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.
Highlights
Oral cavity cancers represent 6% of all diagnosed cancers worldwide, and oral squamous cell carcinoma (OSCC) is the most frequent, accounting for 90% of all cases at this site [1]
Comparison across microarray gene expression studies showed that INHBA mRNA is significantly overexpressed in OSCC samples compared with normal oral mucosa (p = 0.0005)
Our interest in activin A is based on our recent studies demonstrating that OSCC cell proliferation is increased in response to high levels of activin A released by carcinoma-associated fibroblasts (CAFs) present in the tumor microenvironment [7], and that expression of activin A by OSCC cells can be useful for prognostication of OSCC of the tongue, revealing patients with occult lymph node metastasis and lower doi:10.1371/journal.pone.0136599.g007
Summary
Oral cavity cancers represent 6% of all diagnosed cancers worldwide, and oral squamous cell carcinoma (OSCC) is the most frequent, accounting for 90% of all cases at this site [1]. Despite continued improvements in the therapeutic strategies, mortality rates of OSCC continue to be high, giving rise to an overall 5-year survival rate of approximately 50% [1]. This low survival rate is due to an association of factors, including diagnosis at advanced-disease stage, high recurrence rates and our incomplete understanding of the molecular mechanisms responsible for oral tumorigenesis. 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 provide an important impact on patient survival. Overexpression of activin A in OSCCs was associated with increased regional lymph node metastasis and lower patient survival [8]
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