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Not all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy
Clinical cancer research, 2016-06, Vol.22 (12), p.2981-2992
Hayashi, Tetsutaro
Gust, Kilian M
Wyatt, Alexander W
Goriki, Akihiro
Jäger, Wolfgang
Awrey, Shannon
Li, Na
Oo, Htoo Zarni
Altamirano-Dimas, Manuel
Buttyan, Ralph
Fazli, Ladan
Matsubara, Akio
Black, Peter C
2016
Volltextzugriff (PDF)
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Autor(en) / Beteiligte
Hayashi, Tetsutaro
Gust, Kilian M
Wyatt, Alexander W
Goriki, Akihiro
Jäger, Wolfgang
Awrey, Shannon
Li, Na
Oo, Htoo Zarni
Altamirano-Dimas, Manuel
Buttyan, Ralph
Fazli, Ladan
Matsubara, Akio
Black, Peter C
Titel
Not all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy
Ist Teil von
Clinical cancer research, 2016-06, Vol.22 (12), p.2981-2992
Ort / Verlag
United States
Erscheinungsjahr
2016
Quelle
Free E-Journal (出版社公開部分のみ)
Beschreibungen/Notizen
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. We studied genomic aberrations of NOTCH, compared survival and tumor progression according to NOTCH2 expression levels, and studied NOTCH2 function in vitro and vivo We report a high rate of NOTCH2 copy number gain in bladder cancer. High NOTCH2 expression was identified especially in the basal subtype and in mesenchymal tumors. NOTCH2 activation correlated with adverse disease parameters and worse prognosis by immunohistochemistry. Forced overexpression of the intracellular domain of NOTCH2 (N2ICD) induced cell growth and invasion by cell-cycle progression, maintenance of stemness and epithelial-to-mesenchymal transition (EMT). These effects were abrogated by silencing of CSL, indicating that the effects were mediated through the canonical NOTCH signaling pathway. In an orthotopic xenograft model, forced overexpression of N2ICD increased growth, invasion, and metastasis. To explore the potential for therapeutic targeting of NOTCH2, we first silenced the receptor with shRNA and subsequently treated with a specific inhibitory antibody. Both interventions decreased cell growth, invasion, and metastasis in vitro and in the orthotopic xenograft model. We have demonstrated that NOTCH2 acts as an oncogene that promotes bladder cancer growth and metastasis through EMT, cell-cycle progression, and maintenance of stemness. Inhibition of NOTCH2 is a rational novel treatment strategy for invasive bladder cancer. Clin Cancer Res; 22(12); 2981-92. ©2016 AACR.
Sprache
Englisch
Identifikatoren
ISSN: 1078-0432
eISSN: 1557-3265
DOI: 10.1158/1078-0432.CCR-15-2360
Titel-ID: cdi_proquest_miscellaneous_1808694199
Format
–
Schlagworte
Animals
,
Cell Line, Tumor
,
Cell Proliferation - genetics
,
Enzyme Activation - genetics
,
Epithelial-Mesenchymal Transition - genetics
,
Gene Dosage - genetics
,
Humans
,
Lymphatic Metastasis - genetics
,
Mice
,
Neoplasm Invasiveness - genetics
,
Receptor, Notch1 - biosynthesis
,
Receptor, Notch2 - antagonists & inhibitors
,
Receptor, Notch2 - genetics
,
Receptor, Notch2 - metabolism
,
Receptor, Notch3 - biosynthesis
,
RNA Interference
,
RNA, Small Interfering - genetics
,
Signal Transduction - genetics
,
Urinary Bladder Neoplasms - pathology
,
Xenograft Model Antitumor Assays
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