our incomplete understanding of the molecular mechanisms responsible for oral tumorigenesis. Thus, elucidating the cellular and molecular mechanisms behind OSCC is mandatory for a better understanding of the genetic events associated with OSCC progression and to develop novel and individualized therapeutic approaches to this disease, which should ultimately provide an important impact on patient survival. Activin A, the homodimeric protein encoded by the INHBA gene, is a multifunctional member of the transforming growth factor family with important roles in cell growth, differentiation and apoptosis in events related to angiogenesis, inflammation, immunity and embryogenesis. As a result, defects in its expression have been linked to uncontrolled proliferation and survival, leading to cancer development and progression. Although deregulated expression of activin A has been broadly reported in a variety of cancers, its role in OSCCs is not yet well understood. In 
a recent study our group demonstrated that immunodetection of activin A correlates with occult lymph node metastasis in patients with early OSCCs of the tongue and that its expression is an independent marker of patient outcome, supporting a role of activin A as a prognostic marker of OSCCs. Additionally, we showed that carcinoma-associated fibroblasts promote tumorigenesis of OSCC cell lines via secretion of activin A. Furthermore, overexpression of activin A in OSCCs was associated with increased regional lymph node metastasis and lower patient survival. In this study we confirm the prognostic significance of activin A overexpression in OSCCs and examine the molecular mechanism by which activin A influences oral tumorigenesis. We show that activin A overexpression in OSCCs is significantly correlated with regional Digitoxin custom synthesis PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19731037 lymph node metastasis and poorly differentiated tumors, and patients with high expression of activin A show shortened survival. In vitro PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19730426 analysis revealed that activin A blocks apoptosis whereas it controls proliferation via regulation of p16, p21 and p27. Our data also demonstrate that activin A promotes motility and invasiveness of OSCC cells, as well as epithelial-mesenchymal transition, as revealed by modulation of the expression of EMT markers E-cadherin, Ncadherin and vimentin. Finally, we showed that expression of the miR-143/miR-145 cluster is inversely correlated with INHBA levels in OSCC cell lines and specimens, and overexpression of those microRNAs downregulated INHBA mRNA. Materials and Methods INHBA mRNA levels in previously published microarrays To examine the expression pattern of INHBA in published microarray data, we performed a metanalysis using data mining from the Oncomine Research Premium Edition database. The first step was to identify previously published microarray gene expression data comparing normal oral mucosa and OSCC. Filters for selection of the data were studies that included INHBA in the analysis, comparing cancer vs normal tissue, cancer type and primary tumor sites in the oral cavity. After applying those filters, we ended up with 9 datasets from published studies. The expression level was considered the median rank for the gene across each of the analysis, and the given p-value was based in the median-ranked analysis at a cut off 0.01. 2 / 22 Activin A Overexpression in Oral Cancer Samples and clinicopathological data To confirm the overexpression of activin A in OSCCs, fresh samples of OSCC and normal oral mucosa were used to inve
