ;

Chiang, Derek Y. ;

Bass, Adam J. ;

Loo, Alice ;

Hoffman, Carter ;

Prensner, John ;

Liefeld, Ted ;

Gao, Qing ;

Yecies, Derek ;

Signoretti, Sabina ;

Maher, Elizabeth ;

Kaye, Frederic J. ;

Sasaki, Hidefumi ;

Tepper, Joel E. ;

Fletcher, Jonathan A. ;

Tabernero, Josep ;

Baselga, Jose ;

Tsao, Ming-Sound ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Janne, Pasi A. ;

Daly, Mark J. ;

Nucera, Carmelo ;

Levine, Ross L. ;

Ebert, Benjamin L. ;

Gabriel, Stacey ;

Rustgi, Anil K. ;

Antonescu, Cristina R. ;

Ladanyi, Marc ;

Letai, Anthony .

NATURE, 2010, 463 (7283) :899-905

[6] Frequency of mutation and deletion of the tumor suppressor gene CDKN2A (MTS1/p16) in hepatocellular carcinoma from an Australian population [J].

Biden, K ;

Young, J ;

Buttenshaw, R ;

Searle, J ;

Cooksley, G ;

Xu, DB ;

Leggett, B .

HEPATOLOGY, 1997, 25 (03) :593-597

[7] p53 ubiquitination: Mdm2 and beyond [J].

Brooks, CL ;

Gu, W .

MOLECULAR CELL, 2006, 21 (03) :307-315

[8] Increased sensitivity to UV radiation in mice with a p53 point mutation at Ser389 [J].

Bruins, W ;

Zwart, E ;

Attardi, LD ;

Iwakuma, T ;

Hoogervorst, EM ;

Beems, RB ;

Miranda, B ;

van Oostrom, CTM ;

van den Berg, J ;

van den Aardweg, GJ ;

Lozano, G ;

van Steeg, H ;

Jacks, T ;

de Vries, A .

MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (20) :8884-8894

[9]

Cancer Genome Atlas Research Network, 2014, Nature, V511, P543, DOI [10.1038/s41586-018-0228-6, 10.1038/nature13385]

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

Cao, Pengbo ;

Yang, Aiqing ;

Wang, Rui ;

Xia, Xia ;

Zhai, Yun ;

Li, Yuanfeng ;

Yang, Fei ;

Cui, Ying ;

Xie, Weimin ;

Liu, Ying ;

Liu, Taotao ;

Jia, Weihua ;

Jiang, Zhengwen ;

Li, Zhuo ;

Han, Yuqing ;

Gao, Chengming ;

Song, Qingfeng ;

Xie, Bobo ;

Zhang, Luo ;

Zhang, Hongxing ;

Zhang, Jinxu ;

Shen, Xizhong ;

Yuan, Yunfei ;

Yu, Feng ;

Wang, Ying ;

Xu, Jing ;

Ma, Yilong ;

Mo, Zengnan ;

Yu, Wuzhong ;

He, Fuchu ;

Zhou, Gangqiao .

GASTROENTEROLOGY, 2018, 155 (02) :542-556

← 1 2 3 4 5 6 →