NOTCH3 limits the epithelial–mesenchymal transition and predicts a favorable clinical outcome in esophageal cancer

• Published in: Cancer medicine (Malden, MA) Vol. 10; no. 12; pp. 3986 - 3996
• Main Authors: Matsuura, Norihiro, Tanaka, Koji, Yamasaki, Makoto, Yamashita, Kotaro, Saito, Takuro, Makino, Tomoki, Yamamoto, Kazuyoshi, Takahashi, Tsuyoshi, Kurokawa, Yukinori, Nakajima, Kiyokazu, Eguchi, Hidetoshi, Nakagawa, Hiroshi, Doki, Yuichiro
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.06.2021; John Wiley and Sons Inc; Wiley
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Antigens; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Binding sites; Biomarkers, Tumor - genetics; Biomarkers, Tumor - physiology; Cancer Biology; Cancer therapies; Chemoresistance; Chemotherapy; Chromatin; Clinical outcomes; Down-Regulation; Drug Resistance, Neoplasm - genetics; Ectopic expression; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; epithelial–mesenchymal transition; Esophageal cancer; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - genetics; Esophageal Neoplasms - surgery; Esophageal Squamous Cell Carcinoma - drug therapy; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - surgery; Esophagectomy; Esophagus; Female; Fluorouracil - pharmacology; Gene Silencing; Humans; Immunoprecipitation; Laboratories; Loss of Function Mutation; Medical prognosis; Medical research; Mesenchyme; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Monoclonal antibodies; Mutation; Notch protein; Notch signaling; NOTCH3; Notch3 protein; Original Research; Patients; Polyclonal antibodies; Receptor, Notch3 - drug effects; Receptor, Notch3 - genetics; Receptor, Notch3 - metabolism; RNA-mediated interference; Squamous cell carcinoma; Surgery; Survival analysis; Transcription; Tumors; Vimentin; Vimentin - metabolism; NOTCH3; epithelial-mesenchymal transition; esophageal cancer; Notch signaling; chemotherapy
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.3933

Background Esophageal squamous cell carcinoma (ESCC) is the deadliest of all human squamous cell carcinomas and is characterized by chemotherapy resistance and poor prognosis associated with the epithelial–mesenchymal transition (EMT). A subset of ESCC displays loss‐of‐function mutations in genes encoding Notch receptor family members, including NOTCH3. Although Notch signaling regulates EMT in ESCC cells, the role of NOTCH3 in EMT and chemotherapy resistance remains elusive. This study aimed to examine the role of NOTCH3 in EMT and chemotherapy resistance, and determine whether NOTCH3 expression can be used to predict the response to chemotherapy. Methods In vitro and in vivo assays were conducted to clarify the contribution of NOTCH3 to chemotherapy resistance. Using specimens from 120 ESCC patients treated with neoadjuvant chemotherapy, we compared the expression levels of NOTCH3 and genes involved in EMT according to the degree of chemotherapy sensitivity. Results In ESCC cells, chemotherapy resistance was associated with NOTCH3 downregulation and concurrent activation of EMT. RNA interference to silence NOTCH3 resulted in induction of the EMT marker Vimentin (VIM), leading to chemotherapy resistance in ESCC cells. Conversely, ectopic expression of the activated form of NOTCH3 suppressed EMT and sensitized cells to chemotherapy. Results of chromatin immunoprecipitation assays suggested that NOTCH3 may repress transcription of the VIM. Conclusions Our findings suggest that NOTCH3 may control chemotherapy sensitivity by regulating EMT. NOTCH3 may serve as a novel biomarker to predict better clinical outcomes in ESCC patients. Notch3 may control chemotherapy sensitivity by regulating the epithelial‐mesenchymal transition. Notch3 may predict better clinical outcomes in esophageal squamous cell carcinoma patients.