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Impaired microRNA processing by DICER1 downregulation endows thyroid cancer with increased aggressiveness

Julia Ramírez-Moya1,2, León Wert-Lamas1,3, Garcilaso Riesco-Eizaguirre1,2,3,4

  • 1Instituto de Investigaciones Biomédicas "Alberto Sols"; Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.

Oncogene
|April 11, 2019
PubMed

Insights

Oncogenic miR-146b suppresses miRNA production by targeting DICER1, promoting thyroid cancer. Restoring DICER1 or inhibiting miR-146b may offer new cancer treatments.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Global microRNA (miRNA) downregulation is a cancer hallmark.
  • Mechanisms driving miRNA downregulation in cancer remain unclear.
  • Dysregulation of miRNA biogenesis pathways is implicated in tumorigenesis.

Purpose of the Study:

  • Investigate the role of miR-146b in miRNA biosynthesis.
  • Determine the impact of DICER1 expression on thyroid cancer progression.
  • Explore therapeutic strategies targeting the miR-146b/DICER1 axis.

Main Methods:

  • In vitro cell culture experiments with thyroid cancer cells.
  • In vivo studies using orthotopic mouse models of thyroid cancer.
  • Analysis of The Cancer Genome Atlas (TCGA) data for DICER1 expression and clinical outcomes.
  • Treatment with anti-miR-146b and the small molecule enoxacin.

Main Results:

  • Oncogenic miR-146b targets and downregulates DICER1, a key enzyme in miRNA biosynthesis.
  • DICER1 overexpression reversed miR-146b-induced aggressive phenotypes in thyroid cells.
  • Anti-miR-146b treatment suppressed tumor growth and restored DICER1 levels in vivo.
  • DICER1 downregulation promoted cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition.
  • Decreased DICER1 expression in thyroid cancer correlated with worse clinical outcomes.
  • Enoxacin treatment reduced tumor aggressiveness by enhancing DICER1 activity.

Conclusions:

  • DICER1 acts as a tumor suppressor in thyroid cancer.
  • Oncogenic miR-146b contributes to cancer progression by downregulating DICER1.
  • Targeting miRNA biogenesis, including miRNA inhibitors and DICER1 restoration, shows therapeutic potential for thyroid and other cancers.

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