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miR-let-7f-1 regulates SPARC mediated cisplatin resistance in medulloblastoma cells

Padmavathi Pannuru1, Ranadheer Dontula1, Anwar A Khan1

  • 1From the Section of Hematology/Oncology, University of Illinois Cancer Center, College of Medicine at Chicago, Chicago, IL 60612, USA.

Cellular Signalling
|July 12, 2014
PubMed

Insights

Secreted Protein Acidic and Rich in Cysteine (SPARC) promotes cisplatin resistance in medulloblastoma by activating autophagy via the miR-let-7f-1/HMGB1 pathway. Inhibiting autophagy or targeting this axis can restore chemotherapy sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Secreted Protein Acidic and Rich in Cysteine (SPARC) has previously shown to suppress medulloblastoma growth.
  • The role of SPARC in medulloblastoma cell response to chemotherapy remains unclear.

Purpose of the Study:

  • To investigate the effect of SPARC expression on medulloblastoma cell sensitivity to chemotherapeutic agents.
  • To elucidate the molecular mechanisms underlying SPARC-mediated chemoresistance, focusing on autophagy and miRNA regulation.

Main Methods:

  • Medulloblastoma cell lines with varying SPARC expression levels were utilized.
  • Cisplatin resistance assays were performed.
  • Autophagy was modulated using 3-methyladenosine (3MA) and Atg5 siRNA.
  • MicroRNA (miR-let-7f-1) and High Mobility Group Box 1 (HMGB1) expression and interactions were analyzed.
  • Forced expression of HMGB1 cDNA was employed.

Main Results:

  • SPARC expression was found to induce resistance to cisplatin in medulloblastoma cells.
  • Autophagy was identified as a key mediator in SPARC-driven cisplatin resistance.
  • Inhibition of autophagy enhanced cisplatin sensitivity in SPARC-expressing cells.
  • SPARC suppressed miR-let-7f-1, leading to increased HMGB1 levels.
  • HMGB1 was confirmed as a direct target of miR-let-7f-1, and its forced expression also enhanced cisplatin sensitivity.

Conclusions:

  • SPARC confers cisplatin resistance in medulloblastoma cells.
  • This resistance is mediated through the modulation of the miR-let-7f-1/HMGB1 axis, which regulates autophagy.
  • Targeting the SPARC/miR-let-7f-1/HMGB1/autophagy pathway presents a potential therapeutic strategy for overcoming chemoresistance in medulloblastoma.
Keywords:
AutophagyHMGB1MedulloblastomaSPARCmiR-let-7f-1

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