title: Low miR-143/miR-145 Cluster Levels Induce Activin A Overexpression in Oral Squamous Cell Carcinomas, Which Contributes to Poor Prognosis.
abstract: 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.
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil.
authors: Andreia
authors: A
authors: Bufalino
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil.
authors: Nilva K
authors: NK
authors: Cervigne
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil.
authors: Carine Ervolino
authors: CE
authors: de Oliveira
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil.
authors: Felipe Paiva
authors: FP
authors: Fonseca
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil.
authors: Priscila Campioni
authors: PC
authors: Rodrigues
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil.
authors: Carolina Carneiro Soares
authors: CC
authors: Macedo
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil.
authors: Lays Martin
authors: LM
authors: Sobral
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil; Department of Dentistry, Federal University of Rio Grande do Norte, Natal-RN, Brazil.
authors: Marcia Costa
authors: MC
authors: Miguel
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil.
authors: Marcio Ajudarte
authors: MA
authors: Lopes
authors: Brazilian Biociences National Laboratory-CNPEM, Campinas-SP, Brazil.
authors: Adriana Franco
authors: AF
authors: Paes Leme
authors: Integrated Biosciences, School of Clinical Dentistry and Sheffield Cancer Centre, University of Sheffield, Sheffield, United Kingdom.
authors: Daniel W
authors: DW
authors: Lambert
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil; Department of Diagnostics and Oral Medicine, Institute of Dentistry and Oulu University Hospital and Medical Research Center, University of Oulu, Oulu and Institute of Dentistry, University of Helsinki, Helsinki, Finland.
authors: Tuula A
authors: TA
authors: Salo
authors: Department of Head and Neck Surgery and Otorhinolaryngology, A. C. Camargo Cancer Center, São Paulo-SP, Brazil.
authors: Luiz Paulo
authors: LP
authors: Kowalski
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil.
authors: Edgard
authors: E
authors: Graner
authors: Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil.
authors: Ricardo D
authors: RD
authors: Coletta
mesh_terms: D028341:Activins / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002470:Cell Survival; D030541:Databases, Genetic; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D009061:Mouth Mucosa / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D005810:Multigene Family; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015996:Survival Rate
chemical_list: C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; C422405:activin A; D028341:Activins