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

• Published in: PloS one Vol. 10; no. 8; p. e0136599
• Main Authors: Bufalino, Andreia, Cervigne, Nilva K., de Oliveira, Carine Ervolino, Fonseca, Felipe Paiva, Rodrigues, Priscila Campioni, Macedo, Carolina Carneiro Soares, Sobral, Lays Martin, Miguel, Marcia Costa, Lopes, Marcio Ajudarte, Leme, Adriana Franco Paes, Lambert, Daniel W., Salo, Tuula A., Kowalski, Luiz Paulo, Graner, Edgard, Coletta, Ricardo D.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.08.2015; Public Library of Science (PLoS)
• Subjects: Activin; Activins; Activins - biosynthesis; Activins - genetics; Adhesion tests; Adult; Aged; Apoptosis; Apoptosis - genetics; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - pathology; Cell growth; Cell proliferation; Cell Survival; Clusters; Databases, Genetic; Dentistry; Deregulation; Development and progression; Disease-Free Survival; Down-Regulation; Female; Follistatin; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic transformation; Growth factors; Humans; Immunohistochemistry; Invasiveness; Lymph nodes; Lymphatic Metastasis; Lymphatic system; Male; Medical prognosis; Mesenchyme; Metastases; Metastasis; MicroRNA; MicroRNAs; MicroRNAs - biosynthesis; MicroRNAs - genetics; Middle Aged; miRNA; Mouth Mucosa - metabolism; Mouth Mucosa - pathology; Mouth Neoplasms - genetics; Mouth Neoplasms - metabolism; Mouth Neoplasms - mortality; Mouth Neoplasms - pathology; Mucosa; Multigene Family; Neoplasm Invasiveness; Neoplasm Proteins - biosynthesis; Oral cancer; Oral carcinoma; Oral squamous cell carcinoma; Otolaryngology; Phenotypes; Physiological aspects; Prostate cancer; Ribonucleic acid; RNA; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Squamous cell carcinoma; Stem cells; Survival; Survival Rate; Transformation; Tumorigenesis; Tumors; Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0136599

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.