Abstract
BackgroundMicrotubule-associated tumor suppressor gene (MTUS1) has been identified as tumor suppressor gene in many malignant tumors. In this study, we investigated the role of MTUS1 in the development of salivary adenoid cystic carcinoma (SACC) and its functional effect on the migration and invasion of SACC.MethodsArchival clinical samples including 49 primary SACC were examined for MTUS1 expression by immunohistochemistry. Statistical analyses were performed to evaluate the correlation between MTUS1 with histopathological features and survival. The expression of MTUS1/ATIP (AT2 receptor-interacting protein) isoforms was determined in SACC tissue samples and cell lines using quantitative RT-PCR assays. Then we investigated whether the migration and invasion of SACC were mediated by MTUS1/ATIP3a using in vitro cell migration and invasion assay.ResultsWe confirmed that the down-regulation of MTUS1 was a frequent event in SACC, and was correlated with distant metastasis and associated with reduced overall survival and disease free survival. Isoform specific quantitative RT-PCR assays revealed that ATIP1, ATIP3a and ATIP3b were the major isoforms of the MTUS1 gene products in SACC, and were significant down-regulation in SACC as compared to matching normal tissues. For functional analyses, we found that SACC-LM cells (SACC cell line with higher migration and invasion ability) possessed a lower expression level of ATIP3a compared to SACC-83 cells (lower migration and invasion ability). Restoration of ATIP3a expression in SACC-LM cells induced anti-proliferative activity and inhibited the migration and invasion ability. Knockdown of ATIP3a promoted the proliferation, migration and invasion ability of SACC-83 cells. Restoration of ATIP3a inhibited the phosphorylation of ERK (extracellular-regulated kinase) 1/2, the expression of Slug and Vimentin in SACC-LM cells, while knockdown of ATIP3a increased the phosphorylation of ERK1/2, the expression of Slug and Vimentin in SACC-83 cells.ConclusionsOur studies confirm that MTUS1 plays an important role in the progression of SACC, and may serve as a biomarker or therapeutic target for patients with SACC. MTUS1/ATIP3a down-regulation contributes to the proliferation, migration and the invasion abilities of SACC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1209-x) contains supplementary material, which is available to authorized users.
Highlights
Microtubule-associated tumor suppressor gene (MTUS1) has been identified as tumor suppressor gene in many malignant tumors
We found that Mitochondrial tumor suppressor 1 (MTUS1) down-regulation is associated with poor prognosis in salivary adenoid cystic carcinoma (SACC); MTUS1/ATIP3a downregulation contributes to the proliferation, migration and the invasion abilities of SACC, which involved extracellular signal-regulated kinase 1/2 (ERK1/2)-Snail homolog 2 (Slug) signaling
MTUS1/AT2 receptor-interacting protein (ATIP) down-regulation in the development and prognosis of SACC To elucidate the role of MTUS1/ATIP in the development of SACC, the expression of the MTUS1/ATIP gene was examined by IHC
Summary
Microtubule-associated tumor suppressor gene (MTUS1) has been identified as tumor suppressor gene in many malignant tumors. We investigated the role of MTUS1 in the development of salivary adenoid cystic carcinoma (SACC) and its functional effect on the migration and invasion of SACC. Salivary adenoid cystic carcinoma (SACC) has unique characteristics, such as perineural and perivascular invasion and distant metastasis [1]. Clinical investigations have shown that SACC has a higher incidence of distant metastasis at an early stage, ranging from 35% to 50%. A number of growth factors, including vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and epidermal growth factor (EGF) have been found to stimulate invasion of SACC cells [3,4]. Other signaling molecules have been implicated in the metastasis of SACC, including mitogen-activated protein kinase 1/2 (MAPK1/2) and snail homolog 2 (Snail, a.k.a., Slug) [5,6]. Substantial progress has been made in defining the genes that contribute to the initiation and
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