| First Author | Yan HH | Year | 2021 |
| Journal | Cancer Lett | Volume | 519 |
| Pages | 185-198 | PubMed ID | 34311032 |
| Mgi Jnum | J:309423 | Mgi Id | MGI:6757936 |
| Doi | 10.1016/j.canlet.2021.07.036 | Citation | Yan HH, et al. (2021) ANGPTL4 accelerates KRAS(G12D)-Induced acinar to ductal metaplasia and pancreatic carcinogenesis. Cancer Lett 519:185-198 |
| abstractText | Oncogenic KRAS(G12D) induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), and drives pancreatic ductal adenocarcinoma (PDAC). Angiopoietin-like 4 (ANGPTL4) is known to be involved in the regulation of cancer growth and metastasis. However, whether ANGPTL4 affects KRAS(G12D)-mediated ADM and early PDAC intervention remains unknown. In the current study, we investigated the role of ANGPTL4 in KRAS(G12D)-induced ADM, PanIN formation, and PDAC maintenance. We found that ANGPTL4 was highly expressed in human and mouse ADM lesions and contributed to the promotion of KRAS(G12D)-driven ADM in mice. Consistently, ANGPTL4 rapidly induced ADM in three-dimensional culture of acinar cells with KRAS mutation and formed ductal cysts that silenced acinar genes and activated ductal genes, which are characteristic of in vivo ADM/PanIN lesions. We also found that periostin works as a downstream regulator of ANGPTL4-mediated ADM/PDAC. Genetic ablation of periostin diminished the ADM/PanIN phenotype induced by ANGPTL4. A high correlation between ANGPTL4 and periostin was confirmed in human samples. These results demonstrate that ANGPTL4 is critical for ADM/PanIN initiation and PDAC progression through the regulation of periostin. Thus, the ANGPTL4/periostin axis is considered a potential target for ADM-derived PDAC. |
