SH3BP1-induced Rac-Wave2 pathway activation regulates cervical cancer cell migration, invasion, and chemoresistance to cisplatin

J Cell Biochem. 2018 Feb;119(2):1733-1745. doi: 10.1002/jcb.26334. Epub 2017 Sep 18.

Abstract

Cervical cancer still remains the fourth most common cancer, affecting women worldwide with large geographic variations in cervical cancer incidence and mortality rates. SH3-domain binding protein-1 (SH3BP1) specifically inactivating Rac1 and its target Wave2 is required for cell motility, thus regarded as an essential regulator of cancer cell metastasis. However, the exact effects and molecular mechanisms of SH3BP1 in cervical cancer progression are still unknown. The present study is aimed to investigate the mechanism of SH3BP1 in regulation of cervical cancer cell metastasis and chemoresistance. In the present study, we demonstrated a high SH3BP1 expression in cervical cancer tissues; a higher SH3BP1 expression is also correlated with a shorter overall survival of patients with cervical cancer. Further, we revealed that SH3BP1 overexpression promoted the invasion, migration, and chemoresistance of cervical cancer cell through increasing Rac1 activity and Wave2 protein level. The promotive effect of SH3BP1 could be partially reversed by a Rac1 inhibitor, NSC 23766. In cisplatin-resistant cervical cancer tissues, SH3BP1, Rac1, and Wave2 mRNA expression was significantly up-regulated compared to that of the cisplatin-sensitive cervical cancer tissues. Taken together, SH3BP1/Rac1/Wave2 pathway may potentially act as an effective therapeutic target combined with traditional cisplatin-based chemotherapy for cervical cancer.

Keywords: Rac1/WAVE2 pathway; SH3-domain binding protein-1 (SH3BP1); cervical cancer; chemoresistance; cisplatin; metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Cisplatin / pharmacology*
  • Disease Progression
  • Drug Resistance, Neoplasm*
  • Female
  • GTPase-Activating Proteins / genetics*
  • GTPase-Activating Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • HeLa Cells
  • Humans
  • Neoplasm Invasiveness
  • Signal Transduction
  • Survival Analysis
  • Up-Regulation
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / metabolism
  • Wiskott-Aldrich Syndrome Protein Family / genetics*
  • Wiskott-Aldrich Syndrome Protein Family / metabolism
  • rac1 GTP-Binding Protein / genetics*
  • rac1 GTP-Binding Protein / metabolism

Substances

  • GTPase-Activating Proteins
  • RAC1 protein, human
  • SH3BP1 protein, human
  • WASF2 protein, human
  • Wiskott-Aldrich Syndrome Protein Family
  • rac1 GTP-Binding Protein
  • Cisplatin