Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin beta 1

doi:10.1172/JCI122779

	Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin beta 1
	Zhao, Gaoxiang 1,2; Gong, Liyan 1,2; Su, Dan 3; Jin, Yujuan 1,2; Guo, Chenchen 1,2; Yue, Meiting 1,2; Yao, Shun 1,2; Qin, Zhen 1,2; Ye, Yi1,2,4 ; Tang, Ying 1,2; Wu, Qibiao 1,2; Zhang, Jian 1,2; Cui, Binghai 1,2; Ding, Qiurong 5; Huang, Hsinyi 1,2; Hu, Liang 1,2; Chen, Yuting1,2,4 ; Zhang, Peiyuan 6; Hu, Guohong 6; Chen, Luonan1,2,4 ; Wong, Kwok-Kin 7; Gao, Daming 1,2; Ji, Hongbin1,2,4
	2019-03
发表期刊	JOURNAL OF CLINICAL INVESTIGATION (IF:13.3[JCR-2023],14.6[5-Year])
ISSN	0021-9738
卷号	129 期号:3 页码:972-987
发表状态	已发表
DOI	10.1172/JCI122779
摘要	Metastasis is the dominant cause of patient death in small-cell lung cancer (SCLC), and a better understanding of the molecular mechanisms underlying SCLC metastasis may potentially improve clinical treatment. Through genome-scale screening for key regulators of mouse Rb1(-/-) Trp53(-/-) SCLC metastasis using the pooled CRISPR/Cas9 library, we identified Cullin5 (CUL5) and suppressor of cytokine signaling 3 (SOCS3), two components of the Cullin-RING E3 ubiquitin ligase complex, as top candidates. Mechanistically, the deficiency of CUL5 or SOCS3 disrupted the functional formation of the E3 ligase complex and prevented the degradation of integrin beta 1, which stabilized integrin beta 1 and activated downstream focal adhesion kinase/SRC (FAK/SRC) signaling and eventually drove SCLC metastasis. Low expression levels of CUL5 and SOCS3 were significantly associated with high integrin beta 1 levels and poor prognosis in a large cohort of 128 clinical patients with SCLC. Moreover, the CUL5-deficient SCLCs were vulnerable to the treatment of the FDA-approved SRC inhibitor dasatinib. Collectively, this work identifies the essential role of CUL5- and SOCS3-mediated integrin beta 1 turnover in controlling SCLC metastasis, which might have therapeutic implications.
收录类别	SCI ; SCIE
语种	英语
资助项目	China Postdoctoral Science Foundation[2016M601667]
WOS研究方向	Research & Experimental Medicine
WOS类目	Medicine, Research & Experimental
WOS记录号	WOS:000460125800013
出版者	AMER SOC CLINICAL INVESTIGATION INC
WOS关键词	DRIVES PROTEASOMAL DEGRADATION ; POOR PROGNOSTIC-FACTOR ; SOCS-BOX ; MOUSE MODEL ; CUL5-RBX2 MODULES ; EXPRESSION ; GROWTH ; SRC ; MYC ; CARCINOMA
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/30450
专题	生命科学与技术学院_硕士生生命科学与技术学院_特聘教授组_季红斌组生命科学与技术学院_特聘教授组_陈洛南组生命科学与技术学院_博士生
通讯作者	Gao, Daming; Ji, Hongbin
作者单位	1.Chinese Acad Sci, Innovat Ctr Cell Signaling Network, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci,State Key Lab Cel, 320 Yue Yang Rd, Shanghai 200031, Peoples R China 2.Univ Chinese Acad Sci, 320 Yue Yang Rd, Shanghai 200031, Peoples R China 3.Zhejiang Canc Hosp, Dept Pathol, Hangzhou, Zhejiang, Peoples R China 4.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Shanghai Inst Biol Sci, CAS Key Lab Nutr Metab & Food Safety, Shanghai, Peoples R China 6.Chinese Acad Sci, Inst Hlth Sci, Shanghai Inst Biol Sci, Key Lab Stem Cell Biol, Shanghai, Peoples R China 7.NYU Langone Med Ctr, Laura & Isaac Perlmutter Canc Ctr, New York, NY USA
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Zhao, Gaoxiang,Gong, Liyan,Su, Dan,et al. Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin beta 1[J]. JOURNAL OF CLINICAL INVESTIGATION,2019,129(3):972-987.
APA	Zhao, Gaoxiang.,Gong, Liyan.,Su, Dan.,Jin, Yujuan.,Guo, Chenchen.,...&Ji, Hongbin.(2019).Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin beta 1.JOURNAL OF CLINICAL INVESTIGATION,129(3),972-987.
MLA	Zhao, Gaoxiang,et al."Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin beta 1".JOURNAL OF CLINICAL INVESTIGATION 129.3(2019):972-987.