國家衛生研究院 NHRI:Item 3990099045/15031
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    题名: Hematopoietic progenitor kinase 1 inhibits the development and progression of pancreatic intraepithelial neoplasia
    作者: Wang, H;Moniruzzaman, R;Li, L;Ji, B;Liu, Y;Zuo, X;Abbasgholizadeh, R;Zhao, J;Liu, G;Wang, R;Tang, H;Sun, R;Su, X;Tan, TH;Maitra, A;Wang, H
    贡献者: Immunology Research Center
    摘要: Ras plays an essential role in the development of acinar to ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC). However, mutant Kras is an inefficient driver for PDAC development. The switching mechanisms from low Ras activity to high Ras activity that is required for development and progression of pancreatic intraepithelial neoplasia (PanIN) are unclear. In this study, we found that HPK1 was upregulated during pancreatic injury and ADM. HPK1 interacted with the SH3 domain and phosphorylated Ras GTPase activating protein (RasGAP) and upregulated RasGAP activity. Using the transgenic mouse models of HPK1 or M46, a kinase-dead mutant of HPK1, we showed that HPK1 inhibited Ras activity and its downstream signaling and regulated acinar cell plasticity. M46 promoted the development of ADM and PanINs. Expression of M46 in KrasG12D;Bac mice promoted the infiltration of myeloid-derived suppressor cells and macrophages, inhibited the infiltration of T cells, and accelerated the progression of PanINs to invasive and metastatic PDAC, while HPK1 attenuated mutant Kras-driven PanIN progression. Our results showed that HPK1 plays an important role in ADM and the progression of PanINs by regulating Ras signaling. Loss of HPK1 kinase activity promotes an immunosuppressive tumor microenvironment and accelerates the progression of PanINs to PDAC.
    日期: 2023-06
    關聯: Journal of Clinical Investigation. 2023 Jun 15;133(12):Article number e163873.
    Link to: http://dx.doi.org/10.1172/jci163873
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0021-9738&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001022654700005
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85163904168
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