High frequency of loss of PTEN expression in human solid salivary adenoid cystic carcinoma and its implication for targeted therapy
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Han Liu1, Li Du2, Ru Wang3, Chao Wei1,3, Bo Liu1, Lei Zhu1, Pixu Liu4, Qiang Liu4, Jiang Li5, Shi-Long Lu2,4, Jing Xiao1
1Department of Oral Pathology, College of Stomatology, Dalian Medical University, Dalian, China
2Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA
3Department of Stomatology, First Affiliated Hospital, Dalian Medical University, Dalian, China
4Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
5Department of Oral Pathology, 9th People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Stomatology, Shanghai, China
Shi-Long Lu, e-mail: [email protected]
Jing Xiao, e-mail: [email protected]
Keywords: salivary gland tumors, adenoid cystic carcinoma, PTEN, targeted therapy
Received: September 25, 2014 Accepted: February 19, 2015 Published: March 20, 2015
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.
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