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

Abstract
Our previous studies indicate that Secreted Protein Acidic and Rich in Cysteine (SPARC) expression suppressed medulloblastoma tumor growth in vitro and in vivo. Here we sought to determine the effect of SPARC expression in medulloblastoma cells to chemotherapeutic agents. In this study, we show that SPARC expression induces cisplatin resistance in medulloblastoma cells. We also demonstrate that the autophagy was involved in SPARC expression mediated resistance to cisplatin. Suppression of autophagy by either autophagy inhibitor, 3-methyladenosine (3MA) or Atg5 siRNA enhanced cisplatin sensitivity in SPARC expressed cells. Further, SPARC expression suppressed miR-let-7f-1 expression which resulted in disrupted repression of High Mobility Group Box 1 (HMGB1), a critical regulator of autophagy. We also show that HMGB1 is a direct target of miR-let-7f-1 and forced expression of HMGB1 cDNA enhanced cisplatin sensitivity in SPARC expressed cells. In summary, our results suggest that SPARC modulates cisplatin resistance by modulating the Let-7f-1 miRNA/HMGB1 axis in medulloblastoma cells.
AuthorsPadmavathi Pannuru, Ranadheer Dontula, Anwar A Khan, Englehard Herbert, Howard Ozer, Chandramu Chetty, Sajani S Lakka
JournalCellular signalling (Cell Signal) Vol. 26 Issue 10 Pg. 2193-201 (Oct 2014) ISSN: 1873-3913 [Electronic] England
PMID25014664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Inc. All rights reserved.
Chemical References
  • ATG5 protein, human
  • Antineoplastic Agents
  • HMGB1 Protein
  • MicroRNAs
  • Microtubule-Associated Proteins
  • Osteonectin
  • RNA, Small Interfering
  • SPARC protein, human
  • 3-methyladenosine
  • Adenosine
  • Cisplatin
Topics
  • Adenosine (analogs & derivatives, pharmacology)
  • Antineoplastic Agents (toxicity)
  • Autophagy (drug effects)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Cisplatin (toxicity)
  • Drug Resistance, Neoplasm
  • HMGB1 Protein (genetics, metabolism)
  • Humans
  • Medulloblastoma (metabolism, pathology)
  • MicroRNAs (genetics, metabolism)
  • Microtubule-Associated Proteins (antagonists & inhibitors, genetics, metabolism)
  • Osteonectin (genetics, metabolism)
  • RNA Interference
  • RNA, Small Interfering (metabolism)

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