title: 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.
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.
authors.affiliation: Molecular Oncology Group & Virology Pathology, Portuguese Institute of Oncology of Porto, Porto, Portugal; Abel Salazar Institute for the Biomedical Sciences (ICBAS) of University of Porto, Porto, Portugal; Research Department, Portuguese League Against Cancer (NRNorte), Porto, Portugal.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Teixeira
authors.affiliation: Molecular Oncology Group & Virology Pathology, Portuguese Institute of Oncology of Porto, Porto, Portugal; Abel Salazar Institute for the Biomedical Sciences (ICBAS) of University of Porto, Porto, Portugal; Research Department, Portuguese League Against Cancer (NRNorte), Porto, Portugal.
authors.forename: Francisca
authors.initials: F
authors.lastname: Dias
authors.affiliation: Oncology Department, Portuguese Institute of Oncology of Porto, Porto, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Ferreira
authors.affiliation: Molecular Oncology Group & Virology Pathology, Portuguese Institute of Oncology of Porto, Porto, Portugal; Abel Salazar Institute for the Biomedical Sciences (ICBAS) of University of Porto, Porto, Portugal; Research Department, Portuguese League Against Cancer (NRNorte), Porto, Portugal.
authors.forename: Mónica
authors.initials: M
authors.lastname: Gomes
authors.affiliation: Molecular Oncology Group & Virology Pathology, Portuguese Institute of Oncology of Porto, Porto, Portugal; Abel Salazar Institute for the Biomedical Sciences (ICBAS) of University of Porto, Porto, Portugal.
authors.forename: Juliana I
authors.initials: JI
authors.lastname: Santos
authors.affiliation: Urology Department, Portuguese Institute of Oncology of Porto, Porto, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Lobo
authors.affiliation: Oncology Department, Portuguese Institute of Oncology of Porto, Porto, Portugal.
authors.forename: Joaquina
authors.initials: J
authors.lastname: Maurício
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Faculty of Medicine- University of Porto, Porto, Portugal.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Machado
authors.affiliation: Molecular Oncology Group & Virology Pathology, Portuguese Institute of Oncology of Porto, Porto, Portugal; Abel Salazar Institute for the Biomedical Sciences (ICBAS) of University of Porto, Porto, Portugal; Research Department, Portuguese League Against Cancer (NRNorte), Porto, Portugal; Faculty of Health Sciences of Fernando Pessoa University, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
mesh_terms: D000328:Adult; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D004815:Epidermal Growth Factor / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D035683:MicroRNAs / Q000097:blood; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D016019:Survival Analysis; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D004815:Epidermal Growth Factor; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1; C525709:MIR221, human; C525710:MIR222, human; C549242:MIRN7-1 microRNA, human; C508960:TGFB1 protein, human