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Targeting STAT3/miR-21 axis inhibits epithelial-mesenchymal transition via regulating CDK5 in head and neck squamous

Shan-Shan Sun1, Xuan Zhou2, Yuan-Yuan Huang3

  • 1The Maxillary Facial and Otorhinolaryngology Head & Neck Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, TJ, 300060, China. 416638617sss@163.com.

Molecular Cancer
|December 23, 2015
PubMed
Abstract

Insights

MicroRNA-21 (miR-21) and cyclin-dependent kinase 5 (CDK5) promote head and neck cancer invasion. Targeting this axis offers a new strategy for metastasis-blocking therapy in HNSCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • STAT3 and miR-21 abnormal activation drive solid tumor progression and invasion.
  • Cyclin-dependent kinase 5 (CDK5) is implicated in cancer metastasis via epithelial-mesenchymal transition (EMT).
  • The specific roles of the STAT3/miR-21 axis and CDK5 in head and neck squamous cell carcinoma (HNSCC) remain largely uncharacterized.

Purpose of the Study:

  • To investigate the roles of the STAT3/miR-21 axis and CDK5 in HNSCC metastasis.
  • To explore the therapeutic potential of targeting miR-21 and CDK5 in HNSCC.
  • To elucidate the molecular mechanisms underlying HNSCC invasion involving miR-21 and CDK5.

Main Methods:

  • Expression analysis of miR-21, CDK5, and EMT markers in 60 HNSCC samples.
  • Immunohistochemistry and in situ hybridization to assess STAT3/miR-21 axis and CDK5 activation in HNSCC invasiveness.
  • In vitro (cell lines) and in vivo (xenograft model) experiments to evaluate the anti-invasion effects of targeting miR-21.
  • Kaplan-Meier and COX regression analyses for clinical survival relevance.

Main Results:

  • miR-21 and CDK5 expression positively correlated with lymph node metastasis in HNSCC.
  • Co-overexpression of miR-21 and CDK5 observed in Hep-2 and Tca8113 cell lines.
  • Targeting miR-21 (using WP1066 or asON-miR-21) significantly inhibited HNSCC cell migration and invasion by downregulating CDK5, N-cadherin, vimentin, β-catenin, and upregulating E-cadherin.
  • Overexpression of CDK5 promoted tumor cell motility and EMT, and rescued the phenotype after miR-21 inhibition.

Conclusions:

  • miR-21 and CDK5 cooperate to promote EMT and invasion in HNSCC.
  • CDK5 acts as a crucial cofactor in the STAT3/miR-21 axis promoting HNSCC metastasis.
  • Targeting the STAT3/miR-21 axis with STAT3 inhibitors or miR-21 antisense oligonucleotides, in conjunction with CDK5 targeting, presents a promising strategy for metastasis-blocking therapy in HNSCC.

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