Sphk1 promotes salivary adenoid cystic carcinoma progression via PI3K/Akt signaling.

The progression of salivary adenoid cystic carcinoma (SACC) is closely related to abnormal gene expression. Herein, the role of Sphk1 in SACC was explored. Sphk1 was overexpressed in SACC tissues. In SACC cell lines, Sphk1 induced cell proliferation, inhibited apoptosis, and promoted cell migration. Moreover, Sphk1 overexpression induced up-regulation of the PI3K protein level and AKT phosphorylation level. Rescue assays further showed that activation of the Sphk1 /PI3K/Akt pathway affected various biological functions of SACC cells. Together, these findings suggested that Sphk1 promotes salivary tumorigenesis by activating the PI3K/ Akt pathway, which may provide novel intervention targets for SACC treatment.

Matrix metalloproteinase-7, -8, -9, -15, and -25 in minor salivary gland adenoid cystic carcinoma.

Knowledge on the role of matrix metalloproteinases (MMPs) in adenoid cystic carcinoma (ACC) is limited. MMPs are capable of degrading almost all extracellular and pericellular components to promote invasion and metastasis. This study aimed to evaluate the immunohistochemical expression of MMP-7, -8, -9, -15, and -25 in ACC and to relate the results with clinicopathological factors and survival. The study included 68 patients with minor salivary gland ACC treated at the Helsinki University Hospital (Helsinki, Finland) in 1974-2012. Samples from 52 patients were available, consisting of 44 primary tumours and eight recurrent tumours. We scored immunostaining of MMP-7, -8, -9, -15, and -25 and analysed the immunoscore against clinical and pathological parameters using statistical correlation test. MMP-9 immunoexpression in pseudocysts of ACC and in peritumoural inflammatory cells associated with better survival and fewer treatment failures. High tumoural MMP-7 and -25 associated with better survival. High tumoural MMP-15 associated with poorer survival and high tumoural MMP-9 with advanced stage and regional recurrences. Tumour cells did not show MMP-8 immunopositivity. These results suggest that MMP-9 may contribute to ACC carcinogenesis in different roles. MMP-7, -8, and -9 can stimulate signalling pathways that may promote tissue modulation and metastatic potential. MMP-15 and -25 may reflect prognosis.

RhoG/Rac1 signaling pathway involved in migration and invasion of salivary adenoid cystic carcinoma cells.

OBJECTIVES: This study aimed to explore whether RhoG/Rac1 was involved in migration and invasion of salivary adenoid cystic carcinoma (SACC). MATERIALS AND METHODS: RhoG and Rac1 were evaluated in two SACC cell lines, namely SACC-83 and SACC-LM, with low and high rates of lung metastasis, respectively. Functional changes were evaluated using cell proliferation, transwell, and wound-healing assays, and molecular events were investigated using real-time PCR and Western blot assays. RESULTS: RhoG and Rac1 were highly expressed and more activated in SACC-LM cells than in SACC-83 cells. RhoG overexpression promoted SACC-83 cell migration and invasion through activating Rac1. The knockdown of RhoG or Rac1 partially blocked epiregulin-induced migration and invasion in SACC-83 cells. Epiregulin-induced activation of RhoG/Rac1 in SACC-83 cells was blocked by a Src inhibitor, or an AKT inhibitor or AKT siRNA, or an ERK1/2 inhibitor. Moreover, the epiregulin-induced phosphorylation of AKT and ERK1/2 in SACC-83 cells was blocked by a Src inhibitor, and the epiregulin-induced phosphorylation of ERK1/2 was blocked by an AKT inhibitor or AKT siRNA. Overexpression of activated AKT induced activation of ERK1/2 and RhoG. CONCLUSIONS: RhoG/Rac1 signaling pathway was involved in SACC cell migration and invasion. RhoG/Rac1 at least partially mediated epiregulin/Src/AKT/ERK1/2 signaling to promote SACC cell migration and invasion.

Regulation of ß-Catenin Phosphorylation by PR55ß in Adenoid Cystic Carcinoma.

BACKGROUND/AIM: Adenoid cystic carcinoma (AdCC) is a rare cancer of the salivary gland with high risk of recurrence and metastasis. Wnt signalling is critical for determining tumor grade in AdCC, as it regulates invasion and migration. ß-catenin dephosphorylation plays an important role in the Wnt pathway, but its underlying molecular mechanism remains unclear. MATERIALS AND METHODS: Because the regulatory subunits of protein phosphatase 2A (PP2A) drive Wnt signalling via target molecules, including ß-catenin, we used qRT-PCR and immunoblot analysis to investigate the expression of these subunits in an AdCC cell line (ACCS) and a more aggressive subline (ACCS-M). RESULTS: PR55ß was highly expressed in ACCS-M, suggesting its functional importance. In addition, PR55ß expression was associated with tumor grade, with ACCS-M exhibiting higher PR55ß levels. More importantly, knockdown of PR55ß in ACCS-M cells significantly reduced invasiveness and metastatic ability. Furthermore, dephosphorylation and total levels of ß-catenin were dependent on PR55ß in ACCS-M. Finally, we confirmed a correlation between PR55ß staining intensity and histopathological type in human AdCC tissues. CONCLUSION: Our study provides new insight into the interaction between PR55ß and ß-catenin and suggests that PR55ß may be a target for the clinical treatment of AdCC.

AKT3 drives adenoid cystic carcinoma development in salivary glands.

Salivary gland cancer is an aggressive and painful cancer, but a rare tumor type accounting for only ~0.5% of cancer cases. Tumors of the salivary gland exhibit heterogeneous histologic and genetic features and they are subdivided into different subtypes, with adenoid cystic carcinomas (ACC) being one of the most abundant. Treatment of ACC patients is afflicted by high recurrence rates, the high potential of the tumors to metastasize, as well as the poor response of ACC to chemotherapy. A prerequisite for the development of targeted therapies is insightful genetic information for driver core cancer pathways. Here, we developed a transgenic mouse model toward establishment of a preclinical model. There is currently no available mouse model for adenoid cystic carcinomas as a rare disease entity to serve as a test system to block salivary gland tumors with targeted therapy. Based on tumor genomic data of ACC patients, a key role for the activation of the PI3K-AKT-mTOR pathway was suggested in tumors of secretory glands. Therefore, we investigated the role of Akt3 expression in tumorigenesis and report that Akt3 overexpression results in ACC of salivary glands with 100% penetrance, while abrogation of transgenic Akt3 expression could revert the phenotype. In summary, our findings validate a novel mouse model to study ACC and highlight the druggable potential of AKT3 in the treatment of salivary gland patients.

[Expression of midkine and microvessel density in salivary adenoid cystic carcinoma].

OBJECTIVE: This study aimed to investigate the expression of midkine (MK) and microvessel density (MVD) in patients with salivary adenoid cystic carcinoma (SACC) and its clinical significance, as well as detect the correlation between the expression of MK and MVD in SACC. METHODS: Immunohistochemistry analysis (SP method) for MK and MVD were performed on 60 cases of SACC and 26 cases of normal salivary gland tissue. The expression of MK and MVD, as well as the correlation between the expression of MK and MVD in SACC were detected. RESULTS: In SACC, the MK expression rate was 70.0% (42/60), and MK was not expressed in normal tissue. Statistical significance was found between SACC and normal tissue (P<0.05). The MVD values in SACC and normal salivary gland tissues were 38.73 +/- 8.96 and 11.15 +/- 3.33, respectively. These values were statistically significant (P<0.05). The expression levels of MK and MVD were unrelated to age, gender, and type in SACC (P>0.05), but correlated with tumor size, lymph node metastasis, and tumor-node-metastasis in SACC (P<0.05). The expression of MK and MVD was positively correlated with SACC (r=0.560, P<0.05). CONCLUSION: SACC is correlated with the expression of MK protein and the increase in MVD, which may be some of the early diagnostic markers in SACC.

Immunohistochemical expression of caspases 9 and 3 in adenoid cystic carcinoma of salivary glands and association with clinicopathological parameters.

PURPOSE: Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. It is characterized by a high rate of recurrence, perineural invasion and development of distant metastases many years after removal of the primary tumor. Disorders of the induction of apoptosis and its cascade reactions where caspases are involved may be significant in the pathogenesis of this tumor. METHODS: The immunohistochemical expression of caspase 9 and caspase 3 was analyzed by tissue microarray (TMA) in 50 cases of ACC in relation with different clinicopathological parameters (gender, age, localization, histological type and overall survival). RESULTS: Caspase 9 was expressed in the cytoplasm and nuclei of ACC tumor cells with varying degrees of staining intensity (1+, 6%; 2+, 54%, 3+, 40%). Comparison of caspase 9 expression in tumor cells with clinicopathological parameters (gender, age, localization, histological type and overall survival) showed no statistically significant difference except that the expression was more pronounced in females. Caspase 3 was expressed in the cytoplasm of tumor cells with varying degrees of staining intensity (1+, 22%; 2+, 36%; 3+, 42%). No correlation between the expression of caspase 3 and clinicopathological parameters was noticed. CONCLUSIONS: The expression of caspases 9 and 3 in ACC of the salivary glands can contribute in the better characterization of molecules involved in apoptosis of tumor cells.

High frequency of loss of PTEN expression in human solid salivary adenoid cystic carcinoma and its implication for targeted therapy.

Salivary gland tumor (SGT) is one of the least studied cancers due to its rarity and heterogeneous histological types. Here, we reported that loss of PTEN expression was most frequently found in the poorly differentiated, high grade solid adenoid cystic carcinomas. Loss of PTEN expression correlated with activation of mTOR by increased phosphorylated S6 ribosome protein. We further functionally studied the role of PTEN in a pair of human SACC cell lines, SACC-83 and SACC-LM. Reduced PTEN level was correlated with the metastasis potential. When we knocked down PTEN in the SACC-83 cell line, we observed increased proliferation and enhanced migration/invasion in vitro, and increased tumor size in vivo. We further tested the therapeutical effect by applying a PI3K/mTOR inhibitor NVP-BEZ235 to both SACC cell lines. Decreased cell proliferation, increased apoptosis, as well as reduced cell migration/invasion were observed in both cell lines upon the NVP-BEZ235 treatment. Moreover, the NVP-BEZ235 treatment in a SGT xenograft mouse model significantly reduced primary tumor size and lung metastasis. Taken together, our results demonstrated that PTEN is a potent tumor suppressor in human SGTs, and targeting PI3K/mTOR pathway may be effective in the targeted therapy for human SGT patients with loss of PTEN expression.

Kallikrein-related peptidase 10 expression in salivary gland tissues and tumours.

OBJECTIVES: Kallikrein-related peptidase 10 (KLK10) has been implicated in the development of several types of cancer. The purpose of this study was to analyze the expression of KLK10 in 3 types of salivary gland tumour and normal salivary glands. MATERIALS AND METHODS: A standard immunoperoxidase staining technique was used to assess the immunoexpression profile of KLK10 in normal salivary glands and 3 types of salivary gland tumour: pleomorphic adenoma, adenoid cystic carcinoma and mucoepidermoid carcinoma. RESULTS: Pleomorphic adenomas showed significantly lower KLK10 levels than control tissues. Neither of the malignant tumours (adenoid cystic carcinoma and mucoepidermoid carcinoma) showed a significant alteration in the immunoreactive scores of KLK10 in comparison with the normal salivary gland tissues. KLK10 immunoreactive scores were comparable in adenoid cystic carcinoma and mucoepidermoid carcinoma. Pleomorphic adenoma had significantly lower levels of KLK10 than mucoepidermoid carcinoma. CONCLUSIONS: The finding of lower KLK10 levels in pleomorphic adenoma suggests aberrant expression in a tumour that develops primarily from myoepithelial cells. A kallikrein cascade may play a role in the development and/or outcome of some salivary gland tumours.

Immuno-histochemical evaluation of Cathepsin D in malignant salivary gland carcinomas.

OBJECTIVE: Cathepsin D is a lysosomal acid protease secreted in increased levels in several malignancies. However, its role in salivary gland tumors has not been studied extensively. The present study aims to assess the expression of Cathepsin D in malignant salivary gland tumors and to compare its expression in these tumors. STUDY DESIGN: A total of 30 cases of malignant salivary gland carcinomas which included 16 cases of adenoid cystic carcinoma (ACC), 9 cases of mucoepidermoid carcinoma (MEC), and 5 cases of polymorphous low grade adenocarcinoma (PLGA) were evaluated immunohistochemically using anti-Cathepsin D antibody. RESULT: All the cases showed positivity (100%) for Cathepsin D with intense expression noted in ACC and MEC as compared to PLGA. Comparison of these tumors revealed statistical significant difference in expression between ACC and PLGA. CONCLUSION: Intense expression of Cathepsin D in high grade carcinomas may be a marker for invasive potential and aggressive behavior.

[Expression of p38MAPK in salivary adenoid cystic carcinoma and their significance].

OBJECTIVE: To investigate the expression of p38 mitogen-activated protein kinase (p38MAPK) in salivary adenoid cystic carcinoma (SACC) tissues and their clinicopathologic significance. METHODS: The protein and mRNA expressions of p38MAPK were examined by immunohistochemistry and in situ hybridization, respectively, in 52 cases of SACC and in 11 normal salivary gland tissues adjacent to the tumors on a tissue microarray platform. RESULTS: The positive rate of p38MAPK protein expression in the paracancerous normal salivary gland tissues and that in SACC were 36.4% and 96.2%, respectively, showing a significant statistical difference (P < 0.01). The protein expression of p38MAPK was positively correlated with the lymph node metastasis and nerve involvement (P < 0.05). The positive rates of p38MAPK mRNA in the paracancerous tissues and in the SACC tissues were 45.5% and 94.2%, respectively, with a significant statistical difference (P < 0.01). The mRNA expression of p38MAPK was positively correlated with the lymph node metastasis and nerve involvement (P < 0.05). In the SACC, there was a notable positive correlation between the p38MAPK protein and mRNA expressions (r = 0.409, P < 0.01). CONCLUSIONS: The expression of p38MAPK is up-regulated in salivary adenoid cystic carcinoma. p38MARK may be involved in the tumorigenesis, development and metastasis of this cancer.

Curcumin dually inhibits both mammalian target of rapamycin and nuclear factor-κB pathways through a crossed phosphatidylinositol 3-kinase/Akt/IκB kinase complex signaling axis in adenoid cystic carcinoma.

Adenoid cystic carcinoma (ACC) is a highly malignant tumor that is generally unresponsive or only weakly responsive to the currently available antineoplastic agents. Thus, novel therapeutic strategies and agents are urgently needed to treat this aggressive neoplasm. Curcumin, a component of turmeric (Curcuma longa), has been shown to have a diversity of antitumor activities. We show here that curcumin is a potent inhibitor of ACC progression in vitro and in vivo. Curcumin concentration-dependently inhibited the growth of ACC cells via induction of apoptosis. The ability of ACC cells to migrate/invade and induce angiogenesis was also significantly attenuated by curcumin, accompanied by the down-regulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 and -9. Moreover, our data also demonstrated that the inhibitory effects of curcumin on ACC cells were due to its dual inhibition of both mammalian target of rapamycin (mTOR) and nuclear factor-κB (NF-κB) pathways through a crossed phosphatidylinositol 3-kinase/Akt/IκBα kinase signaling axis. Most importantly, curcumin effectively prevented the in vivo growth and angiogenesis of ACC xenografts in nude mice, as revealed by the induction of cell apoptosis and reduction of microvessel density in tumor tissues. In addition, we further assessed the nature activation status of both mTOR and NF-κB pathways in ACC tissues and confirmed the concurrent high activation of these two pathways in ACC for the first time. Taken together, our findings suggest that further clinical investigation is warranted to apply curcumin as a novel chemotherapeutic regimen for ACC because of its dual suppression of both mTOR and NF-κB pathways.

Inhibiting adenoid cystic carcinoma cells growth and metastasis by blocking the expression of ADAM 10 using RNA interference.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

erbB2 gene silencing and its effect on PTEN in SACC-83 salivary adenoid cystic carcinoma cells.

erbB2 gene plays an important role in carcinoma formation. erbB2 overexpression was observed in many types of tumours, including salivary carcinoma. However, a putative erbB2 and PTEN interaction remains largely unknown in salivary adenoid cystic carcinoma cells. The purpose of this study was to silence erbB2 gene and investigate the functional relationship between erbB2 and PTEN in SACC-83 salivary adenoid cystic carcinoma cells. erbB2-specific siRNAs were transfected into SACC-83 cells using cationic liposome. RT-PCR, immunocytochemistry and Western blotting were employed to detect erbB2 and PTEN expression. Compared with the control groups, erbB2 mRNA expression was decreased in the erbB2-siRNA transfection group, and immunocytochemistry and Western blotting indicated a concordant erbB2 protein reduction. The average optical density values for erbB2 proteins in erbB2-siRNA transfected group were significantly lower than that in the control groups (P<0.05). On the other hand, PTEN expression at both mRNA and protein levels were not significantly affected by erbB2 silencing (P>0.05). In conclusion, the data indicate that siRNA could effectively silence erbB2 gene expression in SACC-83 cells, but PTEN expression appeared unaltered following erbB2 silencing. PTEN expression might not be strictly associated with erbB2 amplification in SACC-83 cells. Future studies will more closely examine the molecular and biological relationships of erbB2 and PTEN in salivary adenoid cystic carcinoma.

Activation of c-Jun N-terminal kinase is required for mevastatin-induced apoptosis of salivary adenoid cystic carcinoma cells.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, originally developed for lowering cholesterol. Statins also have pleiotropic effects, independent of cholesterol-lowering effects, including induction of apoptosis in various cell lines. However, the mechanism underlying statin-induced apoptosis is still not fully understood. This study aims to explore the proapoptotic effects and underlying mechanisms of statins on human salivary adenoid cystic carcinoma (SACC). Exposure of SACC cells to mevastatin resulted in cell growth inhibition and apoptosis in a dose-dependent manner, accompanied by the release of cytochrome c and cleavage of caspase-3. A remarkable decrease in phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and increase in phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase were observed. Furthermore, the JNK-specific inhibitor SP600125, but not the p38-specific inhibitor SB203580, abolished mevastatin-induced cell growth inhibition and apoptosis in SACC cells. This was supported by results in which the JNK inhibitor efficiently blocked mevastatin-induced JNK phosphorylation, but not p38 phosphorylation, and further decreased mevastatin-induced phosphorylation of ERK1/2. Taken together, the results suggest that the JNK pathway was required for mevastatin-induced cell growth inhibition and apoptosis in SACC cells. Statins could be potential anticancer agents for SACC chemotherapy.

ALDH high adenoid cystic carcinoma cells display cancer stem cell properties and are responsible for mediating metastasis.

The cancer stem cell (CSC) theory has been proposed to explain the tumor heterogeneity and carcinogenesis process. Recent studies indicate that aldehyde dehydrogenase (ALDH) activity represents a promising CSC marker. Here, we aimed to determine whether human adenoid cystic carcinoma (AdCC) also follows CSC model by exploring the CSC properties of AdCC cells expressing high level of ALDH activity. Utilizing in-vivo series transplantation assays, we found ALDH(high) AdCC cells were capable of self-renewal and of generating tumors that recapitulate the heterogeneity of the parental tumor. Utilizing in-vitro assay, we found only ALDH(high) AdCC cells have tumorsphere-forming ability in anchorage-independent cultures. Finally, we showed ALDH(high) AdCC cells possess highly invasive capability and are responsible for mediating metastasis. These findings suggest the existence of a developmental hierarchy within human AdCC and further elucidation of the unique survival mechanism of AdCC derived CSC population may provide novel therapeutic strategies to treat AdCC.

Activation of PI3K/Akt/IKK-alpha/NF-kappaB signaling pathway is required for the apoptosis-evasion in human salivary adenoid cystic carcinoma: its inhibition by quercetin.

Quercetin, one of the most common natural flavonoids, has been reported to possess significant anti-tumor activities both in vitro and in vivo. The present study was to investigate the effects of quercetin on growth and apoptosis in human salivary adenoid cystic carcinoma (ACC). The result from MTT assay showed that quercetin decreased cell viability of both low metastatic cell line ACC-2 and high metastatic cell line ACC-M in a concentration- and time-dependent manner. Moreover, treatment with quercetin resulted in significantly increased apoptosis in ACC cells. Our data also revealed that the apoptosis induced by quercetin treatment was through a mitochondria-dependent pathway which showed close correlation with the down-regulation of the PI3K/Akt/IKK-alpha/NF-kappaB pathway. Most importantly, quercetin significantly prevented in vivo growth of ACC xenografts in nude mice, accompanied by induction of tumor cell apoptosis, suppression of NF-kappaB nuclear translocation, as well as down-regulation of Akt and IKK-alpha activation. In addition, we explored the clinical significance of the PI3K/Akt/IKK-alpha/NF-kappaB signaling axis in ACC by immunohistochemical analysis of tissue specimens followed by the clustering analyses. We determined that the PI3K/Akt/IKK-alpha/NF-kappaB pathway is ubiquitously activated in ACC and plays an essential role in the evasion of apoptosis. Taken together, the results from our study implicated that quercetin would be a promising chemotherapeutic agent against ACC through its function of down-regulating the PI3K/Akt/IKK-alpha/NF-kappaB signaling pathway.

Human kallikrein 14 (KLK14) expression in salivary gland tumors.

OBJECTIVE: To analyze the expression of human kallikrein 14 (KLK14) in salivary gland tumors. METHODS: A standard immunoperoxidase staining technique was used to assess the expression profile of KLK14 in normal salivary glands and tumors including pleomorphic adenoma (PA; n=17), adenoid cystic carcinoma (ACC; n=13) and mucoepidermoid carcinoma (MEC; n=9). Tumor stage, grade, patient age and gender, and site of occurrence were recorded. These clinical parameters were correlated with KLK14 levels in malignant tumors. The expression profiles for KLK3, 5, 6, 8 and 13 were also retrieved. RESULTS: Normal salivary glands, PA, ACC and MEC showed strong expression of KLK14 in ductal and non-ductal cells. Both PA and ACC showed higher KLK14 levels than normal glands and MEC tissues. There were no statistically significant associations between levels of KLK14 and clinical parameters. CONCLUSIONS: The differences in the levels of KLK14 suggest that KLKs may aid in the differential diagnosis of salivary gland tumors. The coexpression of KLKs suggests their possible involvement in an enzymatic pathway activated in salivary gland. KLK14 may be a promising new biomarker in salivary gland tumors.

Effect of ERK inhibitor on pulmonary metastasis of inoculated human adenoid cystic carcinoma cells in nude mice.

In this study, we detected the expression of phosphylated ERK1/2 in human salivary adenoid cystic carcinoma (SACC) by immunohistochemical method, the effect of various concentrations of PD98059 on the growth of ACC-M cells (a cell line of human adenoid cystic carcinoma of the salivary glands) by MTT assay, and the effect of PD98059 on the lung metastasis of inoculated ACC-M cells in nude mice. The results showed that the phosphylated ERK1/2 was overexpressed in SACC, the ACC-M cell line proliferation was inhibited by PD98059, and the lung metastasis level was reduced by PD98059, indicating that ERK may be a key molecule in targeted therapy of adenoid cystic carcinoma.