title: MicroRNA-375 plays a dual role in prostate carcinogenesis.
abstract: BACKGROUND
  Prostate cancer (PCa), a highly incident and heterogeneous malignancy, mostly affects men from developed countries. Increased knowledge of the biological mechanisms underlying PCa onset and progression are critical for improved clinical management. MicroRNAs (miRNAs) deregulation is common in human cancers, and understanding how it impacts in PCa is of major importance. MiRNAs are mostly downregulated in cancer, although some are overexpressed, playing a critical role in tumor initiation and progression. We aimed to identify miRNAs overexpressed in PCa and subsequently determine its impact in tumorigenesis.
  
  
  RESULTS
  MicroRNA expression profiling in primary PCa and morphological normal prostate (MNPT) tissues identified 17 miRNAs significantly overexpressed in PCa. Expression of three miRNAs, not previously associated with PCa, was subsequently assessed in large independent sets of primary tumors, in which miR-182 and miR-375 were validated, but not miR-32. Significantly higher expression levels of miR-375 were depicted in patients with higher Gleason score and more advanced pathological stage, as well as with regional lymph nodes metastases. Forced expression of miR-375 in PC-3 cells, which display the lowest miR-375 levels among PCa cell lines, increased apoptosis and reduced invasion ability and cell viability. Intriguingly, in 22Rv1 cells, which displayed the highest miR-375 expression, knockdown experiments also attenuated the malignant phenotype. Gene ontology analysis implicated miR-375 in several key pathways deregulated in PCa, including cell cycle and cell differentiation. Moreover, CCND2 was identified as putative miR-375 target in PCa, confirmed by luciferase assay.
  
  
  CONCLUSIONS
  A dual role for miR-375 in prostate cancer progression is suggested, highlighting the importance of cellular context on microRNA targeting.
authors.affiliation: Cancer Biology and Epigenetics Group - Research Center (Lab3), Portuguese Oncology Institute - Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, Porto, 4200-072 Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Costa-Pinheiro
authors.affiliation: Cancer Biology and Epigenetics Group - Research Center (Lab3), Portuguese Oncology Institute - Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, Porto, 4200-072 Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Ramalho-Carvalho
authors.affiliation: Cancer Biology and Epigenetics Group - Research Center (Lab3), Portuguese Oncology Institute - Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, Porto, 4200-072 Portugal.|School of Allied Health Sciences (ESTSP), Polytechnic of Porto, Rua Valente Perfeito 322, Vila Nova de Gaia, 4400-330 Portugal.
authors.forename: Filipa Quintela
authors.initials: FQ
authors.lastname: Vieira
authors.affiliation: Cancer Biology and Epigenetics Group - Research Center (Lab3), Portuguese Oncology Institute - Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, Porto, 4200-072 Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Torres-Ferreira
authors.affiliation: Department of Urology, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, Porto, 4200-072 Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Oliveira
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Rua da Universidade, 4704-553 Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Universidade do Minho, Campus de Gualtar, 4710-057 Guimarães, Braga Portugal.
authors.forename: Céline S
authors.initials: CS
authors.lastname: Gonçalves
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Rua da Universidade, 4704-553 Braga, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Universidade do Minho, Campus de Gualtar, 4710-057 Guimarães, Braga Portugal.
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Costa
authors.affiliation: Cancer Biology and Epigenetics Group - Research Center (Lab3), Portuguese Oncology Institute - Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, Porto, 4200-072 Portugal.|Department of Pathology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, Porto, 4200-072 Portugal.|Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313 Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.affiliation: Cancer Biology and Epigenetics Group - Research Center (Lab3), Portuguese Oncology Institute - Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, Porto, 4200-072 Portugal.|Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313 Portugal.
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
keywords: CCND2; Epigenetics; MicroRNAs; Prostate cancer; miR-375