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miR-96-5p targets PTEN to mediate sunitinib resistance in clear cell renal cell carcinoma

Sang Eun Park1, Wonju Kim2,3, Ji-Ye Hong1

  • 1Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.

Scientific Reports
|March 4, 2022
PubMed

Insights

High miR-96-5p and low PTEN levels are linked to sunitinib resistance in clear cell renal cell carcinoma (CCRCC). This microRNA directly suppresses PTEN, contributing to treatment failure and poor prognosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Sunitinib is a first-line therapy for clear cell renal cell carcinoma (CCRCC).
  • CCRCC patients often develop resistance to sunitinib, limiting its long-term efficacy.
  • Identifying mechanisms of resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the role of microRNA (miRNA) and its target in sunitinib resistance in CCRCC.
  • To identify specific miRNAs and their targets associated with sunitinib resistance.

Main Methods:

  • miRNA profiling to identify differentially expressed miRNAs in resistant CCRCC tumors.
  • Bioinformatic analysis to predict miRNA targets.
  • Correlation analysis with The Cancer Genome Atlas (TCGA) kidney renal clear cell carcinoma cohort.
  • Luciferase reporter assays to confirm direct miRNA-target interaction.
  • In vitro studies using cell lines and patient-derived xenograft models.

Main Results:

  • miR-96-5p was upregulated in sunitinib-resistant CCRCC tumors.
  • PTEN was identified as a direct target of miR-96-5p and was downregulated in resistant tumors.
  • Negative correlation between miR-96-5p and PTEN levels was observed in CCRCC patients.
  • High miR-96-5p and low PTEN predicted poor prognosis.
  • Sunitinib treatment increased miR-96-5p and decreased PTEN in a resistant xenograft model.
  • miR-96-5p-mediated repression of PTEN increased cell proliferation and migration.

Conclusions:

  • miR-96-5p directly suppresses PTEN expression in CCRCC.
  • Upregulation of miR-96-5p and subsequent downregulation of PTEN contribute to sunitinib resistance.
  • This miR-96-5p/PTEN axis represents a potential therapeutic target for overcoming sunitinib resistance in CCRCC.

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