PLoS ONE (Jan 2015)

Low miR-143/miR-145 Cluster Levels Induce Activin A Overexpression in Oral Squamous Cell Carcinomas, Which Contributes to Poor Prognosis.

  • Andreia Bufalino,
  • Nilva K Cervigne,
  • Carine Ervolino de Oliveira,
  • Felipe Paiva Fonseca,
  • Priscila Campioni Rodrigues,
  • Carolina Carneiro Soares Macedo,
  • Lays Martin Sobral,
  • Marcia Costa Miguel,
  • Marcio Ajudarte Lopes,
  • Adriana Franco Paes Leme,
  • Daniel W Lambert,
  • Tuula A Salo,
  • Luiz Paulo Kowalski,
  • Edgard Graner,
  • Ricardo D Coletta

DOI
https://doi.org/10.1371/journal.pone.0136599
Journal volume & issue
Vol. 10, no. 8
p. e0136599

Abstract

Read online

Deregulated expression of activin A is reported in several tumors, but its biological functions in oral squamous cell carcinoma (OSCC) are unknown. Here, we investigate whether activin A can play a causal role in OSCCs. Activin A expression was assessed by qPCR and immunohistochemistry in OSCC tissues. Low activin A-expressing cells were treated with recombinant activin A and assessed for apoptosis, proliferation, adhesion, migration, invasion and epithelial-mesenchymal transition (EMT). Those phenotypes were also evaluated in high activin A-expressing cells treated with follistatin (an activin A antagonist) or stably expressing shRNA targeting activin A. Transfections of microRNA mimics were performed to determine whether the overexpression of activin A is regulated by miR-143/miR-145 cluster. Activin A was overexpressed in OSCCs in comparison with normal oral mucosa, and high activin A levels were significantly associated with lymph node metastasis, tumor differentiation and poor survival. High activin A levels promoted multiple properties associated with malignant transformation, including decreased apoptosis and increased proliferation, migration, invasion and EMT. Both miR-143 and miR-145 were markedly downregulated in OSCC cell lines and in clinical specimens, and inversely correlated to activin A levels. Forced expression of miR-143 and miR-145 in OSCC cells significantly decreased the expression of activin A. Overexpression of activin A in OSCCs, which is controlled by downregulation of miR-143/miR-145 cluster, regulates apoptosis, proliferation and invasiveness, and it is clinically correlated with lymph node metastasis and poor survival.