Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Clausen Thomas Mandel, Weiss Ryan J, Tremblay Jacob R, Kellman Benjamin P, Coker Joanna, Dworkin Leo A, Rodriguez Jessica P, Chang Ivy M, Chen Timothy, Padala Vikram, Karlsson Richard, Song Hyemin, Peck Kristina L, Ogawa Satoshi, Sandoval Daniel R, Joshi Hiren J, Wang Gaowei, Ferguson L Paige, Bhalerao Nikita, Moores Allison, Reya Tannishtha, Sander Maike, Caffrey Thomas C, Grem Jean L, Aicher Alexandra, Heeschen Christopher, Le Dzung, Lewis Nathan E, Hollingsworth Michael A, Grandgenett Paul M, Bellis Susan L, Miller Rebecca L, Fuster Mark M, Dawson David W, Engle Dannielle D, Esko Jeffrey D
Аннотация
3-O-sulfation of heparan sulfate (HS) is the key determinant for binding and activation of antithrombin III (AT). This interaction is the basis of heparin treatment to prevent thrombotic events and excess coagulation. Antithrombin-binding HS (HSAT) is expressed in human tissues but is thought to be expressed in the subendothelial space, mast cells, and follicular fluid. Here, we show that HSAT is ubiquitously expressed in the basement membranes of epithelial cells in multiple tissues. In the pancreas, HSAT is expressed by healthy ductal cells, and its expression is increased in premalignant pancreatic intraepithelial neoplasia lesions but not in pancreatic ductal adenocarcinoma (PDAC). Inactivation of HS3ST1, a key enzyme in HSAT synthesis, in PDAC cells eliminated HSAT expression, induced an inflammatory phenotype, suppressed markers of apoptosis, and increased metastasis in an experimental mouse PDAC model. HSAT-positive PDAC cells bind AT, which inhibits the generation of active thrombin by tissue factor and factor VIIa. Furthermore, plasma from patients with PDAC showed accumulation of HSAT, suggesting its potential as a marker of tumor formation. These findings suggest that HSAT exerts a tumor-suppressing function through recruitment of AT and that the decrease in HSAT during progression of pancreatic tumorigenesis increases inflammation and metastatic potential.