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Published on: March 30, 2019

Suppression of non-small cell lung tumor development by the let-7 microRNA family

Madhu S Kumar1, Stefan J Erkeland, Ryan E Pester

  • 1Center for Cancer Research and Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 1, 2008
PubMed

Insights

The let-7 miRNA family suppresses non-small cell lung cancer (NSCLC) development. Restoring let-7g levels in lung cancer cells reduced tumor growth, arrested cell cycles, and induced cell death, particularly in K-Ras mutated cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • MicroRNAs (miRNAs) regulate gene expression and are often dysregulated in cancer.
  • The let-7 miRNA family is frequently downregulated in non-small cell lung cancer (NSCLC) and is proposed to have tumor-suppressive functions.

Purpose of the Study:

  • To investigate the functional role of let-7g in non-small cell lung cancer (NSCLC) development and tumor suppression.
  • To elucidate the molecular mechanisms underlying let-7g-mediated tumor suppression in NSCLC.

Main Methods:

  • Ectopic expression of let-7g in K-Ras(G12D)-expressing murine lung cancer cells and human NSCLC cell lines.
  • Tumor xenograft studies in mice with lentiviral vector-mediated let-7g overexpression.
  • Analysis of protein levels of Ras family members and HMGA2 in tumors.
  • Investigating the effect of K-Ras(G12D) and HMGA2 overexpression on let-7g-mediated tumor suppression.
  • Assessment of let-7g in an autochthonous mouse model of NSCLC.

Main Results:

  • Ectopic let-7g expression induced cell cycle arrest and cell death in murine lung cancer cells.
  • Overexpression of let-7g significantly reduced the growth of both murine and human NSCLC xenografts.
  • let-7g expression led to decreased levels of Ras family proteins and HMGA2.
  • let-7g-mediated tumor suppression was more pronounced in NSCLC lines with oncogenic K-Ras mutations.
  • K-Ras(G12D) overexpression partially rescued let-7g's tumor-suppressive effects, while HMGA2 overexpression had a lesser impact.
  • let-7g expression substantially decreased tumor burden in a mouse model of NSCLC.

Conclusions:

  • let-7g functions as a tumor suppressor in non-small cell lung cancer (NSCLC).
  • The tumor-suppressive activity of let-7g is, in part, mediated through the downregulation of Ras family proteins and HMGA2.
  • let-7g holds therapeutic potential for NSCLC, particularly in tumors with K-Ras mutations.

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