Trefoil factor 1 suppresses stemness and enhances chemosensitivity of pancreatic cancer.
Animals
Pancreatic Neoplasms
/ drug therapy
Trefoil Factor-1
/ metabolism
Humans
Mice
Epithelial-Mesenchymal Transition
/ drug effects
Neoplastic Stem Cells
/ metabolism
Drug Resistance, Neoplasm
Cell Line, Tumor
Tumor Suppressor Proteins
/ metabolism
Xenograft Model Antitumor Assays
Gemcitabine
Mice, Transgenic
Female
Male
Cell Proliferation
/ drug effects
Deoxycytidine
/ analogs & derivatives
Apoptosis
/ drug effects
Gene Expression Regulation, Neoplastic
/ drug effects
cancer stem cell
chemosensitivity
epithelial‐mesenchymal transition
pancreatic cancer
trefoil factor
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
Jun 2024
Jun 2024
Historique:
revised:
30
05
2024
received:
12
11
2023
accepted:
06
06
2024
medline:
14
6
2024
pubmed:
14
6
2024
entrez:
14
6
2024
Statut:
ppublish
Résumé
Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer. To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRAS The deficiency of TFF1 was associated with increased EMT of cancer cells in mouse models of pancreatic cancer, KPC. The expression of TFF1 in cancer cells was associated with better survival rate of the patients who underwent chemotherapy, and loss of TFF1 deteriorated the benefit of gemcitabine in KPC mice. Extracellular administration of TFF1 inhibited gemcitabine-induced EMT, Wnt pathway activation and cancer stemness, eventually increased apoptosis of pancreatic cancer cells in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model and resulted in the better survival of KPC mice by inhibiting EMT and cancer stemness. These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer.
METHODS
METHODS
To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRAS
RESULTS
RESULTS
The deficiency of TFF1 was associated with increased EMT of cancer cells in mouse models of pancreatic cancer, KPC. The expression of TFF1 in cancer cells was associated with better survival rate of the patients who underwent chemotherapy, and loss of TFF1 deteriorated the benefit of gemcitabine in KPC mice. Extracellular administration of TFF1 inhibited gemcitabine-induced EMT, Wnt pathway activation and cancer stemness, eventually increased apoptosis of pancreatic cancer cells in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model and resulted in the better survival of KPC mice by inhibiting EMT and cancer stemness.
CONCLUSION
CONCLUSIONS
These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity.
Substances chimiques
Trefoil Factor-1
0
TFF1 protein, human
0
Tumor Suppressor Proteins
0
Gemcitabine
0
Deoxycytidine
0W860991D6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e7395Subventions
Organisme : Japan Society for the Promotion of Science
ID : JSPS KAKENHI grant number 17K10695
Organisme : Japan Society for the Promotion of Science
ID : JSPS KAKENHI grant number 20H03751
Informations de copyright
© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.
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