Combined Influence of EGF+61G>A and TGFB+869T>C Functional Polymorphisms in Renal Cell Carcinoma Progression and Overall Survival: The Link to Plasma Circulating MiR-7 and MiR-221/222 Expression

PLoS One. 2015 Apr 24;10(4):e0103258. doi: 10.1371/journal.pone.0103258. eCollection 2014.

Abstract

The epidermal growth factor (EGF) is responsible for the activation of intracellular signal transducers that act on cell-cycle progression, cell motility, angiogenesis and inhibition of apoptosis. However, cells can block these effects activating opposite signaling pathways, such as the transforming growth factor beta 1 (TGFβ1) pathway. Thus changes in expression levels of EGF and TGFB1 in renal cells might modulate the renal cell carcinoma (RCC) development, in consequence of changes in regulatory elements of signaling networks such as the microRNAs (miRNAs). Our purpose was to investigate the synergic role of EGF+61G>A and TGFB1+869T>C polymorphisms in RCC development. Genetic polymorphisms were studied by allelic discrimination using real-time PCR in 133 RCC patients vs. 443 healthy individuals. The circulating EGF/EGFR-MAPK-related miR-7, miR-221 and miR-222 expression was analyzed by a quantitative real-time PCR in plasma from 22 RCC patients vs. 27 healthy individuals. The intermediate/high genetic proliferation profile patients carriers present a significantly reduced time-to-progression and a higher risk of an early relapse compared with the low genetic proliferation profile carriers (HR = 8.8, P = 0.038) with impact in a lower overall survival (Log rank test, P = 0.047). The RCC patients presented higher circulating expression levels of miR-7 than healthy individuals (6.1-fold increase, P<0.001). Moreover, the intermediate/high genetic proliferation profile carriers present an increase in expression levels of miR-7, miR-221 and miR-222 during the RCC development and this increase is not observed in low genetic proliferation profile (P<0.001, P = 0.004, P<0.001, respectively). The stimulus to angiogenesis, cell-cycle progression and tumoral cells invasion, through activation of EGFR/MAPK signaling pathway in intermediate/high proliferation profile carriers is associated with an early disease progression, resulting in a poor overall survival. We also demonstrated that the intermediate/high proliferation profile is an unfavorable prognostic factor of RCC and miR-7, miR-221 and miR-222 expressions may be useful phenotype biomarkers of EGFR/MAPK activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / mortality
  • Carcinoma, Renal Cell / pathology*
  • Epidermal Growth Factor / genetics*
  • Humans
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / mortality
  • Kidney Neoplasms / pathology*
  • MicroRNAs / blood
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Signal Transduction
  • Survival Analysis
  • Transforming Growth Factor beta1 / genetics*

Substances

  • MIRN221 microRNA, human
  • MIRN222 microRNA, human
  • MIRN7 microRNA, human
  • MicroRNAs
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • Epidermal Growth Factor

Grants and funding

The authors would like to thank the Liga Portuguesa Contra o Cancro—Centro Regional do Norte (Portuguese League Against Cancer) and FCT—Fundação para a Ciência e Tecnologia. ALT is a Doctoral degree grant holder from FCT (SFRH/BD/47381/2008). This project was partially sponsored by an unrestricted educational grant for basic research in Molecular Oncology from AstraZeneca Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.