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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
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Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting

Z Gong1,2, L Xue1, A C Vlantis1

  • 1Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.

Journal of Endocrinological Investigation
|December 7, 2023
PubMed
Abstract

Insights

Nuclear factor erythroid 2-related factor 2 (Nrf2) is upregulated by KRAS in differentiated thyroid cancer (DTC), promoting dedifferentiation. Inhibiting Nrf2 with Brusatol suppressed KRAS-driven tumor growth, suggesting Nrf2 as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) arise from differentiated thyroid cancer (DTC).
  • Dedifferentiation of DTC leads to poor prognosis and high mortality.
  • The role of Nrf2 in KRAS-induced DTC dedifferentiation is unclear.

Purpose of the Study:

  • To investigate the function of Nrf2 in KRAS-mediated dedifferentiation of DTC.
  • To determine if Nrf2 is a downstream target of KRAS in thyroid cancer.
  • To evaluate Nrf2 as a potential therapeutic target for KRAS-driven thyroid cancer.

Main Methods:

  • Utilized two DTC cell lines (BCPAP and WRO) with wild-type KRAS (KRAS-WT) and KRAS G12V mutation (KRAS-G12V) overexpression.
  • Assessed cell proliferation, invasion, and morphology.
  • Examined Nrf2 expression via immunohistochemistry (IHC) and Western blotting.
  • Administered Nrf2 inhibitor Brusatol and conducted xenograft assays.

Main Results:

  • KRAS overexpression increased proliferation and invasion in DTC cells, inducing aggressive morphology.
  • KRAS-WT and KRAS-G12V upregulated Nrf2 expression in DTC cells.
  • Nrf2 protein levels were significantly higher in thyroid cancer tissues than normal tissues, correlating with poor prognosis.
  • Brusatol treatment inhibited KRAS-induced proliferation and invasion, and suppressed tumor growth in vivo.

Conclusions:

  • Nrf2 is a downstream molecule of KRAS in thyroid cancer.
  • Nrf2 plays a crucial role in KRAS-mediated DTC dedifferentiation.
  • Nrf2 inhibition represents a promising therapeutic strategy for KRAS-driven thyroid cancer.
Keywords:
BrusatolDedifferentiationKRASNrf2Thyroid cancer

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