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.

Salivary adenoid cystic carcinoma (SACC) is one of the most common subtypes of salivary gland carcinomas and frequently metastasizes to distant organs. However, little is known about the molecular mechanisms that promote SACC metastasis. In this study, we report that transforming growth factor (TGF)-β1 was highly expressed in the highly metastatic SACC-LM cell line as compared with its parental low-metastatic SACC-83 cell line. Exogenous addition of TGF-β1 induced Smad2 phosphorylation and promoted the migration and invasion of SACC-83 cells. Consistently, the inhibition of endogenous TGF-β1 signaling in SACC-LM cells by an inhibitor specific to the type I TGF-β1 receptor (TβRI) suppressed cell migration and invasion. Moreover, we found that TGF-β1 expression was significantly increased in human primary SACC samples with metastasis. Taken together, our results suggest that TGF-β1 may play a crucial role in SACC metastasis.

The incidence of recurrent t(6;9) translocation of the MYB proto‑oncogene to NFIB (the gene that encodes nuclear factor 1 B‑type) in adenoid cystic carcinoma (ACC) tumour tissues is high. However, MYB [the gene that encodes transcriptional activator Myb (MYB)] overexpression is more common, indicating that MYB serves a key role in ACC. The current study aimed to investigate the role of MYB in salivary (S)ACC growth and metastasis. A total of 50 fresh‑frozen SACC tissues and 41 fresh‑frozen normal submandibular gland (SMG) tissues were collected to measure MYB mRNA expression, and to analyse the associations between MYB and epithelial‑mesenchymal transition (EMT) markers. Compared with normal SMG tissue, SACC tissues demonstrated significantly increased MYB expression, with a high expression rate of 90%. Interestingly, MYB tended to be negatively correlated with CDH1 [the gene that encodes cadherin‑1 (E‑cadherin)] and positively correlated with VIM (the gene that encodes vimentin), suggesting that MYB is associated with SACC metastasis. To explore the role of MYB in SACC, the authors stably overexpressed and knocked down MYB in SACC cells. The authors of the current study demonstrated that MYB overexpression promoted SACC cell proliferation, migration and invasion, whereas its knockdown inhibited these activities. Additionally, when MYB was overexpressed, CDH1 expression was downregulated, and CDH2 (the gene that encodes cadherin‑2), VIM and ACTA2 (the gene that encodes actin, aortic smooth muscle) expression was upregulated. Then, the effect of MYB on lung tumour metastasis was investigated in vivo in non‑obese diabetic/severe combined immunodeficiency mice. MYB overexpressing and control cells were injected into the mice through the tail vein. The results revealed that MYB promoted SACC lung metastasis. Collectively, these results demonstrated that MYB is aberrantly overexpressed in SACC tissues, and promotes SACC cell proliferation and metastasis, indicating that MYB may be a novel therapeutic target for SACC.

Objectives: To evaluate the effect of stem cells from exfoliated deciduous teeth on the hyposalivation caused by Sjögren syndrome (SS) and investigate the mechanism.Methods: Stem cells were injected into the tail veins of non‐obese diabetic mice, the animal model of SS. The saliva flow was measured after pilocarpine intraperitoneal injection. Apoptosis and autophagy were evaluated by TUNEL and Western blot. Lymphocyte proportions were detected by flow cytometer.Results: Fluid secretion was decreased in 21‐week‐old mice. Stem cell treatment increased fluid secretion, alleviated inflammation in the submandibular glands and reduced inflammatory cytokine levels in the serum, submandibular glands and saliva. Stem cells decreased the apoptotic cell number and the expressions of ATG5 and Beclin‐1 in the submandibular glands. Stem cells have no effect on other organs. Furthermore, the infused stem cells migrated to the spleen and liver, not the submandibular gland. Stem cells directed T cells towards Treg cells and suppressed Th1 and Tfh cells in spleen lymphocytes.Conclusion: Stem cells from exfoliated deciduous teeth alleviate the hyposalivation caused by SS via decreasing the inflammatory cytokines, regulating the inflammatory microenvironment and decreasing the apoptosis and autophagy. The stem cells regulated in T‐cell differentiation are involved in the immunomodulatory effects.

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.

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.