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WIP1 stimulates migration and invasion of salivary adenoid cystic carcinoma by inducing MMP-9 and VEGF-C.

ABSTRACT: The wild-type p53 induced phosphatase 1 (WIP1) is an oncogene overexpressed in a variety of human cancers. Here, we demonstrated that WIP1 silencing reduced MMP-9 and VEGF-C expression as well as migration and invasion of salivary adenoid cystic carcinoma (ACC) cells. Overexpression of MMP-9 or VEGF-C restored migration and invasion in WIP1 knockdown cells, indicating that MMP-9 and VEGF-C are downstream targets of WIP1 signaling. Levels of cyclin D1 and c-Myc, targets of Wnt/?-catenin pathway, were significantly decreased by WIP1 silencing. In addition, WIP1 expression was positively associated with metastasis and prognosis of ACC patients as well as with MMP-9 or VEGF-C in ACC tissues.

SUBMITTER: Tang YL

PROVIDER: S-EPMC4496200 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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WIP1 stimulates migration and invasion of salivary adenoid cystic carcinoma by inducing MMP-9 and VEGF-C.

Tang Ya-ling YL Liu Xin X Gao Shi-yu SY Feng Hao H Jiang Ya-ping YP Wang Sha-sha SS Yang Jing J Jiang Jian J Ma Xiang-rui XR Tang Ya-jie YJ Chen Yu Y Liang Xin-hua XH

Oncotarget 20150401 11

The wild-type p53 induced phosphatase 1 (WIP1) is an oncogene overexpressed in a variety of human cancers. Here, we demonstrated that WIP1 silencing reduced MMP-9 and VEGF-C expression as well as migration and invasion of salivary adenoid cystic carcinoma (ACC) cells. Overexpression of MMP-9 or VEGF-C restored migration and invasion in WIP1 knockdown cells, indicating that MMP-9 and VEGF-C are downstream targets of WIP1 signaling. Levels of cyclin D1 and c-Myc, targets of Wnt/β-catenin pathway, ...[more]

PMID: 25797250

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CD133+ cancer stem-like cells promote migration and invasion of salivary adenoid cystic carcinoma by inducing vasculogenic mimicry formation.

Project description:Cancer stem cells (CSCs) have gained much attention due to their roles in the invasion and metastasis of numerous kinds of human cancers. Here, we showed that the positive expression of CD133, the stemness marker, was positively associated with vasculogenic mimicry (VM) formation, local regional recurrence, distant metastasis and poorer prognosis in salivary adenoid cystic carcinoma (ACC) specimens. Compared with CD133- ACC cells, CD133+ cancer stem-like cells had more migration and invasion capabilities, as well as more VM formation. The levels of endothelial cell marker VE-cadherin, MMP-2 and MMP-9 expression in CD133+ cancer stem-like cells and xenograft tumors of nude mice injected with CD133+ cells were significantly higher than those with CD133- cells. The data indicated that CD133+ cancer stem-like cells might contribute to the migration and invasion of ACC through inducing VM formation.

| S-EPMC5045377 | biostudies-literature

SOD2 deregulation enhances migration, invasion and has poor prognosis in salivary adenoid cystic carcinoma.

Project description:This study aimed to investigate the role of SOD2 in the progression and metastasis of salivary adenoid cystic carcinoma (SACC). We analyzed the expression of SOD2 in 50 SACC patients. Then, the effects and mechanism of SOD2 on cell metastasis in a pair of different metastatic potential cell lines was investigated. SOD2 was deregulated in patients with SACC. Up-regulation of SOD2 was associated with distant metastasis and reduced overall survival and disease free - survival. Compared to SACC-83 cells (lower metastasis ability), SACC-LM cells (higher metastasis ability) had higher SOD2 activity and intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug, but had similar catalase protein level and activity. In SACC-LM, reducing the expression of SOD2 by SiRNA inhibited the metastasis ability and reduced the SOD2 activities, intracellular H2O2 concentrations, and protein levels of pERK1/2 and Slug. These effects were revised in SACC-83 after SOD2 overexpression. Moreover, in SACC-83, treated with H2O2, the metastasis was enhanced accompanied by increased protein levels of pERK1/2 and Slug. We confirmed that SOD2 play an important role in the development and prognosis of SACC and SOD2-dependent production of H2O2 contributes to metastasis of SACC through the ERK-Slug signaling pathway.

| S-EPMC4867643 | biostudies-literature

PRL-3 promotes migration and invasion and is associated with poor prognosis in salivary adenoid cystic carcinoma.

Project description:BackgroundPRL-3 had been found to be involved in tumorigenesis in various malignancies. In this study, we investigated the role of PRL-3 in the development, migration, and invasion of salivary adenoid cystic carcinoma (SACC).MethodsImmunohistochemistry (IHC) was used to analyze the role of PRL-3 in the development and prognosis of SACC. Then, we overexpressed or inhibited the expression of PRL-3 in paired SACC cells to analyze the role of PRL-3 in the migration and invasion of SACC. In vitro migration and invasion assays were used. Western blotting was used to detect metastasis-related protein levels.ResultsIHC results confirmed that the deregulation of PRL-3 was a frequent event in SACC; the upregulation of PRL-3 was related to clinical stages, vital status, and distant metastasis, which was associated with reduced overall survival and disease-free survival. SACC-LM cells with higher migratory and invasive abilities had more robust PRL-3 protein expression than SACC-83 cells with lower migratory and invasive abilities. PRL-3 overexpression promoted cell migration, invasion, and proliferation, led to simultaneous upregulation of phosphorylated PRL-3, pERK1/2, Slug, vimentin, and downregulation of E-cadherin in SACC-83 cells. However, the inhibition of PRL-3 by PRL-3 inhibitor or PRL-3 siRNA in SACC-LM cells inhibited cell migration, invasion, and proliferation, resulted in simultaneous downregulation of phosphorylated PRL-3, pERK1/2, Slug, vimentin, and upregulation of E-cadherin.ConclusionsOur results confirm that PRL-3 plays an important role in the development of SACC and contributes to the migratory and invasive abilities of SACC.

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Overexpression Cathepsin D Contributes to Perineural Invasion of Salivary Adenoid Cystic Carcinoma.

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| S-EPMC6220369 | biostudies-literature

Inhibition of STAT3 reduces proliferation and invasion in salivary gland adenoid cystic carcinoma.

Project description:In this study, we accessed the expression and correlation of p-STAT3 with Survivin, Cyclin D1, CD147, Slug and Ki67 by immunohistochemical staining of human tissue microarray which contains 72 adenoid cystic carcinoma (AdCC), 12 pleomorphic adenoma (PMA) and 18 normal salivary gland (NSG) using digital pathological scanner and scoring system. We found that the expression of p-STAT3, Survivin, Slug, Cyclin D1 and CD147 was significantly increased in AdCC as compared with PMA and (or) NSG (p<0.05). While, the level of p-STAT3 and expression of Cyclin D1 and CD147 was not associated with pathological type of human AdCC (p>0.05). Correlation analysis of these proteins revealed that p-STAT3 up-regulates the expression of Survivin, Slug, Cyclin D1 and CD147 (p<0.05). Moreover, the activation of STAT3 was associated with proliferation marker Ki-67 (p<0.05). Selective inhibition of STAT3 by a small molecule S3I-201 significantly reduced human SACC-83 and SACC-LM cells proliferation, migration and invasion with the corresponding decrease in expression of Survivin, Slug, Cyclin D1 and CD147. These findings indicate that high phosphorylation level of STAT3 in AdCC is related to Survivin, Slug, Cyclin D1 and CD147. We suggest that the inhibition of STAT3 may be a novel strategy for neoadjuvant chemotherapeutic treatment of AdCC.

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CXCR5 induces perineural invasion of salivary adenoid cystic carcinoma by inhibiting microRNA-187.

Project description:CXCR5 played critical roles in tumorigenesis and metastasis. Nevertheless, little was known about the involvement of CXCR5 in perineural invasion (PNI) of salivary adenoid cystic carcinoma (SACC). Here, we confirmed upregulation of CXCR5 in SACC specimens and cells and identified that CXCR5 exhibited a significant positive correlation with PNI. Functionally, knockdown of CXCR5 suppressed SACC cells migration, invasion and PNI ability, whereas CXCR5 overexpression displayed the opposite effects. Moreover, CXCR5 downregulated microRNA (miR)-187, which could competitively sponge S100A4. The PNI-inhibitory effect of CXCR5 knockdown or miR-187 overexpression could be reversed by elevated expression of S100A4. Conjointly, our data revealed that CXCR5 facilitated PNI through downregulating miR-187 to disinhibit S100A4 expression in SACC.

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Cathepsin B defines leader cells during the collective invasion of salivary adenoid cystic carcinoma.

Project description:Cathepsin B (CTSB) has been reported to be involved in cancer metastasis by altering extracellular matrix (ECM) remodeling and facilitating invasion. However, the contribution of CTSB to collective cell invasion in salivary adenoid cystic carcinoma (SACC) and the underlying mechanisms remain unclear. The present study demonstrated that collective cell invasion is commonly observed in SACC without a complete epithelial‑mesenchymal transition signature. CTSB was found to be overexpressed in the invasive front of SACC compared to the tumor center, and was associated with a poor prognosis of patients with SACC. Subsequently, a 3D spheroid invasion assay was established in order to recapitulate the collective cell invasion of SACC and the results revealed that CTSB was only expressed in leader cells. The knockdown of CTSB by siRNA inhibited the migration and invasion of SACC‑83 cells and impaired the formation of leader cells. CTSB knockdown also disrupted cytoskeletal organization, altered cell morphology and inhibited ECM remodeling by downregulating matrix metalloproteinase‑9, focal adhesion kinase and Rho/ROCK function. Therefore, the present study provides evidence that CTSB may define leader cells in SACC and is required for collective cell invasion as a potential key regulator of ECM remodeling.

| S-EPMC6411368 | biostudies-literature

Interactive role of miR-29, miR-93, miR-205, and VEGF in salivary adenoid cystic carcinoma.

Project description:ObjectivesSalivary adenoid cystic carcinoma (SACC) is one of the most common salivary gland tumors in which patients encounter local recurrence and lung metastases. Understanding prognostic biomarkers in SACC is essential for future development in prognosis and treatment. This study aimed to assess the expression level of vascular endothelial growth factor (VEGF) and its potential regulatory microRNAs in SACC for prognostic determination. MATERIAL AND METHODS: The expression of VEGF in SACC samples was assessed using immunohistochemistry. Potential regulatory microRNAs were evaluated using quantitative reverse transcription-polymerase chain reaction. Associations between VEGF and microRNAs expression and clinicopathological parameters were investigated.ResultsVEGF expression levels positively correlated with histologic grade (p = .004) and treatment modality (p = .04). Decreased expression of miR-29a (p = .01) and increased expression of miR-93-5p and miR-205 (both p < .0001) were observed in SACC compared to normal salivary gland tissue. MiR-93-5p showed a positive association (p = .02) with VEGF overexpression.ConclusionsOur results showed the downregulation of miR-29 and overexpression of miR-93 and miR-205 in the SACC group, and the correlation between miR-93 and VEGF suggests these biomarkers as potential prognostic markers in the future.

| S-EPMC9932236 | biostudies-literature

Notch-1 knockdown suppresses proliferation, migration and metastasis of salivary adenoid cystic carcinoma cells.

Project description:BackgroundNotch-1 promotes invasion and metastasis of cancer cells but its role in salivary adenoid cystic carcinoma (SACC) remains unelucidated. Here, we sought to investigate the effect of Notch-1 knockdown on the invasion and metastasis of SACC cells.MethodsStable ACC-M cells whose Notch-1 was silenced by lentiviral vectors were established. Cellular proliferation was evaluated by the MTT assays and clonogenic assays, apoptosis by flow cytometry and the migration of ACC-M cells by Transwell assays. Metastasis was evaluated by examining the number of lung nodules in Balb⁄c nu⁄nu nude mice bearing subcutaneous SACC xenografts.ResultsOur MTT assay revealed that Notch-1 knockdown significantly suppressed the proliferation of ACC-M cells compared with non-infected or scrambled control cells. Clonogenic assays further showed that Notch-1 knockdown significantly suppressed the clonogenic growth of ACC-M cells (p < 0.01 vs. controls). Our flow cytometry demonstrated that Notch-1 knockdown was associated with a significantly higher proportion of late apoptotic and necrotic cells (p < 0.01 vs. controls). Transwell assays revealed that Notch-1 knockdown markedly reduced the migratory capacity of ACC-M cells (p < 0.01 vs. controls) and xenograft studies showed that the number of metastatic nodules in the lung surface was significantly lower in nude mice bearing xenografts with Notch-1 knockdown compared to those bearing control xenografts (p < 0.01 vs. controls).ConclusionNotch-1 knockdown suppresses the growth and migration of SACC cells in vitro and the metastasis of SACC cells in vivo. Notch-1 may be a new candidate target in SACC.

| S-EPMC4445799 | biostudies-literature

AGR2 promotes the proliferation, migration and regulates epithelial-mesenchymal transition in salivary adenoid cystic carcinoma.

Project description:Salivary adenoid cystic carcinoma (AdCC) is a common head and neck cancer with the propensity for local spread and distant metastasis. In our previous study, elevated expression of Anterior gradient 2 (AGR2) was detected in head and neck squamous cell carcinoma (HNSCC), associated with epithelial-mesenchymal transition (EMT) and cancer stemness. However, to date, the expression and function of AGR2 in AdCC has yet to be elucidated. In the present study, human AdCC tissue microarrays including 18 cases of normal salivary gland (NSG), 12 cases of pleomorphic adenoma (PMA) and 72 cases of AdCC were employed for immunohistochemical staining analysis. Results indicated that AGR2, which was remarkably correlated with Ki-67, transforming growth factor beta-1 (TGF-β1) and CD147, was significantly elevated in human salivary AdCC tissues. Knockdown of AGR2 significantly repressed the proliferation and migration of human SACC-83 and SACC-LM cell lines. Additionally, AGR2 silencing obviously reversed the EMT phenomena induced by TGF-β1. Taken together, our present study revealed the potential pro-metastasis role of AGR2 in AdCC, indicating that AGR2 might be a novel therapeutic target of AdCC with distant metastasis.

| S-EPMC5340686 | biostudies-literature

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