CDKN3 mRNA as a Biomarker for Survival and Therapeutic Target in Cervical Cancer

PLoS One. 2015 Sep 15;10(9):e0137397. doi: 10.1371/journal.pone.0137397. eCollection 2015.

Abstract

The cyclin-dependent kinase inhibitor 3 (CDKN3) gene, involved in mitosis, is upregulated in cervical cancer (CC). We investigated CDKN3 mRNA as a survival biomarker and potential therapeutic target for CC. CDKN3 mRNA was measured in 134 CC and 25 controls by quantitative PCR. A 5-year survival study was conducted in 121 of these CC patients. Furthermore, CDKN3-specific siRNAs were used to investigate whether CDKN3 is involved in proliferation, migration, and invasion in CC-derived cell lines (SiHa, CaSki, HeLa). CDKN3 mRNA was on average 6.4-fold higher in tumors than in controls (p = 8 x 10-6, Mann-Whitney). A total of 68.2% of CC patients over expressing CDKN3 gene (fold change ≥ 17) died within two years of diagnosis, independent of the clinical stage and HPV type (Hazard Ratio = 5.0, 95% CI: 2.5-10, p = 3.3 x 10-6, Cox proportional-hazards regression). In contrast, only 19.2% of the patients with lower CDKN3 expression died in the same period. In vitro inactivation of CDKN3 decreased cell proliferation on average 67%, although it had no effect on cell migration and invasion. CDKN3 mRNA may be a good survival biomarker and potential therapeutic target in CC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Biomarkers, Tumor / genetics*
  • Carcinogenesis
  • Cell Movement
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor Proteins / genetics*
  • Cyclin-Dependent Kinase Inhibitor Proteins / metabolism*
  • Down-Regulation
  • Dual-Specificity Phosphatases / genetics*
  • Dual-Specificity Phosphatases / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • HeLa Cells
  • Humans
  • Middle Aged
  • Molecular Targeted Therapy*
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Papillomaviridae / physiology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • Survival Analysis
  • Uterine Cervical Neoplasms / drug therapy*
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology

Substances

  • Biomarkers, Tumor
  • Cyclin-Dependent Kinase Inhibitor Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • CDKN3 protein, human
  • Dual-Specificity Phosphatases

Grants and funding

This work was supported by the National Council of Science and Technology (CONACYT, www.conacyt.mx), grant numbers 8135/A1, 24341 (to JB), National University of Mexico (www.unam.mx), grant number SDI.PTID.05.2 (to JB), and National Council of Science and Technology (CONACYT, www.conacyt.mx), scholarship (to EVB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.