The miR-491-3p/mTORC2/FOXO1 regulatory loop modulates chemo-sensitivity in human tongue cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Multidrug resistance (MDR) significantly limits chemotherapy effectiveness in tongue cancer (TC).
• MicroRNAs (miRNAs) play crucial roles in cancer progression and drug resistance.
• The specific role of miR-491-3p in TC MDR remains largely unexplored.

Purpose of the Study:

• To investigate the role of miR-491-3p in the development of multidrug resistance in tongue cancer.
• To elucidate the molecular mechanisms underlying miR-491-3p's function in TC chemotherapy resistance.
• To explore the therapeutic potential of targeting the miR-491-3p/mTORC2 axis in TC.

Main Methods:

• Quantitative real-time PCR to assess miR-491-3p expression levels in TC cells and tissues.
• Western blotting to evaluate protein expression and phosphorylation status (Akt, SGK1, FOXO1).
• Luciferase reporter assays to confirm direct targeting of Rictor by miR-491-3p.
• Cell viability assays and chemoresistance assays following miR-491-3p or Rictor manipulation.
• Analysis of patient data to correlate miR-491-3p/Rictor levels with prognosis.

Main Results:

• miR-491-3p expression was significantly decreased in multidrug-resistant TC cells and tissues.
• Overexpression of miR-491-3p sensitized TC cells to chemotherapy, while inhibition enhanced resistance.
• miR-491-3p directly targets Rictor, inhibiting mTORC2 activity and downstream signaling (p-Akt, p-SGK1, p-FOXO1).
• Rictor overexpression or mTORC2 activation promoted chemoresistance, whereas Rictor knockdown or mTOR inhibition sensitized cells to chemotherapy.
• A feedback loop was identified where mTORC2 inactivates FOXO1, downregulating miR-491-3p transcription.
• Low miR-491-3p and high Rictor levels correlated with poor prognosis in TC patients.

Conclusions:

• miR-491-3p acts as a tumor suppressor by inhibiting the mTORC2 pathway in tongue cancer.
• The miR-491-3p/mTORC2 axis represents a critical regulator of chemotherapy resistance in TC.
• Targeting the miR-491-3p/mTORC2 axis offers a promising therapeutic strategy to overcome drug resistance and improve outcomes for TC patients.