論文 - 詳細
| RRC ID | 73334 |
|---|---|
| 著者 | Liu Z, Hayashi H, Matsumura K, Ogata Y, Sato H, Shiraishi Y, Uemura N, Miyata T, Higashi T, Nakagawa S, Mima K, Imai K, Baba H. |
| タイトル | Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer. |
| ジャーナル | Br J Cancer |
| Abstract |
BACKGROUND:Hyperglycaemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT). METHODS:The biological impact of hyperglycaemia on malignant behaviour in PDAC was examined by in vitro and in vivo experiments. RESULTS:Hyperglycaemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycaemia enhanced chemoresistance by upregulating ABCB1 expression and triggered PDAC switch into pure basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterised by abundant stroma that harbours tumour-promoting properties and chemoresistance. Hyperglycaemia promotes the production of collagen fibre-related proteins (fibronectin, fibroblast activation protein, COL1A1 and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance and a favourable tumour microenvironment even under hyperglycemic conditions in vitro and in vivo. CONCLUSION:Hyperglycaemia induces metabolic reprogramming into glycolytic phenotype and promotes EMT via YAP/TAZ-Hedgehog signalling axis, and YAP/TAZ could be a novel therapeutic target in PDAC. |
| 巻・号 | 128(5) |
| ページ | 844-856 |
| 公開日 | 2023-3-1 |
| DOI | 10.1038/s41416-022-02106-9 |
| PII | 10.1038/s41416-022-02106-9 |
| PMID | 36536047 |
| PMC | PMC9977781 |
| MeSH | Adaptor Proteins, Signal Transducing / metabolism Carcinoma, Pancreatic Ductal* / pathology Epithelial-Mesenchymal Transition Hedgehog Proteins / genetics Humans Hyperglycemia* Pancreatic Neoplasms* / pathology Phenotype Trans-Activators / genetics Transcription Factors / genetics Tumor Microenvironment YAP-Signaling Proteins |
| IF | 5.791 |
| リソース情報 | |
| ヒト・動物細胞 | PK-8(RCB2700) MIA Paca2(RCB2094) PANC-1(RCB2095) PK-59(RCB1901) KLM-1(RCB2138) |