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

Autor: Kotaro Yamashita, Kiyokazu Nakajima, Hiroshi Nakagawa, Takuro Saito, Makoto Yamasaki, Hidetoshi Eguchi, Tomoki Makino, Koji Tanaka, Norihiro Matsuura, Tsuyoshi Takahashi, Yuichiro Doki, Yukinori Kurokawa, Kazuyoshi Yamamoto
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Cancer Research
Esophageal Neoplasms
medicine.medical_treatment
Cell
Vimentin
chemotherapy
epithelial–mesenchymal transition
0302 clinical medicine
Loss of Function Mutation
NOTCH3
Antineoplastic Combined Chemotherapy Protocols
Medicine
esophageal cancer
Receptor
Notch3
Notch signaling
RC254-282
Original Research
Cancer Biology
Aged
80 and over
Mice
Inbred BALB C
biology
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Middle Aged
Esophageal cancer
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Female
Esophageal Squamous Cell Carcinoma
Fluorouracil
Adult
Antimetabolites
Antineoplastic
Epithelial-Mesenchymal Transition
Notch signaling pathway
Down-Regulation
Mice
Nude
03 medical and health sciences
Downregulation and upregulation
Biomarkers
Tumor
Animals
Humans
Radiology
Nuclear Medicine and imaging
Gene Silencing
Epithelial–mesenchymal transition
Aged
Chemotherapy
business.industry
medicine.disease
Esophagectomy
030104 developmental biology
Drug Resistance
Neoplasm
Cancer research
biology.protein
Ectopic expression
business
Zdroj: Cancer Medicine, Vol 10, Iss 12, Pp 3986-3996 (2021)
Cancer Medicine
ISSN: 2045-7634
Popis: 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.
Databáze: OpenAIRE
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