NOTCH pathway inactivation promotes bladder cancer progression.
نویسندگان
چکیده
NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial phenotype through its effector HES1 and, consequently, loss of NOTCH activity favors the process of epithelial-mesenchymal transition. Evaluation of human bladder cancer samples revealed that tumors with low levels of HES1 present mesenchymal features and are more aggressive. Together, our results indicate that NOTCH serves as a tumor suppressor in the bladder and that loss of this pathway promotes mesenchymal and invasive features.
منابع مشابه
Bladder cancer and the Notch pathway
The implication of the Notch pathway in cancer has been known since it was found hyperactivated in acute T-cell lymphoblastic leukemias (TALL) one decade ago. During this time, the link between the Notch pathway and cancer has been extended to many types of malignancies. A unique feature of the pathway is the fact that it can be oncogenic or tumor suppressive depending on the tumor type. For ex...
متن کاملNot all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy.
PURPOSE Recent molecular analyses of bladder cancer open the door to significant advances in targeted therapies. NOTCH has been identified as a tumor suppressor in bladder cancer, but prior reports have focused on NOTCH1 Here we hypothesized that NOTCH2 is an oncogene suitable for therapeutic targeting in bladder cancer. EXPERIMENTAL DESIGN We studied genomic aberrations of NOTCH, compared su...
متن کاملInactivation of p53 and Pten promotes invasive bladder cancer.
Although bladder cancer represents a serious health problem worldwide, relevant mouse models for investigating disease progression or therapeutic targets have been lacking. We show that combined deletion of p53 and Pten in bladder epithelium leads to invasive cancer in a novel mouse model. Inactivation of p53 and PTEN promotes tumorigenesis in human bladder cells and is correlated with poor sur...
متن کاملThe role of Notch signaling in gastric carcinoma: molecular pathogenesis and novel therapeutic targets
Notch signaling, an evolutionarily conserved signaling cascade system, is involved in promoting the progression of different types of cancers. Within the past decades, the Notch signaling pathway has increasingly been shown to have a primary role in deciding the fate of cancer cells and cancer stem cells in the stomach. Most components of Notch signaling are strongly expressed at different leve...
متن کاملNotch-1 Signaling Promotes the Malignant Features of Human Breast Cancer through NF-κB Activation
The aberrant activation of Notch-1 signaling pathway has been proven to be associated with the development and progression of cancers. However, the specific roles and the underlying mechanisms of Notch-1 signaling pathway on the malignant behaviors of breast cancer are poorly understood. In this study, using multiple cellular and molecular approaches, we demonstrated that activation of Notch-1 ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- The Journal of clinical investigation
دوره 125 2 شماره
صفحات -
تاریخ انتشار 2015