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miR-1298 Inhibits Mutant KRAS-Driven Tumor Growth by Repressing FAK and LAMB3

Ying Zhou1, Jason Dang2, Kung-Yen Chang2

  • 1Program for RNA Biology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.

Cancer Research
|October 5, 2016
PubMed

Insights

Researchers discovered miR-1298, a microRNA targeting FAK and LAMB3, which inhibits KRAS-driven cancer growth. LAMB3 upregulation by KRAS suggests it as a potential biomarker for lung cancer survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Synthetic lethal interactions offer therapeutic strategies for cancer. KRAS-mutant cancers remain challenging to treat.
  • MicroRNAs (miRNAs) regulate gene expression and can be leveraged for cancer therapy.

Purpose of the Study:

  • To identify novel gene interactions and therapeutic targets in KRAS-mutant cancer cells using miRNA functional screens.
  • To investigate the role of miR-1298 in KRAS-driven cancers and its functional targets.

Main Methods:

  • Global miRNA functional screening in KRAS-mutant cancer cells.
  • miR-TRAP affinity purification to identify miRNA targets.
  • In vitro and in vivo assays to assess cell growth inhibition.
  • Analysis of FAK and LAMB3 expression in cancer specimens.

Main Results:

  • Discovery of miR-1298, a novel miRNA inhibiting KRAS-driven cancer cell growth.
  • Identification of FAK (tyrosine kinase) and LAMB3 (laminin subunit) as functional targets of miR-1298.
  • Silencing FAK or LAMB3 mimicked miR-1298's synthetic lethal effect; co-expression rescued cell death.
  • Mutant KRAS upregulated LAMB3 expression, not FAK.
  • Elevated LAMB3 correlated with poorer survival in lung cancer patients with KRAS mutations.

Conclusions:

  • miR-1298 represents a novel therapeutic target for KRAS-driven cancers.
  • LAMB3 is a potential therapeutic target and a candidate biomarker for KRAS-mutant lung cancer.
  • This study defines a new regulatory pathway in KRAS-driven cancers.

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