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Activation of integrin-ERBB2 signaling in undifferentiated thyroid cancer

Xuguang Zhu1, Yuelin J Zhu2, Dong Wook Kim1

  • 1Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892.

American Journal of Cancer Research
|December 19, 2014
PubMed

Insights

This study reveals that combined mutations in thyroid hormone receptor (TRβPV) and KRAS (KrasG12D) drive aggressive undifferentiated thyroid cancer. Integrin-activated ERBB2 signaling is a key mechanism promoting tumor growth in this aggressive cancer.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Undifferentiated thyroid carcinoma (UTC) is an aggressive human cancer with poorly understood genetic drivers.
  • RAS mutations are frequently identified in UTC.
  • Mice with mutant thyroid hormone receptor (Thrb(PV/PV)) develop differentiated thyroid cancer, and introducing Kras(G12D) mutation promotes undifferentiated thyroid cancer.

Purpose of the Study:

  • To identify genes driving the aggressive phenotype in undifferentiated thyroid cancer.
  • To understand the synergistic mechanisms between TRβPV and KRASG12D signaling in thyroid tumorigenesis.

Main Methods:

  • Comparative gene expression profiling using cDNA microarrays.
  • Analysis of thyroid cells from Kras(G12D) mice and thyroid tumor lesions from Thrb(PV/PV) and Thrb(PV/PV) Kras(G12D) mice.
  • Identification of upstream regulators and signaling pathways altered in thyroid tumors.

Main Results:

  • Microarray analysis identified 14 significantly altered upstream regulators in thyroid tumors.
  • Elevated integrin levels were observed, acting as upstream activators.
  • Integrin activation stimulates ERBB2-mediated downstream signaling, promoting aggressive tumor growth.

Conclusions:

  • Integrin-activated ERBB2 signaling is a key mechanism in the synergy between TRβPV and KRASG12D.
  • This synergistic signaling promotes aggressive tumor growth in undifferentiated thyroid cancer.
  • Understanding these pathways offers potential therapeutic targets for aggressive thyroid cancer.
Keywords:
ERBB2Growth regulationgene expressionintegrinsmicroarraysthyroid cancer

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