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1.  Expression of RECK and MMP-2 in salivary adenoid cystic carcinoma: Correlation with tumor progression and patient prognosis 
Oncology Letters  2014;7(5):1549-1555.
Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol-anchored glycoprotein, inhibits the enzymatic activities of certain matrix metalloproteinases (MMPs). RECK has been studied in numerous human tumors, but the expression of RECK in salivary adenoid cystic carcinoma (SACC), and its correlation with patient prognosis, has never been investigated thus far. In the present study, the expression of RECK and MMP-2 was evaluated in two ACC cell lines and in 83 patients with SACC. The results of quantitative polymerase chain reaction and western blot analysis revealed that the ACC-2 and ACC-M cell lines expressed RECK and MMP-2 mRNA and protein. The immunohistochemical staining in the patients demonstrated that positive expression of RECK and MMP-2 was observed in 21/83 (25.3%) and 69/83 (83.1%) cases, respectively, and that RECK expression was significantly associated with the tumor-node-metastasis stage, histological grade and perineural invasion of patients with SACC (P<0.05). Furthermore, there was a significant association between the positive expression of RECK and that of MMP-2 (P<0.0001). Univariate and multivariate analyses confirmed that a lack of RECK expression was an independent and significant factor for the prediction of a poor prognosis. In conclusion, RECK is a promising prognostic marker and potential therapeutic agent in SACC.
PMCID: PMC3997680  PMID: 24765174
adenoid cystic carcinoma; RECK; MMP-2; prognosis
2.  Morphological heterogeneity of oral salivary gland carcinomas: A clinicopathologic study of 41 cases with long term follow-up emphasizing the overlapping spectrum of adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma 
We analyzed 41 oral salivary gland carcinomas from consecutive 290 salivary gland carcinoma database (14%) with emphasis on the histological spectrum and clinical outcome of adenoid cystic carcinoma (ACC) and polymorphous low-grade adenocarcinoma (PLGA). The cohort included 14 ACCs, 14 mucoepidermoid carcinomas (MECs), 8 PLGAs, 3 adenocarcinomas, not otherwise specified and 2 acinic cell carcinomas. Mean age was 48, 58 and 61 yrs for ACC, MEC and PLGA, respectively. Eight patients (19.5%) died of tumor at a mean interval of 66.5 months. ACC and PLGA showed similar mean age, gender distribution, predominant palatal localization, nodal metastasis, perineural invasion and MIB-1 index. However, ACC tended to show higher tumor stage and residual tumor (R1/R2) more frequently than PLGA, but this was statistically not significant. ACC and PLGA showed overlapping architectural patterns. However, ACCs displayed well organized basal-luminal differentiation, highlighted by CK5/CK7 immunostaining. In contrast, PLGA showed a disorganized histological and immunohistological pattern. C-Kit expression (CD117) was common in ACC, generally mirroring that of CK7 and virtually lacking in PLGA. Kaplan-Meier analysis demonstrated a similar clinical course for ACC and PLGA with 5 years survivals of 87% and 80%, respectively. Fluorescence in situ hybridization (FISH) performed on all 290 salivary carcinomas confirmed the specificity of the translocation t (11; 19) for MEC and its absence in all other carcinomas including ACC and PLGA. Our results emphasize the diversity of oral salivary gland carcinomas and the overlapping clinicopathological features of ACC and PLGA.
PMCID: PMC3093058  PMID: 21577319
Oral salivary gland carcinoma; adenoid cystic carcinoma; polymorphous low-grade adenocarcinoma; acinic cell carcinoma
3.  Identification of microRNA profiles in salivary adenoid cystic carcinoma cells during metastatic progression 
Oncology Letters  2014;7(6):2029-2034.
Salivary adenoid cystic carcinoma (SACC) is a common type of salivary gland cancer. The poor long-term prognosis of patients with SACC is primarily due to local recurrence, distant metastasis and perineural invasion. MicroRNAs (miRNAs) have been identified as important post-transcriptional regulators, which are involved in various biological processes. The aim of the present study was to identify the miRNA expression profiles that are involved in the metastatic progression of SACC. Therefore, microarray technology was employed to identify miRNA expression profiles in an SACC cell line, ACC-2, and a highly metastatic SACC cell line, ACC-M, which was screened from ACC-2 by a combination of in vivo selection and cloning in vitro. Differences in miRNA expression were assessed by quantitative polymerase chain reaction (qPCR) assay. In addition, the potential target genes that are regulated by selected miRNAs were analyzed by various target prediction tools. The microarray data revealed that the levels of 38 miRNAs significantly differed between the ACC-M cells and the control ACC-2 cells. Six miRNAs (miR-4487, -4430, -486-3p, -5191, -3131 and -211-3p) were selected to validate the microarray data via qPCR. The expression of two miRNAs (miR-4487 and -4430) was significantly upregulated in the ACC-M cells, while the expression of two other miRNAs (miR-5191 and -3131) was significantly downregulated in the ACC-M cells. The potential target genes that were identified to be controlled by the six selected miRNAs were divided into four groups according to function, as follows: Apoptosis and proliferation (46 genes), cell cycle (30 genes), DNA damage and repair (24 genes) and signaling pathway (30 genes). The identification of microRNA expression profiles in highly metastatic SACC cells may provide an improved understanding of the mechanisms involved in metastatic progression, which would aid in the development of novel strategies for the treatment of SACC.
PMCID: PMC4049696  PMID: 24932284
microRNA profile; adenoid cystic carcinoma; metastasis
4.  c-Kit Expression is Rate-Limiting for Stem Cell Factor-Mediated Disease Progression in Adenoid Cystic Carcinoma of the Salivary Glands12 
Translational Oncology  2014;7(5):537-545.
Adenoid cystic carcinoma (ACC) is an aggressive malignant neoplasm of the salivary glands in which c-Kit is overexpressed and activated, although the mechanism for this is as yet unclear. We analyzed 27 sporadic ACC tumor specimens to examine the biologic and clinical significance of c-Kit activation. Mutational analysis revealed expression of wild-type c-Kit in all, eliminating gene mutation as a cause of activation. Because stem cell factor (SCF) is c-Kit's sole ligand, we analyzed its expression in the tumor cells and their environment. Immunohistochemistry revealed its presence in c-Kit–positive tumor cells, suggesting an activation of autocrine signaling. We observed a significant induction of ERK1/2 in the cells. SCF staining was also found in other types of non-cancerous cells adjacent to tumors within salivary glands, including stromal fibroblasts, neutrophils, peripheral nerve, skeletal muscle, vascular endothelial cells, mucous acinar cells, and intercalated ducts. Quantitative PCR showed that the top quartile of c-Kit mRNA expression distinguished ACCs from normal salivary tissues and was cross-correlated with short-term poor prognosis. Expression levels of SCF and c-Kit were highly correlated in the cases with perineural invasion. These observations suggest that c-Kit is potentially activated by receptor dimerization upon stimulation by SCF in ACC, and that the highest quartile of c-Kit mRNA expression could be a predictor of poor prognosis. Our findings may support an avenue for c-Kit-targeted therapy to improve disease control in ACC patients harboring the top quartile of c-Kit mRNA expression.
PMCID: PMC4225653  PMID: 25389449
5.  High Expression of SOX2 Is Associated with Poor Prognosis in Patients with Salivary Gland Adenoid Cystic Carcinoma 
Sex determining region Y-BOX2 (SOX2), one of the key members of the SOX family, is a transcription factor that is involved in the maintenance of embryonic stem cell pluripotency and in multiple developmental processes. Recent studies have shown that SOX2 is aberrantly expressed in several types of tumors. The present study aimed to investigate the clinicopathological and prognostic significance of SOX2 in adenoid cystic carcinoma (ACC) of salivary gland. In this study, the expression of SOX2 in ACC tissues and matched adjacent non-cancerous tissues was measured by immunohistochemistry, western blot, and quantitative polymerase chain reaction. High SOX2 expression occurred in approximately 62.6% of primary ACC. In addition, high expression of SOX2 was significantly associated with T classification (p = 0.003) and distant metastasis (p = 0.002). The 5-year overall survival (OS) and disease-free survival (DFS) in patients with high SOX2 expression is poorer than those with low SOX2 expression. When adjusted by multivariate analysis, high SOX2 expression, together with distant metastasis, was an independent prognostic factor. The findings of the present study provide evidence that SOX2 represents a potential novel prognostic biomarker for ACC patients.
PMCID: PMC4057738  PMID: 24828201
sex determining region Y-BOX2; adenoid cystic carcinoma; prognosis; biomarker
6.  Recurrent prognostic factors and expression of GLUT-1, PI3K and p-Akt in adenoid cystic carcinomas of the head and neck: Clinicopathological features and biomarkers of adenoid cystic carcinoma 
Oncology Letters  2012;4(6):1234-1240.
The purpose of this study was to explore the factors associated with the recurrence of adenoid cystic carcinomas (ACCs). We examined the recurrence values of clinicopathological variables and GLUT-1, p-Akt and PI3K expression in 42 patients with ACC. Of the 42 patients, 17 developed recurrence following initial surgery. The positive rates of GLUT-1, PI3K and p-Akt protein expression in ACC were 38.1, 38.1 and 50.0%, respectively. The expression of GLUT-1, p-Akt or PI3K protein in ACC was higher than that in inflammatory lesions or benign tumors. Our study demonstrated that T stage, a positive resection margin, perineural invasion, surgery without postoperative radiotherapy and the expression of GLUT-1, PI3K and p-Akt were factors predictive of recurrence by univariate analyses. In multivariate analyses, perineural invasion, a positive resection margin and p-Akt were significant predictors of recurrence. Initial surgery is very significant in the recurrence of ACC. Overexpression of GLUT-1, PI3K and p-Akt may also play a role in its development and recurrence.
PMCID: PMC3506780  PMID: 23226799
adenoid cystic carcinomas; recurrence; immunohistochemistry; glucose transporter-1; PI3K/Akt pathway
7.  Inhibiting adenoid cystic carcinoma cells growth and metastasis by blocking the expression of ADAM 10 using RNA interference 
Adenoid cystic carcinoma is one of the most common types of salivary gland cancers. The poor long-term prognosis for patients with adenoid cystic carcinoma is mainly due to local recurrence and distant metastasis. Disintegrin and metalloprotease 10 (ADAM 10) is a transmembrane protein associated with metastasis in a number of diverse of cancers. The aim of this study was to analyze the relationship between ADAM 10 and the invasive and metastatic potentials as well as the proliferation capability of adenoid cystic carcinoma cells in vitro and in vivo.
Immunohistochemistry and Western blot analysis were applied to detect ADAM 10 expression levels in metastatic cancer tissues, corresponding primary adenoid cystic carcinoma tissues, adenoid cystic carcinoma cell lines with high metastatic potential, and adenoid cystic carcinoma cell lines with low metastatic potential. RNA interference was used to knockdown ADAM 10 expression in adenoid cystic carcinoma cell lines with high metastatic potential. Furthermore, the invasive and metastatic potentials as well as the proliferation capability of the treated cells were observed in vitro and in vivo.
It was observed that ADAM 10 was expressed at a significantly higher level in metastatic cancer tissues and in adenoid cystic carcinoma cell lines with high metastatic potential than in corresponding primary adenoid cystic carcinomas and adenoid cystic carcinoma cell lines with low metastatic potential. Additionally, silencing of ADAM 10 resulted in inhibition of cell growth and invasion in vitro as well as inhibition of cancer metastasis in an experimental murine model of lung metastases in vivo.
These studies suggested that ADAM 10 plays an important role in regulating proliferation and metastasis of adenoid cystic carcinoma cells. ADAM 10 is potentially an important therapeutic target for the prevention of tumor metastases in adenoid cystic carcinoma.
PMCID: PMC3017514  PMID: 21171968
8.  Suprabasin Is Hypomethylated and Associated with Metastasis in Salivary Adenoid Cystic Carcinoma 
PLoS ONE  2012;7(11):e48582.
Salivary gland adenoid cystic carcinoma (ACC) is a rare cancer, accounting for only 1% of all head and neck malignancies. ACC is well known for perineural invasion and distant metastasis, but its underlying molecular mechanisms of carcinogenesis are still unclear.
Principal Findings
Here, we show that a novel oncogenic candidate, suprabasin (SBSN), plays important roles in maintaining the anchorage-independent and anchorage-dependent cell proliferation in ACC by using SBSN shRNA stably transfected ACC cell line clones. SBSN is also important in maintaining the invasive/metastatic capability in ACC by Matrigel invasion assay. More interestingly, SBSN transcription is significantly upregulated by DNA demethylation induced by 5-aza-2′-deoxycytidine plus trichostatin A treatment and the DNA methylation levels of the SBSN CpG island located in the second intron were validated to be significantly hypomethylated in primary ACC samples versus normal salivary gland tissues.
Taken together, these results support SBSN as novel oncogene candidate in ACC, and the methylation changes could be a promising biomarker for ACC.
PMCID: PMC3492451  PMID: 23144906
9.  In vitro angiogenesis and expression of nuclear factor κB and VEGF in high and low metastasis cell lines of salivary gland Adenoid Cystic Carcinoma 
BMC Cancer  2007;7:95.
Adenoid cystic carcinoma is a high malignant carcinoma characterized by intensive local invasion and high incidence of distant metastasis. Although many reports have demonstrated that angiogenesis has played an important role in tumor metastasis, the relationship between metastasis characters and angiogenesis ability in high and low metastasis cell lines of Adenoid cystic carcinoma has rarely been reported. The present study aimed to compare the angiogenesis ability of ACC-M (high metastasis) and ACC-2 (low metastasis) cell lines in vitro. Furthermore, the activity of nuclear factor κappa B and the expression of vascular endothelial growth factor (VEGF) in ACC-2 and ACC-M were also detected.
Electrophoretic mobility shift assay was used to detect nuclear factor κappa B activity. Semi-quantitative RT-PCR was used to quantify the mRNA level of VEGF. Immuofluorescence double staining and semi-quantitative confocal laser scanning analysis was carried out to detect nuclear factor κappa B nuclear localization and staining intensity of VEGF. The angiogenesis ability of ACC-M and ACC-2 was compared by an in vitro three-dimensional angiogenic model assay. The vector transfection assay was performed to transfect the PCMV-IκBαM vector into ACCs cell lines expressing the phosphorylation defective IκBαM.
Nuclear factor κappa B activity and the rate of nuclear factor κappa B nuclear localization in ACC-M was significantly higher than that in ACC-2. Moreover, ACC-M exhibited higher mRNA and protein levels of vascular endothelial growth factor than ACC-2. VEGF mRNA expression was effectively decreased by inhibition of nuclear factor κappa B activity. Furthermore, ACC-M could remarkably stimulate the migration and tube formation of endothelial cells and induce The umbilical vein endothelial cells sprouting into the gel matrix.
These results implicated that ACCs cells with higher metastasis feature might present greater angiogenesis ability.
PMCID: PMC1903362  PMID: 17543095
10.  Intracranial extension of adenoid cystic carcinoma: potential involvement of EphA2 expression and epithelial-mesenchymal transition in tumor metastasis: a case report 
BMC Research Notes  2014;7:131.
Adenoid cystic carcinoma is a malignant epithelial tumor derived from salivary glands and tends to invade the surrounding structures including nervous system. We present a case of adenoid cystic carcinoma with intracranial extension and propose a novel molecular mechanism of adenoid cystic carcinoma metastasis.
Case presentation
A 29-year-old Japanese male presented with left trigeminal nerve disturbance. Neuroimaging revealed a tumor located at the right middle cranial and infratemporal fossa. The tumor was removed via a subtemporal extradural and infratemporal fossa approach and histologically diagnosed as adenoid cystic carcinoma. Radiological and operative findings confirmed a perineural spread of the tumor along the mandibular nerve. Immunohistochemical analyses of molecular consequences in this case were performed for better understanding of the biological processes associated with adenoid cystic carcinoma metastasis. First, the neoplastic cells were not immunoreactive for E-cadherin, an epithelial marker, but for vimentin, a mesenchymal marker, suggesting changes in cell phenotype from epithelial to mesenchymal states. Correspondingly, immunoreactivity of transcriptional factors, such as Slug, Twist, matrix metalloproteinase-2 and -9, which are involved in epithelial–mesenchymal transition, were observed. Second, elevated expression of EphA2 receptor, not ephrin-A1, was notable in the neoplastic cells, suggesting morphological changes reminiscent of epithelial–mesenchymal transition and ligand-independent promotion of tumor cell migration and invasion.
We report a case of adenoid cystic carcinoma with perineural spread and provide the first published evidence that EphA2 expression without ephrin-A1 and epithelial–mesenchymal transition might play important roles in adenoid cystic carcinoma progression.
PMCID: PMC3975335  PMID: 24606764
Adenoid cystic carcinoma; Migration; Invasion; Metastasis; EphA2; Epithelial-mesenchymal transition
11.  Prognostic value of expression of molecular markers in adenoid cystic cancer of the salivary glands compared with lymph node metastasis: a retrospective study 
Adenoid cystic cancer arising in the salivary glands has distinctive features such as perineural invasion, distant metastasis, and a variable prognosis. In salivary gland cancer, c-kit, EGFR, and VEGF are representative molecular markers that may predict remnant and recurrent tumors. In this study, the expression of c-kit, EGFR, and VEGF in adenoid cystic cancer was evaluated, and the relationships between the expression of these markers and the clinical findings were investigated.
The medical records of 48 patients who were treated for parotid adenoid cystic cancer from January 1990 to January 2006 were reviewed. The tumor location, size, histological subtypes, perineural invasion, the resected margin status, and lymph node metastasis were assessed. Immunohistochemical staining and semiquantitative analysis of c-kit, EGFR and VEGF were performed. The relationship between the expression of each marker and the clinicopathological factors were analyzed.
Positive c-kit immunostaining was present in 45 patients (94%), with weak positivity (+1) in 23, moderate positivity (+2) in 19 and strong positivity (+3) in three. Positive EGFR immunostaining was observed in 27 (56%), with weak positivity (+1) in 19 and moderate positivity (+2) in eight with no strong positive staining. Positive VEGF immunostaining was present in 42 patients (88%) with weak positivity (+1) in 12, moderate positivity (+2) in 17, and strong positivity (+3) in 13. Only the expression of VEGF was significantly higher in parotid gland tumors than in any other gland (P = 0.032). Marginal involvement was associated with strong VEGF expression (P = 0.02). No marker was significantly correlated with recurrence or the survival rate. Lymph node status was related to the survival rate.
The expression of c-kit, EGRF, and VEGF had no predictive value for recurrence or the prognosis of adenoid cystic cancer. Only the lymph node status was related to the prognosis.
PMCID: PMC3556129  PMID: 23231994
Salivary gland cancer; Adenoid cystic cancer; c-kit; Epithelial growth factor receptor; Vascular endothelial growth factor; Lymph node metastasis
12.  Epithelial Mesenchymal Transition Is Required for Acquisition of Anoikis Resistance and Metastatic Potential in Adenoid Cystic Carcinoma 
PLoS ONE  2012;7(12):e51549.
Human adenoid cystic carcinoma (ACC) is characterized by diffused invasion of the tumor into adjacent organs and early distant metastasis. Anoikis resistance and epithelial mesenchymal transition (EMT) are considered prerequisites for cancer cells to metastasize. Exploring the relationship between these processes and their underlying mechanism of action is a promising way to better understand ACC tumors. We initially established anoikis-resistant sublines of ACC cells; the variant cells revealed a mesenchymal phenotype through Slug-mediated EMT-like transformation and displayed enhanced metastatic potential both in vitro and in vivo. Suppression of EMT by knockdown of Slug significantly impaired anoikis resistance, migration, and invasion of the variant cells. With overexpression of Slug and Twist, we determined that induction of EMT in normal ACC cells could prevent anoikis, albeit partially. These findings strongly suggest that EMT is indispensable in anoikis resistance, at least in ACC cells. Furthermore, we found that the EGFR/PI3K/Akt pathway acts as the common regulator for EMT-like transformation and anoikis resistance, as confirmed by their specific inhibitors. Gefitinib and LY294003 restored the sensibilities of anoikis-resistant cells to anoikis and simultaneously impaired their metastatic potential. In addition, the results from our in vivo model of metastasis suggest that pretreatment with gefitinib promotes mouse survival by alleviating pulmonary metastasis. Most importantly, immunohistochemistry of human ACC specimens showed a correlation between the overexpression of Slug and EGFR staining. This study has demonstrated that Slug-mediated EMT-like transformation is required by human ACC cells to achieve anoikis resistance and their metastatic potential. Targeting the EGFR/PI3K/Akt pathway holds potential as a preventive strategy against distant metastasis of ACC.
PMCID: PMC3522696  PMID: 23272116
13.  An unusual presentation of adenoid cystic carcinoma of the minor salivary glands with cranial nerve palsy: a case study 
BMC Cancer  2007;7:157.
Adenoid Cystic Carcinoma (ACC) is a rare tumor entity and comprises about 1% of all malignant tumor of the oral and maxillofacial region. It is slow growing but a highly invasive cancer with a high recurrence rate. Intracranial ACC is even more infrequent and could be primary or secondary occurring either by direct invasion, hematogenous spread, or perineural spread. We report the first case of the 5th and 6th nerve palsy due to cavernous sinus invasion by adenoid cystic carcinoma.
Case presentation
A 49-year-old African American female presented to the emergency room complaining of severe right-sided headache, photophobia, dizziness and nausea, with diplopia. The patient had a 14 year history migraine headaches, hypertension, and mild intermittent asthma. Physical examination revealed right lateral rectus muscle palsy with esotropia. There was numbness in all three divisions of the right trigeminal nerve. Motor and sensory examination of extremities was normal. An MRI of the brain/brain stem was obtained which showed a large mass in the clivus extending to involve the nasopharynx, pterygoid plate, sphenoid and right cavernous sinuses.
Biopsy showed an ACC tumor with a cribriform pattern of the minor salivary glands. The patient underwent total gross surgical resection and radiation therapy.
This is a case of ACC of the minor salivary glands with intracranial invasion. The patient had long history of headaches which changed in character during the past year, and symptoms of acute 5th and 6th cranial nerve involvement. Our unique case demonstrates direct invasion of cavernous sinus and could explain the 5th and 6th cranial nerve involvement as histopathology revealed no perineural invasion.
PMCID: PMC1994955  PMID: 17697321
14.  RASSF1A Promoter Hypermethylation Is a Strong Biomarker of Poor Survival in Patients with Salivary Adenoid Cystic Carcinoma in a Chinese Population 
PLoS ONE  2014;9(10):e110159.
In addition to the clinicopathological parameters, molecular biomarkers are becoming increasingly important in the prognostic evaluation of cancer patients. This study aimed to determine the molecular alterations in the RAS association domain family protein1A gene (RASSF1A) in salivary adenoid cystic carcinoma (ACC) and to evaluate the potential of such alterations as prognostic markers. One hundred and sixty-seven ACC tumor tissues and 50 samples of matched normal salivary gland tissues from the same patients were analyzed for RASSF1A promoter methylation status by bisulfite sequencing PCR (BSP) and/or methylation-specific PCR (MSP). Fifty ACC tumor tissues and matched normal salivary gland tissues were analyzed for loss of heterozygosity (LOH) by examining two microsatellite markers (D3S1478, D3S1621) at 3p21. RASSF1A gene mutations were detected by direct sequencing of all six exons in 50 tumor and normal tissue specimens. Over-all, RASSF1A promoter hypermethylation was detected in 35.3% (59/167) of ACC tissues and was associated with histologically solid tumor pattern (P = 0.002) and advanced TNM stage (P = 0.014). RASSF1A LOH was observed in 18.0% (9/50) of cases, and no somatic mutation of RASSF1A was detected in any cases. RASSF1A promoter methylation was associated with the poor over-all survival (Log-rank test, P <0.001) and disease-free survival (Log-rank test, P <0.001) and identified as an independent predicator of over-all patient survival (P = 0.009) and disease-free survival (P <0.001). It was concluded that RASSF1A methylation is involved in the development, differentiation and progression of ACC and is a strong independent biomarker of poor survival in ACC patients in a Chinese population.
PMCID: PMC4193867  PMID: 25302792
15.  Pim-1 acts as an oncogene in human salivary gland adenoid cystic carcinoma 
Pim-1 (Provirus integration site for Moloney murine leukemia virus 1) belongs to the Ser/Thr kinase family and plays a pivotal role in occurrence and development of oncogenesis. Recent studies have demonstrated that Pim-1 phosphorylates RUNX3 and alters its subcellular localization. However, few studies have concerned the implications of Pim-1 in the salivary gland adenoid cystic carcinoma (ACC). In this study, we aimed to clarify the function of Pim-1 in ACC in vitro. Meanwhile, we measured the levels of Pim-1 and RUNX3 in the ACC tissues. The correlations between Pim-1/RUNX3 levels and clinical parameters were also analyzed.
SACC-83 and SACC-LM cells were transfected with the Pim-1 siRNA. Pim-1 mRNA and protein expression were measured using real-time PCR and immnuoblot, respectively. Cell proliferation was analyzed by CCK-8 assay. Cell cycle, apoptosis, and mitochondrial membrane potential were detected by flow cytometry. Effects of Pim-1 on cells’ invasion were evaluated by transwell migration assay. Pim-1 and RUNX3 levels in ACC tissues were examined by immunohistochemistry.
Pim-1 siRNA reduces cell proliferation, induces apoptosis, causes cell cycle arrest through cell cycle related proteins (Cyclin D1 and CDK4), mitochondrial depolarization, and decreases invasive ability in SACC-83 and SACC-LM cells. Pim-1 and RUNX3 levels are significantly relevant and associated with T-stage and nerve invasion in the ACC tissues.
This study demonstrates the oncogenic role of Pim-1 in ACC. The findings also suggest that Pim-1 may serve as a neoteric therapeutic target and potential prognostic marker for ACC cancer.
PMCID: PMC4304190  PMID: 25551195
Salivary gland adenoid cystic carcinoma; Pim-1; RUNX3
16.  Increased numbers of P63-positive/CD117-positive cells in advanced adenoid cystic carcinoma give a poorer prognosis 
Diagnostic Pathology  2012;7:119.
This study consisted of two parts. One part was to analyze the survival rates of adenoid cystic carcinoma (ACC) in Chinese and explain the difference between our data and the literature. The other was to analyze the relationship between the expression of CD117 and the histological grade and the prognosis.
A retrospective study of 80 ACC patients was performed. Clinical data were collected, and p63, CD117 were detected by immunohistochemical staining.
Eighty patients received follow-ups 3 to 216 months after initial diagnosis. ACC occurred in the lacrimal gland (26.3%, n = 21), nasal cavity and parasinus (33.8%, n = 27) and other sites (40.0%, n = 33). The 5-year and 10-year survival rates were 66.41% and 10.16%, respectively. Over expression of CD117 was detected in p63-negative cells in 94.3% of cases and in p63-positive cells in 45.8%. The expression of CD117 in p63-positive cells was significantly associated with the histological grade (P<0.001) and prognosis (P = 0.037) in patients in the advanced stage.
ACC had a good 5-year survival but poor 10-year survival in Chinese, which differed from the occidental data. More p63+/CD117+ cells were associated with a higher histological grade and poorer outcome.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3487809  PMID: 22963430
Carcinoma; Adenoid cystic; CD117; Myoepithelium; Prognosis
17.  Cytodiagnosis of intracranial metastatic adenoid cystic carcinoma: Spread from a primary tumor in the lacrimal gland 
Adenoid cystic carcinoma (ACC) of the lacrimal gland is a rarely encountered orbital tumor. It invades intracranially more frequently than carcinomas of other glands in the head and neck. A 61-year-old man underwent right orbital exenteration for a tumor in the supraorbital region. He had lost all records and presented to us with a diffuse swelling in the right forehead, six years later. Fine-needle aspiration cytology of the right frontal swelling revealed monomorphic population of small, slightly atypical cells, arranged in multilayered groups with abundant fine intercellular metachromatic substance between cell groups. There were hyaline globules of varying size with attached tumor cells. Cytological diagnosis of metastatic intracranial ACC with a lacrimal gland primary was suggested. Biopsy of the swelling confirmed our cytological diagnosis of ACC with perineural, vascular and lymphatic invasion. Thus, the authors report this case of intracranial metastasis of ACC of the lacrimal gland to remind neurosurgeons planning intervention that this disease shows a tendency to invade intracranially.
PMCID: PMC3214467  PMID: 22090696
Adenoid cystic carcinoma; fine-needle aspiration cytology; intracranial metastasis; lacrimal gland
18.  Expression of beclin 1 in primary salivary adenoid cystic carcinoma and its relation to Bcl-2 and p53 and prognosis 
Beclin 1 plays a critical role in autophagy and functions as a haploinsufficient tumor suppressor. The expression and prognostic significance of beclin 1 in head and neck adenoid cystic carcinoma (ACC) are largely unexplored. Therefore, we investigated the expression of beclin 1, Bcl-2, and p53 in head and neck ACC tissue. Tissue samples from 35 cases (15 females, 20 males) of head and neck ACC were utilized for immunohistochemistry. Beclin 1 expression was observed in 32 cases (91.4%) and considered to be high in 15 cases (42.9%) and low in 20 cases (57.1%). Beclin 1 expression was significantly correlated with a histological growth pattern (P=0.046) and histological grade (P=0.037). Beclin 1 expression was inversely correlated with Bcl-2 expression (P=0.013) and significantly associated with overall survival (P=0.006). Bcl-2 and p53 expression were observed in 21 cases (60.0%) and 16 cases (45.7%). Bcl-2 expression was significantly correlated with perineural invasion (P=0.041) and not associated with overall survival (P=0.053). p53 expression was directly correlated with beclin 1 expression (P=0.044). Our results indicated that beclin 1 may be a novel, promising prognostic factor for clinical outcome in head and neck ACC patients and may play a part in the development of head and neck ACC by interacting with Bcl-2 and p53.
PMCID: PMC3982947  PMID: 24554038
Adenoid cystic carcinoma; Autophagy; Beclin 1; Bcl-2; p53
19.  Ubiquitin-Specific Peptidase 22, a Histone Deubiquitinating Enzyme, Is a Novel Poor Prognostic Factor for Salivary Adenoid Cystic Carcinoma 
PLoS ONE  2014;9(1):e87148.
Salivary Adenoid Cystic Carcinoma (SACC) is characterized by a high rate of local recurrence and infiltration, strong invasion to peripheral nerves or late distant metastasis. Our aim was to investigate the expression of Ubiquitin-specific protease 22 (USP22) in SACC patients and its possible relationship to the outcome of the disease. A total of 135 SACC tissues and adjacent non-cancerous tissues which were diagnosed between 2002 and 2007 were enrolled in this study. Immunohistochemistry was used to compare the expression pattern of USP22 in SACC and adjacent non-cancerous groups, and the prognostic significance was assessed by Kaplan-Meier analysis and Cox proportional hazards regression in SACC patients. The rate of high expression of USP22 was significantly higher in SACC group than that in adjacent non-cancerous group. High expression of USP22 was significantly correlated with histological subtype, lymph node metastasis, grade, Ki-67 and SOX2 expression. Furthermore, USP22 acts as an oncogene by regulation the BMI-1 pathway and c-Myc pathway. SACC patients with high USP22 expression showed the poorer overall survival (OS) and disease-free survival (DFS) than those patients with low USP22 expression. In multivariate analysis, only lymph node metastasis and USP22 expression were the independent prognostic factors for OS and DFS in SACC. Our study provides evidence that USP22 expression is an independent prognostic factor for SACC patients.
PMCID: PMC3900714  PMID: 24466336
20.  Expression of tumor-associated calcium signal transducer 2 in patients with salivary adenoid cystic carcinoma: Correlation with clinicopathological features and prognosis 
Oncology Letters  2014;8(4):1670-1674.
Salivary adenoid cystic carcinoma (SACC) is a common salivary malignancy. The current treatment option for SACC is complete surgical excision with postoperative radiotherapy. The prognosis remains unsatisfactory, due to frequent local recurrence and distant metastases that directly reduce the overall survival time. Previous studies have shown that overexpression of tumor-associated calcium signal transducer 2 (TACSTD2) is associated with poor prognosis in various human epithelial cancers. The expression of TACSTD2 in SACC is currently unknown. The present study therefore aimed to retrospectively investigate TACSTD2 protein expression by immunohistochemistry on paraffin-embedded primary tumor tissue samples from a series of consecutive SACC patients (n=81). The correlation of TACSTD2 expression with clinicopathological variables was evaluated using either the Kruskal-Wallis or Mann-Whitney statistical tests. The survival curves were plotted using the Kaplan-Meier method. The parameters of prognostic significance found by univariate analysis were verified in a multivariate Cox regression model. Overexpression of TACSTD2 was detected in 35/81 (44%) SACC patients and was significantly associated with a decreased overall survival (P<0.01). Univariate analysis showed that TACSTD2 overexpression was correlated with TNM stage (P=0.020), local recurrence (P=0.002) and distant metastasis (P=0.001). Multivariate analyses further revealed that TACSTD2 may be an independent prognostic indicator. In conclusion, TACTSD2 could be recognized as an independent prognostic indicator for SACC. Gene therapy targeting TACSTD2 may be a possible treatment approach for patients with SACC overexpressing this cell-surface marker.
PMCID: PMC4156178  PMID: 25202389
salivary adenoid cystic carcinoma; TACSTD2; prognosis; clinicopathological feature
21.  Integrated, genome-wide screening for hypomethylated oncogenes in salivary gland adenoid cystic carcinoma 
Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy that is poorly understood. In order to look for relevant oncogene candidates under the control of promoter methylation, an integrated, genome-wide screen was performed.
Experimental Design
Global demethylation of normal salivary gland cell strains using 5-aza-2′-deoxycytidine (5-Aza dC) and Trichostatin A (TSA), followed by expression array analysis was performed. ACC-specific expression profiling was generated using expression microarray analysis of primary ACC and normal samples. Next, the two profiles were integrated to identify a subset of genes for further validation of promoter demethylation in ACC versus normal. Finally, promising candidates were further validated for mRNA, protein, and promoter methylation levels in larger ACC cohorts. Functional validation was then performed in cancer cell lines.
We found 159 genes that were significantly re-expressed after 5-Aza dC/TSA treatment and overexpressed in ACC. After initial validation, eight candidates showed hypomethylation in ACC: AQP1, CECR1, C1QR1, CTAG2, P53AIP1, TDRD12, BEX1, and DYNLT3. Aquaporin 1 (AQP1) showed the most significant hypomethylation and was further validated. AQP1 hypomethylation in ACC was confirmed with two independent cohorts. Of note, there was significant overexpression of AQP1 in both mRNA and protein in the paraffin-embedded ACC cohort. Furthermore, AQP1 was up-regulated in 5-Aza dC/TSA treated SACC83. Lastly, AQP1 promoted cell proliferation and colony formation in SACC83.
Our integrated, genome-wide screening method proved to be an effective strategy for detecting novel oncogenes in ACC. AQP1 is a promising oncogene candidate for ACC and is transcriptionally regulated by promoter hypomethylation.
PMCID: PMC3131484  PMID: 21551254
22.  ALDH1 immunohistochemical expression and its significance in salivary adenoid cystic carcinoma 
Head & neck  2012;35(4):575-578.
Adenoid cystic carcinoma (ACC) cells with a high level of ALDH1, a known cancer stem cell (CSC) marker, had higher tumorigenic, invasive, and metastatic abilities. We examined the immunohistochemical expression of ALDH1 in ACC and its correlation with survival.
Archival paraffin blocks of ACC were analyzed. A tissue microarray was constructed and immunohistochemical expression of ALDH1 was analyzed using anti-ALDH1 monoclonal antibody. Correlations between ALDH1 expression and clinical and histological parameters were assessed by chi-square tests. Survival was assessed by the Kaplan–Meier method and log-rank test.
Most of the tumors (63%) showed stromal staining only, 11% of the tumors showed both epithelial and stromal expression, and 26% of the tumors did not show either epithelial or stromal staining. Statistical analyses did not show any correlation between the pattern of ALDH1 expression and tumor histology, tumor size, or perineural invasion. There were no significant differences in survival among the 3 patterns of ALDH1 expression.
Other factors, besides CSCs, may play important roles in tumorigenesis, cell differentiation, and tumor progression in these tumors.
PMCID: PMC4186659  PMID: 22581680
ALDH1 expression; adenoid cystic carcinoma; tissue microarray; predictive marker
23.  A Comparison of the Demographics, Clinical Features, and Survival of Patients with Adenoid Cystic Carcinoma of Major and Minor Salivary Glands Versus Less Common Sites within the SEER Registry 
Cancer  2011;118(16):3945-3953.
The scientific literature to date lacks population-based studies on the demographics, clinical features, and survival of patients with adenoid cystic carcinoma (ACC) of different anatomic sites.
We identified 5349 ACC cases in major salivary glands (N=1850), minor salivary glands (N=2077), breast (N=696), skin (N=291), lung and bronchus (N=203), female genital system (N=132), and eye and orbit (N=100) from the Surveillance, Epidemiology, and End Results (SEER) registry. Differences in demographics, clinical features, and survival of patients were assessed.
ACC of the eye and orbit was associated with younger age at presentation (mean=49.9 years). ACC of the skin or breast tended to present with less aggressive prognostic features, while ACC of the lung and bronchus or eye and orbit tended to present with more aggressive prognostic features. In multivariate survival analysis of patients presenting with localized disease, patients with ACC of breast (HR=0.40) or skin (HR=0.40) had a significantly lower risk death than patients with ACC of major salivary glands, while patients with ACC of lung and bronchus (HR=3.72) or eye and orbit (HR=3.67) had a significantly higher risk. For patients presenting with regional disease, the only clear prognostic difference in multivariate analysis was that patients with ACC of skin did significantly better.
The demographics and clinical features of ACC differ by disease site. Site may be an important predictor of survival for patients presenting with localized disease but is less important for patients presenting with regional disease.
PMCID: PMC3412946  PMID: 22179977
Adenoid Cystic Carcinoma; SEER; Epidemiology; Site; Survival
24.  Prognostic Significance of Nuclear Survivin Expression in Resected Adenoid Cystic Carcinoma of the Head and Neck 
Head & Neck Oncology  2010;2:30.
The expression of survivin, an inhibitor of apoptosis, in tumor cells is associated with poor clinical outcome for various cancers. We conducted this study to determine survivin expression in patients with adenoid cystic carcinoma (ACC) of the head and neck and to identify its clinical significance as a prognostic factor.
Materials and methods
We performed immunohistochemical staining for survivin, p53, bcl-2 protein, and Ki-67 in formalin fixed, paraffin-embedded blocks from 37 cases of head and neck ACC. We also reviewed the patients' clinical records to determine the association of staining with clinical course.
Of the 37 cases of head and neck ACC, 31 (83.8%) were positive for cytoplasmic survivin expression, and 23 (62.2%) were positive for nuclear survivin expression. There was a significant association between nuclear survivin expression and bcl-2 (P = 0.031). A larger tumor was more commonly a survivin-positive tumor (cytoplasmic survivin, P = 0.043; nuclear survivin, P = 0.057). Median overall survival (OS) was significantly longer in patients not expressing nuclear survivin (P = 0.035). A multivariate analysis revealed that nuclear survivin expression significantly impacted OS (hazard ratio 8.567, P = 0.018) in addition to lymph node involvement (hazard ratio 7.704, P = 0.016).
The immunohistochemical expression of nuclear survivin has a prognostic impact in patients with head and neck ACC. These results suggest that nuclear survivin expression may be a useful biomarker for predicting prognosis in patients with head and neck ACC who were treated with surgical resection.
PMCID: PMC2988778  PMID: 21034499
25.  EMMPRIN contributes to the in vitro invasion of human salivary adenoid cystic carcinoma cells 
Oncology Reports  2011;27(4):1123-1127.
Extracellular matrix metalloproteinase inducer (EMMPRIN) is a transmembrane glycoprotein that is involved in tumor invasion by stimulating matrix metalloproteinase (MMP) expression. Our previous immunohistochemical study found that the expression of EMMPRIN in salivary adenoid cystic carcinoma (SACC) was positively correlated with tumor perineural and perivascular invasion. The present study was designed to further investigate the role of EMMPRIN in the invasion of SACC. Western blot results showed that EMMPRIN was upregulated in the highly metastatic SACC cell line SACC-LM, compared to SACC-83, a SACC cell line with low metastatic ability. Blocking of EMMPRIN by its antibody significantly decreased the adhesion, secretion of MMP-2 and MMP-9, and invasion activity of SACC-LM cells in vitro (P<0.01). Co-cultures of SACC-LM cells with fibroblasts significantly produced elevated levels of MMP-2 and MMP-9, and promoted the in vitro invasion activity of SACC-LM cells, compared with cultures of SACC-LM cells alone (P<0.01). These results indicate that EMMPRIN may play an important role in the invasion of SACC by stimulating the expression of MMP-2 and MMP-9 in tumor and stromal cells.
PMCID: PMC3583551  PMID: 22200897
salivary adenoid cystic carcinoma; invasion; extracellular matrix metalloproteinase inducer; matrix metalloproteinases

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