Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes
Mohit Sachdeva, … , Diana M. Cardona, David G. Kirsch
Mohit Sachdeva, … , Diana M. Cardona, David G. Kirsch
Published September 2, 2014
Citation Information: J Clin Invest. 2014;124(10):4305-4319. https://doi.org/10.1172/JCI77116.
View: Text | PDF | Corrigendum
Research Article

MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes

  • Text
  • PDF
Abstract

Metastasis causes most cancer deaths, but is incompletely understood. MicroRNAs can regulate metastasis, but it is not known whether a single miRNA can regulate metastasis in primary cancer models in vivo. We compared the expression of miRNAs in metastatic and nonmetastatic primary mouse sarcomas and found that microRNA-182 (miR-182) was markedly overexpressed in some tumors that metastasized to the lungs. By utilizing genetically engineered mice with either deletion of or overexpression of miR-182 in primary sarcomas, we discovered that deletion of miR-182 substantially decreased, while overexpression of miR-182 considerably increased, the rate of lung metastasis after amputation of the tumor-bearing limb. Additionally, deletion of miR-182 decreased circulating tumor cells (CTCs), while overexpression of miR-182 increased CTCs, suggesting that miR-182 regulates intravasation of cancer cells into the circulation. We identified 4 miR-182 targets that inhibit either the migration of tumor cells or the degradation of the extracellular matrix. Notably, restoration of any of these targets in isolation did not alter the metastatic potential of sarcoma cells injected orthotopically, but the simultaneous restoration of all 4 targets together substantially decreased the number of metastases. These results demonstrate that a single miRNA can regulate metastasis of primary tumors in vivo by coordinated regulation of multiple genes.

Authors

Mohit Sachdeva, Jeffrey K. Mito, Chang-Lung Lee, Minsi Zhang, Zhizhong Li, Rebecca D. Dodd, David Cason, Lixia Luo, Yan Ma, David Van Mater, Rebecca Gladdy, Dina C. Lev, Diana M. Cardona, David G. Kirsch

×

Figure 2

Change in miR-182 levels modulates cell migration and invasion in primary mouse sarcoma cell lines.

Options: View larger image (or click on image) Download as PowerPoint
Change in miR-182 levels modulates cell migration and invasion in primar...
(A) Northern blot detects miR-182 in multiple primary sarcoma cell lines from KP mice. (B) Levels of miR-182 in cells correlates with the relative migration and invasion ability of these KP cells. Average of migration and invasion index was plotted on the y axis. (C) Real-time RT-PCR and (D) Northern blot validates knockdown of miR-182 in KP cell lines B and C by an anti–miR-182 oligo. (E) Knockdown of miR-182 in B and C decreases migration and (F) invasion (n = 6 independent experiments). (G) Stably transduced cell line A with anti–miR-182 lentiviral construct. (H) Northern blot validates stable knockdown of miR-182 in 2 different clones. (I and J) Stable knockdown of miR-182 does not affect orthotopic tumor growth in nude mice, but prevents lung metastasis after surgical resection of the orthotopic tumor, as shown in a Kaplan-Meier plot (K) (Mantel-Cox log-rank test). (L) Quantification of the number of lung metastases and (M) percentage of lung area with metastasis shows significant difference between the 2 genotypes. One-way ANOVA (C, E, and F) and 2-tailed Student’s t test (L and M) were used for statistical analysis. All data are mean ± SEM. Scale bars: 100 μm. *P < 0.05; **P < 0.01; ***P < 0.005.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts