Go to JCI Insight
Jci spelled out white on transparent.20160208
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • Fibrosis (Jan 2018)
    • Glia and Neurodegeneration (Sep 2017)
    • Transplantation (Jun 2017)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

Jci only white

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1
Gaoxiang Zhao, … , Daming Gao, Hongbin Ji
Gaoxiang Zhao, … , Daming Gao, Hongbin Ji
Published January 31, 2019; First published January 28, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI122779.
View: Text | PDF
Categories: Research Article Oncology

Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1

  • Text
  • PDF
Abstract

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 β1, which stabilized integrin β1 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 β1 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 β1 turnover in controlling SCLC metastasis, which might have therapeutic implications.

Authors

Gaoxiang Zhao, Liyan Gong, Dan Su, Yujuan Jin, Chenchen Guo, Meiting Yue, Shun Yao, Zhen Qin, Yi Ye, Ying Tang, Qibiao Wu, Jian Zhang, Binghai Cui, Qiurong Ding, Hsinyi Huang, Liang Hu, Yuting Chen, Peiyuan Zhang, Guohong Hu, Luonan Chen, Kwok-Kin Wong, Daming Gao, Hongbin Ji

×

Figure 1

In vivo genome-scale CRISPR/Cas9 screening identified potential tumor suppressor genes involved in SCLC metastasis using the mGeCKOa library.

Options: View larger image (or click on image) Download as PowerPoint
In vivo genome-scale CRISPR/Cas9 screening identified potential tumor su...
(A) Schematic of the genome-scale screen using the mouse CRISPR/Cas9-knockout library (mGeCKOa) in a mouse RT (Rb1–/– Trp53–/–) SCLC allograft assay. (B) Representative H&E, NCAM, and Ki-67 immunostaining of primary tumors from nude mice subcutaneously transplanted with mouse RT SCLC cells transduced with tomato control sgRNA (sgCtrl) (n = 5) or the mGeCKOa lentiviral library (sgRNA library) (n = 60). Scale bars: 50 μm. (C) Statistical analysis of the Ki-67+ staining results for primary allograft tumors from the sgCtrl and sgRNA library groups. Data represent the mean ± SEM. Statistical analysis was performed using Student’s t test. (D) Representative photos of the lung, liver, chest wall, and diaphragm from mice transplanted with RT cells transduced with sgCtrl or the sgRNA library. Metastatic tumors are indicated by blue arrows. (E) Representative H&E staining of tissue from various organs of nude mice subcutaneously transplanted with RT cells transduced with sgCtrl or sgRNA library. Blue arrows indicated metastatic tumors. Scale bars: 50 μm. (F) Histogram showing the frequency of metastasis enrichment for the top-10 target genes of sgRNAs as revealed by sequencing assays.
Follow JCI: Facebook logo white Twitter logo v2 Rss icon
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts