单位：[1]Laboratory of Precision Oncology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China[2]Department of Otolaryngology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA[3]Department of Oral Pathology, Dalian Medical University, Dalian, Liaoning, China[4]Department of Radiation Oncology, China Japan Friendship Hospital, Beijing, China[5]Department of Otolaryngology, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China[6]Department of Oral Pathology, 9th People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Stomatology, Shanghai, China[7]Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA[8]Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA[9]Department of Oral Pathology, Dental School, China Medial University, Shenyang, Liaoning, China[10]Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Salivary gland tumor (SGT) is a rare tumor type, which exhibits broad-spectrum phenotypic, biological, and clinical heterogeneity. Currently, the molecular mechanisms that cause SGT pathogenesis remain poorly understood. A lack of animal models that faithfully recapitulate the naturally occurring process of human SGTs has hampered research progress on this field. In this report, we developed an inducible keratin 5-driven conditional knockout mouse model to delete gene(s) of interest in murine salivary gland upon local RU486 delivery. We have deleted two major tumor suppressors, Pten, a negative regulator of the PI3K pathway, and Smad4, the central signaling mediator of TGF beta pathway, in the murine salivary gland. Our results have shown that deletion of either Pten or Smad4 in murine salivary gland resulted in pleomorphic adenomas, the most common tumor in human SGT patients. Deletion of both Pten and Smad4 in murine salivary gland developed several malignancies, with salivary adenoid cystic carcinoma (SACC) being the most frequently seen. Molecular characterization showed that SACC exhibited mTOR activation and TGF beta 1 overexpression. Examination of human SGT clinical samples revealed that loss of Pten and Smad4 is common in human SACC samples, particularly in the most aggressive solid form, and is correlated with survival of SACC patients, highlighting the human relevance of the murine models. In summary, our results offer significant insight into synergistic role of Pten and Smad4 in SGT, providing a rationale for targeting mTOR and/or TGF beta signaling to control SGT formation and progression.
基金：
National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01DE021788]; University of Colorado Academic Enrichment Fund; Cancer League of Colorado; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81272431]; THANC foundation; University of Colorado Skin Disease Research Center Morphology Phenotyping Core [P30 AR057212]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA046934] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [P30AR057212] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Dental & Craniofacial Research (NIDCR) [R01DE021788] Funding Source: NIH RePORTER
第一作者单位：[1]Laboratory of Precision Oncology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China[2]Department of Otolaryngology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
共同第一作者：
通讯作者：
通讯机构：[1]Laboratory of Precision Oncology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China[2]Department of Otolaryngology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA[3]Department of Oral Pathology, Dalian Medical University, Dalian, Liaoning, China[7]Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA[9]Department of Oral Pathology, Dental School, China Medial University, Shenyang, Liaoning, China[10]Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA[*1]University of Colorado Anschutz Medical Campus, 12700 E 19th Ave, Mail Stop 8606, Aurora, CO 80045, USA[*2]China Medical University, Shenyang, China
推荐引用方式(GB/T 7714)：
Yu Cao,Han Liu,Liwei Gao,et al.Cooperation Between Pten and Smad4 in Murine Salivary Gland Tumor Formation and Progression[J].NEOPLASIA.2018,20(8):764-774.doi:10.1016/j.neo.2018.05.009.
APA：
Yu Cao,Han Liu,Liwei Gao,Ling Lu,Li Du...&Shi-Long Lu.(2018).Cooperation Between Pten and Smad4 in Murine Salivary Gland Tumor Formation and Progression.NEOPLASIA,20,(8)
MLA：
Yu Cao,et al."Cooperation Between Pten and Smad4 in Murine Salivary Gland Tumor Formation and Progression".NEOPLASIA 20..8(2018):764-774
