机构：[1]Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.[2]Department of Cell and Developmental Biology,Oregon Health and Science University, Portland, Oregon, USA.[3]Department of Dermatology University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.[4]Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.[5]Department of Pathology,The First Affiliated Hospital of Kunming Medical University, Kunming, China.医技科室病理科昆明医科大学附属第一医院[6]Medical Oncology, Department of Medicine,University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.[7]Department of Dermatopathology, Shanghai Skin Diseases Hospital,Shanghai, China.[8]Biostatistics and Informatics, School of Public Health, and[9]Department of Otolaryngology,University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Squamous cell carcinomas (SCCs) originate in stratified epithelia, with a small subset becoming metastatic. Epithelial stem cells are targets for driver mutations that give rise to SCCs, but it is unknown whether they contribute to oncogenic multipotency and metastasis. We developed a mouse model of SCC by targeting two frequent genetic mutations in human SCCs, oncogene Kras(G12D) activation and Smad4 deletion, to mouse keratin 15-expressing (K15(+)) stem cells. We show that transgenic mice developed multilineage tumors, including metastatic SCCs. Among cancer stem cell-enriched (CSC-enriched) populations, those with increased side population (SP) cells correlated with epithelial-mesenchymal transition (EMT) and lung metastasis. We show that microRNA-9 (miR-9) contributed to SP expansion and metastasis, and miR-9 inhibition reduced the number of SP cells and metastasis. Increased miR-9 was detected in metastatic human primary SCCs and SCC metastases, and miR-9-transduced. human SCC cells exhibited increased invasion. We identified a-catenin as a predominant miR-9 target. Increased miR-9 in human SCC metastases correlated with a-catenin loss but not E-cadherin loss. Our results demonstrate that stem cells with Kras(G12D) activation and Smad4 depletion can produce tumors that are multipotent and susceptible to EMT and metastasis. Additionally, tumor initiation and metastatic properties of CSCs can be uncoupled, with miR-9 regulating the expansion of metastatic CSCs.
基金：
NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA89849, DE15953, DE20649, DE019712, CA149456, CA052607, T32 CA 174648]; Radiological Society of North America Medical Student Research Grant; University of Colorado School of Medicine Research Track; University of Colorado Cancer Center FACS Core [P30 CA046934]
第一作者机构：[1]Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.[2]Department of Cell and Developmental Biology,Oregon Health and Science University, Portland, Oregon, USA.
共同第一作者：
通讯作者：
通讯机构：[*1]12800 E. 19th Ave., Mail Stop 8320, Aurora, Colorado 80045, USA.[*2]12800 E. 19th Ave., Mail Stop 8104, Aurora, Colorado 80045, USA.
推荐引用方式(GB/T 7714)：
White Ruth A.,Neiman Jill M.,Reddi Anand,et al.Epithelial stem cell mutations that promote squamous cell carcinoma metastasis[J].JOURNAL OF CLINICAL INVESTIGATION.2013,123(10):4390-4404.doi:10.1172/JCI65856.
医学