BRM/SMARCA2 promotes the proliferation and chemoresistance of pancreatic cancer cells by targeting JAK2/STAT3 signaling

Cancer Lett. 2017 Aug 28:402:213-224. doi: 10.1016/j.canlet.2017.05.006. Epub 2017 Jun 7.

Abstract

Background: BRM is one of two evolutionarily conserved catalytic ATPase subunits of SWI/SNF complexes and plays important role in cell proliferation, linage specification and development, cell adhesion, cytokine responses and DNA repair. BRM is often inactivated in various types of cancer indicating its indispensable roles in oncogenesis but the mechanisms remain poorly understood.

Methods: BRM expression in clinical pancreatic cancer samples was examined by immunohistochemistry and the correlation with patient survival was analyzed. shRNAs targeting BRM were used to establish stable BRM knockdown BxPC-3 and T3M4 cell lines. Cell viability was assessed by CCK-8 assay. Cell proliferation was measured by EdU incorporation assay, colony formation assay and Ki67 staining. Cell cycle and apoptosis were examined by flow cytometry. Growth and chemosensitivity of xenografts initiating from BRM-deficient cells were evaluated, and in situ apoptosis was detected by TUNEL assay. The status of JAK-STAT3 signaling was examined by real-time PCR and Western blot analysis.

Results: High BRM expression was correlated with worse survival of pancreatic cancer patients. BRM shRNA reduced the proliferation and increased the sensitivity of pancreatic cancer cells to gemcitabine in vivo and in vitro, and these effects are associated with the inhibition of STAT3 phosphorylation and reduced transcription of STAT3 target genes.

Conclusion: We reveal a novel mechanism by which BRM could activate JAK2/STAT3 pathway to promote pancreatic cancer growth and chemoresistance. These findings may offer potential therapeutic targets for pancreatic cancer patients with excessive BRM expression.

Keywords: BRM/SMARCA2; Chemoresistance; JAK2/STAT3 signaling; Pancreatic cancer; STAT3 phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm*
  • Female
  • Gemcitabine
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-6 / pharmacology
  • Janus Kinase 2 / metabolism*
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Phosphorylation
  • RNA Interference
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Xenograft Model Antitumor Assays

Substances

  • Antimetabolites, Antineoplastic
  • IL6 protein, human
  • Interleukin-6
  • Nuclear Proteins
  • SMARCA2 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Transcription Factors
  • Deoxycytidine
  • JAK2 protein, human
  • Janus Kinase 2
  • SMARCA4 protein, human
  • DNA Helicases
  • Gemcitabine