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1.  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
2.  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
3.  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
4.  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
5.  EIF4EBP1 Overexpression Is Associated with Poor Survival and Disease Progression in Patients with Hepatocellular Carcinoma 
PLoS ONE  2015;10(2):e0117493.
EIF4EBP1 acts as a crucial effector in mTOR signaling pathway. Studies have suggested that EIF4EBP1 plays a critical role in carcinogenesis. However, the clinical significance and biological role of EIF4EBP1 in hepatocellular carcinoma (HCC) have not been elucidated. Therefore, we aimed to investigate the clinical significance of EIF4EBP1 in HCC.
Total 128 cases of HCCs were included in this study. EIF4EBP1 expression in HCC tissues was detected by qRT-PCR, Western blot and immunohistochemistry, respectively. Then the relationships between EIF4EBP1 expression and clinical features as well as survival were analyzed.
The expression level of EIF4EBP1 mRNA is significantly higher in 60% (24/40) of fresh HCC tissues than that in the matched adjacent nontumor liver (NCL) tissues (P = 0.044). Similarly, EIF4EBP1 protein is notably upregulated in 8 HCC tissues (randomly selected from the 40 HCCs) measured by Western blot and is significantly increased in another 88 paraffin-embedded HCCs (53%, 47/88) by immunohistochemistry compared with the matched NCLs (P < 0.001). EIF4EBP1 protein expression in HCC tissues is significantly correlated with serum AFP (P = 0.003) and marginally significantly associated with pathological grade (P = 0.085), tumor number (P = 0.084), tumor embolus (P = 0.084) and capsulation (P = 0.073). Patients with higher EIF4EBP1 protein expression have a much worse 5-year overall survival (40.3% vs 73.6%) and 5-year disease-free survival (33.0% vs 49.0%) than those with low expression. Furthermore, Cox regression analysis shows that EIF4EBP1 protein is an independent prognostic factor for overall survival (HR, 2.285; 95% CI, 1.154–4.527; P = 0.018) and disease-free survival (HR, 1.901; 95% CI, 1.067–3.386; P = 0.029) in HCC patients.
Our results demonstrate for the first time that EIF4EBP1 mRNA and protein are markedly up-regulated in HCC tissues, and the protein overexpression is significantly associated with poor survival and progression, which provide a potential new prognostic marker and therapeutic target for HCC patients.
PMCID: PMC4319970  PMID: 25658620
6.  Cadherin-12 contributes to tumorigenicity in colorectal cancer by promoting migration, invasion, adhersion and angiogenesis 
Cadherin 12 (CDH12), which encodes a type II classical cadherin from the cadherin superfamily, may mediate calcium-dependent cell adhesion. It has been demonstrated that CDH12 could play an important role in the invasion and metastasis of salivary adenoid cystic carcinoma. We decided to investigate the relationship between CDH12 expression level and clinicopathologic variables in colorectal carcinoma (CRC) patients and to explore the functions of CDH12 in tumorigenesis in CRC.
The expression levels of CDH12 in colorectal carcinoma tissues were detected by immunohistochemistry. Real-time PCR and Western Blot were used to screen CDH12 high-expression cell lines. CCK-8 assay was used to detect the proliferation ability of CRC cells being transfected by shRNAs against CDH12. The wound assay and transwell assay were performed to test migration and invasion ability. The importance of CDH12 in cell-cell junctions was detected by cell adhesion assay and cell aggregation assay. Endothelial tube formation assay was used to test the influence of CDH12 on angiogenesis.
Statistical analysis of clinical cases revealed that the positive rate of CDH12 was higher in the CRC tumor tissues compared with the adjacent non-tumor tissues. The expression levels of CDH12 in CRC patients are significantly correlated with invasion depth. Consistently, the ability of proliferation, migration and invasion were suppressed when CDH12 was decreased in CRC cells transfected with shRNAs. Cell adhesion assay and cell aggregation assay presented that tumor cells tend to disperse with the lack of CDH12. Endothelial tube formation assay showed that down-regulation of CDH12 could obviously inhibit the process of angiogenesis, implying that CDH12 may play an important role in tumor metastasis
Our results showed that CDH12 promotes proliferation, migration, invasion, adhesion and angiogenesis, suggesting that CDH12 may be an oncogene in colorectal cancer. CDH12 is expected to become a new diagnostic and prognostic marker and a novel target of the treatment of colorectal cancer.
PMCID: PMC3879717  PMID: 24237488
Cadherin12; Colorectal cancer; Cell proliferation; Cell migration; Cell invasion; Cell adhesion; Angiogenesis
7.  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
8.  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
9.  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
10.  WIP1 stimulates migration and invasion of salivary adenoid cystic carcinoma by inducing MMP-9 and VEGF-C 
Oncotarget  2015;6(11):9031-9044.
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, 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.
PMCID: PMC4496200  PMID: 25797250
wild-type p53 induced phosphatase 1 (WIP1); adenoid cystic carcinoma (ACC); salivary gland; invasion; metastasis
11.  Activation of Akt/mTOR Pathway Is Associated with Poor Prognosis of Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(8):e106098.
Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck region, which frequently occurs in Southeast Asia, especially in the south of China. It is known that the mammalian target of rapamycin (mTOR) pathway plays a central role in regulating cellular functions, including proliferation, growth, survival, mobility, and angiogenesis. Aberrant expression of the mTOR signaling pathway molecules has been found in many types of cancer. However, whether the alterations of p-Akt, p-p70S6K and p-4EBP1 protein expression are associated with clinicopathological features and prognostic implications in NPC have not been reported. The purposes of the present study are to investigate the association between the expression of p-Akt, p-p70S6K and p-4EBP1 proteins and clinicopathological features in NPC by immunohistochemistry. The results showed that the positive percentage of p-Akt, p-p70S6K and p-4EBP1 proteins expression in NPC (47.2%, 73.0% and 61.7%, respectively) was significantly higher than that in the non-cancerous nasopharyngeal control tissue (33.3%, 59.1% and 47.0%, respectively). There was a significantly higher positive expression of p-Akt in undifferentiated non-keratinizing nasopharyngeal carcinoma than that in differentiated non-keratinizing nasopharyngeal carcinoma (P = 0.014). Additionally, positive expression of p-p70S6K and p-4EBP1 proteins, and positive expression of either of p-Akt, p-p70S6K and p-4EBP1 were significantly correlated inversely with overall survival rates of NPC patients (P = 0.023, P = 0.033, P = 0.008, respectively). Spearman’s rank correlation test showed that expression of p-Akt in NPC was significantly associated with expression of p-p70S6K (r = 0.263, P<0.001) and p-4EBP1(r = 0.284, P<0.001). Also there was an obviously positive association between expression of p-p70S6K and p-4EBP1 proteins in NPC (r = 0.286, P<0.001). Multivariate Cox regression analysis further identified positive expression of p-4EBP1 and p-p70S6K proteins were the independent poor prognostic factors for NPC (P = 0.043, P = 0.027, respectively). Taken together, high expression of p-p70S6K and p-4EBP1 proteins may act as valuable independent biomarkers to predict a poor prognosis of NPC.
PMCID: PMC4148345  PMID: 25165983
12.  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
13.  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
14.  Tumor suppressor function of ezrin-radixin-moesin-binding phosphoprotein-50 through β-catenin/E-cadherin pathway in human hepatocellular cancer 
AIM: To determine the effect and molecular mechanism of ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) in hepatocellular carcinoma (HCC).
METHODS: Three human HCC cell lines, i.e., SM-MC7721, HepG2 and Hep3B, were used. We transfected the Pbk-CMV-HA-EBP50 plasmid into SMMC7721 cells with Lipofectamine 2000 to overexpress EBP50. Western blotting were performed to determine the effects of the plasmid on EBP50 expression and to detect the expression of β-catenin and E-cadherin before and after the transfection of the plasmid into SMMC7721 cells. In vitro cell proliferation was assessed with a Cell Counting Kit-8 (CCK-8) assay. Cell cycle distribution was assessed with flow cytometry. Invasion and migration ability of before and after the transfection were determined with a transwell assay. Cell apoptosis was demonstrated with Annexin V-FITC. The effect of EBP50 overexpressing on tumor growth in vivo was performed with a xenograft tumor model in nude mice.
RESULTS: The transfection efficiency was confirmed with Western blotting (1.36 ± 0.07 vs 0.81 ± 0.09, P < 0.01). The CCK8 assay demonstrated that the growth of cells overexpressing EBP50 was significantly lower than control cells (P < 0.01). Cell cycle distribution showed there was a G0/G1 cell cycle arrest in cells overexpressing EBP50 (61.3% ± 3.1% vs 54.0% ± 2.4%, P < 0.05). The transwell assay showed that cell invasion and migration were significantly inhibited in cells overexpressing EBP50 compared with control cells (5.8 ± 0.8 vs 21.6 ± 1.3, P < 0.01). Annexin V-FITC revealed that apoptosis was significantly increased in cells overexpressing EBP50 compared with control cells (14.8% ± 2.7% vs 3.4% ± 1.3%, P < 0.05). The expression of β-catenin was downregulated and E-cadherin was upregulated in cells overexpressing EBP50 compared with control cells (0.28 ± 0.07 vs 0.56 ± 0.12, P < 0.05; 0.55 ± 0.08 vs 0.39 ± 0.07, P < 0.05). In vivo tumor growth assay confirmed that up-regulation of EBP50 could obviously slow the growth of HCC derived from SMMC7721 cells (28.9 ± 7.2 vs 70.1 ± 7.2, P < 0.01).
CONCLUSION: The overexpression of EBP50 could inhibit the growth of SMMC7721 cells and promote apoptosis by modulating β-catenin, E-cadherin. EBP50 may serve asa potential therapeutic target in HCC.
PMCID: PMC3587489  PMID: 23483729
Hepatocellular carcinoma; Ezrin-radixin-moesin-binding phosphoprotein-50; Growth; Migration; Invasion
15.  Prognostic significance of peroxiredoxin 1 and ezrin-radixin-moesin-binding phosphoprotein 50 in cholangiocarcinoma 
Human pathology  2012;43(10):1719-1730.
We performed a comparative proteomic analysis of protein expression profiles in four cholangiocarcinoma (CCA) cell lines: K100, M156, M213, and M139. The H69 biliary cell line was used as a control. Peroxiredoxin 1 (PRX1) and ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) were selected for further validation by immunohistochemistry (IHC) using a CCA tissue microarray (n=301) to assess their prognostic value in this cancer. Both PRX1 and EBP50 were overexpressed in CCA tissues compared with normal liver tissues. Of the 301 CCA cases, overexpression of PRX1 in 103 (34.3%) was associated with an age-related effect in young patients (P = 0.011) and the absence of cholangiocarcinoma in lymphatic vessels and perineural tissues (P = 0.004 and P = 0.037, respectively). Expression of EBP50 correlated with histopathologic type, being higher in 180 (59.8%) of moderately or poorly differentiated tumors (P = 0.039) and was associated with the presence of cholangiocarcinoma in lymphatic and vascular vessels (P< 0.001 and P< 0.001, respectively). The high expression of EBP50 and the low expression of PRX1 correlated with reduced survival by univariate analysis (P = 0.017 and P = 0.048, respectively). Moreover, the impact of PRX1 and EBP50 expression on patient survival was an independent predictor in multivariate analyses (P = 0.004 and P = 0.025, respectively). Therefore, altered expression of PRX1 and EBP50 may be used as prognostic markers incholangiocarcinoma.
PMCID: PMC3386378  PMID: 22446018
Cholangiocarcinoma; EBP50; Proteomics; PRX1; Prognostic marker; Tumor marker
16.  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
17.  MYB expression and translocation in adenoid cystic carcinomas and other salivary gland tumors with clinicopathologic correlation 
Adenoid cystic carcinoma is a locally aggressive salivary gland neoplasm which has a poor long term prognosis. A chromosomal translocation involving the genes encoding the transcription factors MYB and NFIB has been recently discovered in these tumors.
MYB translocation and protein expression was studied in 37 adenoid cystic carcinomas, 112 other salivary gland neoplasms, and 409 non salivary gland neoplasms by FISH and immunohistochemistry. MYB translocation and expression status in adenoid cystic carcinoma was correlated with clinicopathologic features including outcome, with a median follow up of 77.1 months (range: 23.2–217.5) for living patients.
A balanced translocation between MYB and NFIB is present in 49% of adenoid cystic carcinomas but is not identified in other salivary gland tumors or non-salivary gland neoplasms. There is no apparent translocation of MYB in 35% of the cases. Strong Myb immunostaining is very specific for adenoid cystic carcinomas but is only present in 65% of all cases. Interestingly, Myb immunostaining is confined to the basal cell component though the translocation is present in all the cells. Neoplasms with MYB translocation demonstrate a trend towards higher local relapse rates, but the results are not statistically significant with current case numbers.
MYB translocation and expression are useful diagnostic markers for a subset of adenoid cystic carcinomas. The presence of the translocation may be indicative of local aggressive behavior but a larger cohort may be required to demonstrate statistical significance.
PMCID: PMC3127258  PMID: 21164292
Adenoid cystic carcinoma; salivary gland tumors; MYB; NFIB; translocation; immunohistochemistry
18.  C/EBP-δ regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1α 
Oncogene  2011;30(49):4901-4909.
CCAAT/enhancer-binding protein delta (C/EBP-δ), a transcription factor, is elevated in carcinoma compared to normal tissue. This study reports a novel function of C/EBP-δ in lymphangiogenesis and tumor metastasis. Genetic deletion of C/EBP-δ in mice resulted in a significant reduction of lymphangiogenesis and pulmonary metastases, with a dramatic reduction of VEGF-C and its cognate receptor VEGFR3 in lymphatic endothelial cells (LECs). In contrast, no difference of VEGF-C in tumor tissues and bone marrow was observed between null and wild type mice. Consistently, forced expression of C/EBP-δ increased VEGF-C and VEGFR3 expression in cultured LECs. These findings suggest a specific and important role of C/EBP-δ in regulating VEGFR3 signaling in LECs. Furthermore, expression of C/EBP-δ in cultured LECs significantly increased cell motility, and knockdown of C/EBP-δ inhibited cell motility and lymphatic vascular network formation in vitro. Forced expression of VEGF-C, but not recombinant VEGF-C, rescued knockdown of C/EBP-δ-induced cell apoptosis, indicative of autonomous VEGF-C autocrine signaling essential for LEC survival. Moreover, hypoxia induces C/EBP-δ expression, and C/EBP-δ regulates HIF-1α expression. Blocking HIF-1α activity totally blocked CEBP-δ induced VEGF-C and VEGFR3 expression in LECs. Together, these findings reveal a new function of CEBP-δ in lymphangiogenesis via regulating VEGFR3 signaling in LECs.
PMCID: PMC3175299  PMID: 21666710
C/EBP-δ; VEGF-C; HIF-1α; lymphangiogenesis; metastasis
19.  Differential expression of topoisomerase IIα protein in salivary gland carcinomas: histogenetic and prognostic implications 
BMC Cancer  2009;9:72.
Salivary gland carcinomas are relatively uncommon heterogeneous malignancies characterized by locoregional invasion and distant metastasis. Topoisomerase IIα (topoIIα), located at chromosome 17q21-22, is considered a major mediator of cell proliferation and DNA replication. The purpose of this study was to evaluate the expression of topoIIα in various types of salivary gland tumors and its biological significance.
The protein expression of topoIIα was evaluated immunohistochemically in formalin-fixed, paraffin-embedded tissue from 54 salivary gland carcinomas and 20 benign tumors (10 pleomorphic adenomas and 10 Warthin's tumors). The primary salivary gland carcinoma specimens consisted of 17 adenoid cystic carcinomas, 7 adenocarcinomas not otherwise specified, 7 mucoepidermoid carcinomas, 6 salivary duct carcinomas, 3 acinic cell carcinomas, 3 carcinomas ex pleomorphic adenomas, 3 epithelial-myoepithelial carcinomas, 2 carcinosarcomas, 2 lymphoepithelial carcinomas, 2 myoepithelial carcinomas, 1 oncocytic carcinoma, and 1 squamous cell carcinoma. The associations between clinicopathological factors and outcome were analyzed.
Of the 54 primary salivary gland carcinomas, 38 (70%) showed positive expression (≥10%) of topoIIα protein, and 16 carcinomas (30%) and all benign tumors were negative (p < 0.001). Expression of topoIIα was more frequently observed in salivary duct carcinoma, carcinoma ex pleomorphic adenoma, adenocarcinoma, and adenoid cystic carcinoma, solid type, and it was associated with advanced stage and shortened survival.
The results of the present study suggest that topoIIα expression is associated with histologically aggressive subtypes and shortened survival. Furthermore, it may provide useful prognostic information and suggests the potential efficacy of topoIIα-targeting therapy in patients with salivary gland carcinoma.
PMCID: PMC2654461  PMID: 19250538
20.  Ebp1 expression in benign and malignant prostate 
ErbB3-binding protein 1 (Ebp1) is a member of the PA2G4 family of proliferation-regulated proteins that is expressed in multiple malignant and non-malignant cells. ErbB3 and other members of the EGFR family have been implicated in cancer progression, it however remains unknown whether Ebp1 participate in prostate cancer progression in vivo. Therefore, the present study examines Ebp1 expression in cancerous and non-cancerous prostates tissues. Ebp1 expression was also correlated to known Ebp1 regulated proteins (Androgen receptor (AR), Cyclin D1 & ErbB3) and the proliferation marker Ki67. Furthermore we evaluated whether Ebp1 expression correlated with biochemical recurrence (BCR) following radical prostatectomy.
The expression of Ebp1, AR, Cyclin D1, ErbB3 and Ki67 were evaluated by immunohistochemistry using three separate tissue micro-arrays containing normal prostate tissues, non-cancerous tissue adjacent to the primary tumor, hormone-sensitive and hormone-refractory cancerous tissues. Multivariate COX regression analysis was performed with four clinical parameters in order to correlate Ebp1 expression with PCa progression.
The expression of Ebp1 significantly increased with the progression from normal to hormone sensitive and to hormone refractory PCa. Furthermore, we observed strong correlation between Ebp1 expression and the nuclear expression of AR, Cyclin D1 and ErbB3 in both normal adjacent and cancer tissues. The expression of AR, Cyclin D1 and ErbB3 in normal adjacent tissues correlated with PSA relapse, whereas Ebp1 on its own did not significantly predict PSA relapse. Finally, in a multivariate analysis with a base clinical model (Gleason, Pre-op PSA, surgical margins and P-stage) we identified the multi-marker combination of Ebp1+/Cyclin D1- as an independent predictor of PSA relapse with a hazard ratio of 4.79.
Although not related to disease recurrence, this is the first in vivo study to report that Ebp1 expression correlates with PCa progression.
PMCID: PMC2614409  PMID: 19025630
21.  Expression of survivin in adenoid cystic carcinoma of the lacrimal gland and the effect of intervention with arsenic trioxide in vitro 
The aim of the present study was to investigate the role of survivin in adenoid cystic carcinoma of the lacrimal gland (LGACC) and the effect of arsenic trioxide (As2O3) intervention in vitro. In total, 13 patients with LGACC were recruited from Renmin Hospital of Wuhan University between 2007 and 2012. The patients were divided into different groups, namely tumor-node-metastasis (TNM)1–2 and TNM3–4, according to the TNM classification. A total of eight samples were included in the TNM1–2 group, while five samples were included in the TNM3–4 group. In addition, six patients that suffered from other diseases (no tumor), but underwent eye surgery, were selected as the controls. The mRNA and protein expression levels of survivin were analyzed. In addition, primary adenoid cystic carcinoma (ACC) cells were cultured and the expression of survivin was silenced using short interfering RNA (siRNA), after which the cell proliferation was determined. Furthermore, the primary cultured ACC cells were treated with different doses of As2O3 to observe the effect on the apoptosis rate. The mRNA and protein expression levels of survivin in the LGACC groups were higher when compared with the controls (P<0.01). In addition, the expression levels were higher in the TNM3–4 group when compared with the TNM1–2 group (P<0.01). After silencing survivin expression using siRNA, the rate of ACC cell proliferation was shown to decrease at days 2, 3, 4 and 5 following culture, particularly in the TNM3–4 group at days 2 and 3 (P<0.05), day 4 (P<0.01 vs. TNM1–2 + siRNA); and days 3 and 5 (P<0.05), and day 2 (P<0.01 vs. TNM3–4 + siRNA). The mRNA expression levels of survivin in the TNM1–2 and TNM3–4 groups were significantly decreased following treatment with the various doses of As2O3 (2, 4 and 6 µΜ) for 48 h, and the apoptosis rate of the ACC cells was markedly increased (TNM1–2 and 3–4: As2O3 6 µM vs. As2O3 2 µM, As2O3 6 µM vs. As2O3 4 Μm, P<0.01; TNF3–4, As2O3 4 µM VS. As2O3 2 µM, P<0.01; TNM1–2, As2O3 4 µM vs. As2O3 2 µM, P<0.05). Therefore, survivin was demonstrated to be highly expressed in ACC cells of the lacrimal gland, and inhibition of survivin gene expression was found to suppress the proliferation of the ACC cells. Furthermore, As2O3 treatment was demonstrated to inhibit the mRNA expression of survivin in the ACC cells, while significantly increasing the apoptosis rate.
PMCID: PMC4487053  PMID: 26170957
lacrimal gland; adenoid cystic carcinoma; survivin; arsenic trioxide
22.  Adenoid cystic carcinoma of palate 
Adenoid cystic carcinoma is a rare tumor arising from the minor salivary glands;, the palate being the commonest site. Distant metastasis and perineural invasion areis common in adenoid cystic carcinoma. Diagnosis of adenoid cystic carcinoma is made usually with the help of clinical features, radiographic features and histologic features. We reported a case of adenoid cystic carcinoma of palate involving left maxillary sinus. The diagnosis of the case and brief review of literature of adenoid cystic carcinoma is discussed. The aim here is to highlight the importance of diagnosis, treatment and long-term follow-up of the patients with adenoid cystic carcinoma.
PMCID: PMC3633292  PMID: 23633876
Adenoid cystic carcinoma; cylindroma; salivary gland tumor
23.  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
24.  Clinical significance of EBP50 overexpression assessed by quantum dot analysis in gastric cancer 
Oncology Letters  2013;5(6):1844-1848.
Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is a postsynaptic density-95/disc-large/zonula occludens-1 (PDZ) homologous domain-containing protein that is involved in cell signaling. EBP50 regulates cell apoptosis, proliferation and invasion. In the present study, the prognostic impact factor of EBP50 expression was evaluated using a quantum dot (QD)-based assay and immunohistochemistry (IHC). The EBP50 protein expression in gastric cancer (GC) tissues was evaluated using IHC and QD-IHC. The study included 101 patients with GC (29 females and 72 males, aged 24–81 years), diagnosed and treated at the General Surgery Department of Renmin Hospital of Wuhan University (Wuhan, China) between 2000 and 2005. The survival rate was calculated using the Kaplan-Meier method and log-rank tests. IHC and QD analyses of 101 GC tissue specimens revealed that EBP50-positive tumor cells were frequently present in GC. Increased EBP50 immunostaining was observed in 63 specimens (62.4%). The EBP50 expression levels were correlated with increased tumor size and the male gender. EBP50 was well distributed in the cytoplasm and nuclei of the GC cells. However, EBP50 protein expression exhibited no correlation with age, differentiation, stage or lymph node metastasis. There were no associations between the expression of EBP50 and the mean survival rates (IHC, 50.5 vs. 58.1 months, P>0.05; QD, 55.4 vs. 63.2 months, P>0.05). These findings suggest that EBP50 protein expression is not correlated with the prognosis of patients with GC. QD-IHC and IHC have similar advantages for the detection of EBP50 protein expression.
PMCID: PMC3701077  PMID: 23833653
ezrin-radixin-moesin-binding phosphoprotein 50; tumor marker; gastric cancer; quantum dot; prognosis; immunochemistry
25.  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

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