Loss of tumor suppressor WWOX accelerates pancreatic cancer development through promotion of TGFβ/BMP2 signaling.

Autor: Husanie H; The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Abu-Remaileh M; The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Maroun K; The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Abu-Tair L; The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Safadi H; The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel., Atlan K; Department of Pathology, Hadassah Medical Center, Jerusalem, Israel., Golan T; Oncology Institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel., Aqeilan RI; The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. ramiaq@mail.huji.ac.il.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Dec 27; Vol. 13 (12), pp. 1074. Date of Electronic Publication: 2022 Dec 27.
DOI: 10.1038/s41419-022-05519-9
Abstrakt: Pancreatic cancer is one of the most lethal cancers, owing to its late diagnosis and resistance to chemotherapy. The tumor suppressor WW domain-containing oxidoreductase (WWOX), one of the most active fragile sites in the human genome (FRA16D), is commonly altered in pancreatic cancer. However, the direct contribution of WWOX loss to pancreatic cancer development and progression remains largely unknown. Here, we report that combined conditional deletion of Wwox and activation of KRasG12D in Ptf1a-CreER-expressing mice results in accelerated formation of precursor lesions and pancreatic carcinoma. At the molecular level, we found that WWOX physically interacts with SMAD3 and BMP2, which are known activators of the TGF-β signaling pathway. In the absence of WWOX, TGFβ/BMPs signaling was enhanced, leading to increased macrophage infiltration and enhanced cancer stemness. Finally, overexpression of WWOX in patient-derived xenografts led to diminished aggressiveness both in vitro and in vivo. Overall, our findings reveal an essential role of WWOX in pancreatic cancer development and progression and underscore its role as a bona fide tumor suppressor.
(© 2022. The Author(s).)
Databáze: MEDLINE
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