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Cross-regulation between oncogenic BRAF(V600E) kinase and the MST1 pathway in papillary thyroid carcinoma

Seong Jin Lee1, Min Hee Lee, Dong Wook Kim

  • 1Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.

Plos One
|January 21, 2011
PubMed
Abstract

Insights

The BRAF(V600E) mutation inhibits the MST1 tumor suppressor pathway, crucial for regulating cell cycle and apoptosis in papillary thyroid cancer (PTC). This inactivation by BRAF(V600E) promotes cancer development by disrupting the RASSF1A-MST1-FoxO3 signaling axis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Papillary thyroid cancer (PTC) is often driven by the BRAF(V600E) mutation, which constitutively activates MEK-ERK signaling.
  • Ras association domain family 1A (RASSF1A) acts as a tumor suppressor, regulating MST1 pathways, but is inactivated by promoter hypermethylation in 20-32% of PTC cases.
  • Mechanisms regulating RASSF1A-MST1 pathways in PTC without RASSF1A methylation, and the interplay between BRAF(V600E) and MST1-FoxO3 signaling, remain unclear.

Purpose of the Study:

  • To investigate the functional cooperation and cross-regulation between BRAF(V600E) and the MST1-FoxO3 pathway in papillary thyroid cancer.
  • To elucidate the role of the RASSF1A-MST1-FoxO3 axis in determining the phenotypic characteristics of BRAF(V600E)-driven thyroid tumors.

Main Methods:

  • Investigated the impact of BRAF(V600E) on FoxO3 transactivation, p21, and p27 expression in thyroid cancer cells.
  • Utilized MST1 silencing and coexpression experiments to dissect the role of MST1 in BRAF(V600E)-mediated signaling.
  • Examined the physical interaction between BRAF(V600E) and MST1 using biochemical assays.
  • Generated BRAF(V600E) transgenic mice, including those with an MST1 knockout background, to model PTC development.

Main Results:

  • BRAF(V600E) markedly abolished FoxO3 transactivation, suppressing p21 and p27 expression, thereby inhibiting apoptosis.
  • Coexpression of MST1 exacerbated BRAF(V600E)'s suppression of FoxO3 transactivation, an effect dependent on MST1 kinase activity.
  • BRAF(V600E) directly binds to MST1, inhibiting its kinase activity and disrupting the RASSF1A-MST1-FoxO3 tumor suppressor pathway.
  • BRAF(V600E) transgenic mice developed PTC-like cancers, with accelerated progression and poorly differentiated features observed in the absence of MST1.

Conclusions:

  • The oncogenic effect of BRAF(V600E) in PTC is mediated by the inhibition of the MST1 tumor suppressor pathway.
  • The activity status of the RASSF1A-MST1-FoxO3 pathway is a critical determinant of BRAF(V600E) tumor phenotypes.
  • Targeting MST1 or reactivating the RASSF1A-MST1-FoxO3 pathway could represent a therapeutic strategy for BRAF(V600E)-driven PTC.

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