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Salivary adenoid cystic carcinoma (SACC) exhibits slow continuous growth, frequent local recurrences and a high incidence of blood metastasis, with advanced lung metastasis frequently occurring and being among the primary causes of mortality. MicroRNAs (miR) serve a significant role in the initiation and development of cancer and may be tumour‑specific molecular targets. However, the role of miR‑103a‑3p in SACC remains largely unknown. In the present study, the expression levels of miR‑103a‑3p and tumour protein D52 (TPD52) were detected by reverse transcription‑quantitative PCR. In addition, wound‑healing assays, Transwell assays and mouse models of lung metastasis were used to investigate the biological functions exerted by miR‑103a‑3p. The present results suggested that miR‑103a‑3p expression was significantly upregulated in SACC samples. Gain‑of‑function and loss‑of‑function studies in SACC cells demonstrated that miR‑103a‑3p acted as an oncogene by promoting tumour cell migration in vitro and lung metastasis in vivo. Dual‑luciferase reporter gene assays indicated that miR‑103a‑3p exerted its regulatory functions by binding to the 3' untranslated region of TPD52 mRNA. TPD52 overexpression rescued the effect of miR‑103a‑3p on promoting SACC cell migration, suggesting that miR‑103a‑3p acted as an oncogene to promote cancer metastasis by directly targeting TPD52. Thus, the newly identified miR‑103a‑3p/TPD52 axis contributes to the understanding of SACC pathogenesis, providing insights into the identification of novel biomarkers or potential therapeutic targets in SACC.

Salivary adenoid cystic carcinoma (SACC) is a peculiar malignant tumor, characterized by its slow but inexorable growth, with a high incidence of lung metastasis and poor prognosis. Here, we show the upregulated expression of EGFR ligand epiregulin in a subset of SACC cells correlates with lung metastasis and unfavorable outcome in patients with SACC. We found that upregulation of epiregulin in SACC cells induced epithelial-mesenchymal transition by regulating GLI1/E-cadherin. Elevated epiregulin increased the expression of pro-angiogenic factors, such as VEGFA, bFGF, and IL-8. We also show that epiregulin can be delivered via exosomes and was enriched in exosomes derived from epiregulin-overexpressing SACC cells. Furthermore, treating immunodeficient mice with these epiregulin-enriched exosomes greatly enhanced SACC metastasis to lung. These epiregulin-enriched exosomes significantly enhanced angiogenesis in the neighboring tumor microenvironment and increased vascular permeability in the pre-metastatic lung microenvironment in vivo . Therefore, epiregulin, as well as epiregulin-containing exosomes, may be a novel target for controlling SACC lung metastasis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Salivary adenoid cystic carcinoma is an epithelial tumor in the head and neck region. Despite its slow growth, patients with salivary adenoid cystic carcinoma exhibit poor long term survival because of a high rate of distant metastasis. Lung and bone are common distant metastasis sites. Zoledronic acid, a third generation bisphosphonate, has been used for tumor-induced osteolysis due to bone metastasis and has direct antitumor activity in several human neoplasms. Here, we observed that zoledronic acid inhibited salivary adenoid cystic carcinoma cell line SACC-83 xenograft tumor growth in nude mice. In vitro, zoledronic acid induced apoptosis and reduced clonogenic survival in SACC-83. Flow cytometry and western blotting indicated that the cell cycle was arrested at G0/G1. Zoledronic acid treatment upregulated reactive oxygen species as well as the autophagy marker protein LC-3B. Reactive oxygen species scavenger N-acetylcysteine and autophagy antagonist 3-methyladenine decreased zoledronic acid-induced apoptosis and increased clonogenic survival. Silencing of the autophagy related gene Beclin-1 also decreased zoledronic acid-induced apoptosis and inhibition of clonogenic formation. In addition, isobolographic analysis revealed synergistic effects on apoptosis when zoledronic acid and paclitaxel/cisplatin were combined. Taken together, our results suggest that zoledronic acid induced apoptosis and reduced clonogenic survival via upregulation of reactive oxygen species and autophagy in the SACC-83 cell line. Thus, zoledronic acid should be considered a promising drug for the treatment of salivary adenoid cystic carcinoma.

Objectives: Adenoid cystic carcinoma (ACC) is one of the most common malignancies of salivary glands, characterized by poor prognosis, particularly due to pulmonary metastasis. We previously reported that transforming growth factor (TGF)-β1 promoted ACC cell migration and invasion via the Smad pathway in vitro. The aim of this study was to establish the underlying mechanisms., Materials and Methods: TGF-β1, phospho-Smad2 and β-catenin expression in ACC tissues derived from patients was evaluated by immunohistochemistry. The role of TGF- β1 on the invasive capacity of ACC cells was determined by transwell assays in SACC-83 cells transfected with TGF-β1 and TGF-β type II dominant-negative receptor (TβRIIDN) plasmids or silenced by TGF-β1 siRNA. Expression of the epithelial-mesenchymal transition (EMT) markers, β-catenin, E-cadherin and Nectin-1, was determined by real-time PCR and immunochemistry. In vivo investigations were performed by inoculating nude mice with the transfected ACC cells and examining metastasis in bilateral lung tissues by immunohistochemistry., Results: Overexpression of TGF-β1 and phospho-Smad2, and reduced expression of membrane β-catenin, were closely associated with lung metastasis in ACC. Furthermore, the EMT markers were downregulated. In vitro, cells transfected with TGF-β1 exhibited altered morphology and increased invasive capacity compared to TβRIIDN-transfected cells or TGF-β1 siRNA silenced cells. In vivo, mice inoculated with TGF-β1 transfected ACC cells exhibited more metastases than other cells., Conclusion: TGF-β1, phospho-Smad2 and β-catenin were significantly correlated with ACC metastasis. Blockade of TGF-β signaling by TβRIIDN or siRNA may offer potential gene therapies against pulmonary metastasis in patients with ACC., (Copyright © 2013 Elsevier Ltd. All rights reserved.)