title: High frequency of loss of PTEN expression in human solid salivary adenoid cystic carcinoma and its implication for targeted therapy.
abstract: 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.
authors.affiliation: Department of Oral Pathology, College of Stomatology, Dalian Medical University, Dalian, China.
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Stomatology, First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Ru
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Oral Pathology, College of Stomatology, Dalian Medical University, Dalian, China.|Department of Stomatology, First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Oral Pathology, College of Stomatology, Dalian Medical University, Dalian, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Oral Pathology, College of Stomatology, Dalian Medical University, Dalian, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Pixu
authors.initials: P
authors.lastname: Liu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Oral Pathology, 9th People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Stomatology, Shanghai, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Lu
authors.affiliation: Department of Oral Pathology, College of Stomatology, Dalian Medical University, Dalian, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D003528:Carcinoma, Adenoid Cystic / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D038601:Ribosomal Protein S6 / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D038601:Ribosomal Protein S6; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C531198:dactolisib
keywords: PTEN; adenoid cystic carcinoma; salivary gland tumors; targeted therapy